缝隙连接蛋白与动脉粥样硬化性脑梗死的相关性研究
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摘要
目前,脑卒中(stroke)是严重危害人类健康的常见病、多发病,具有发病率高、致残率高及死亡率高的特点。其中脑梗死占全部脑卒中的60%-80%,而动脉粥样硬化(atherosclerosis, AS)是引起脑梗死的最主要原因的之一。动脉粥样硬化斑块表面的纤维帽或是内膜损伤导致斑块破裂从而发生严重的并发症如脑梗死等。因此对AS发病机理进行研究并对高危人群采取适当的干预措施,将有助于减少动脉粥样硬化性脑梗死的发生。
近几十年来人们致力于研究动脉粥样硬化的发病机制,已经发现其与炎症、高血脂等多种因素相关,但其具体作用机制仍不甚明确。血管壁由内皮细胞、平滑肌细胞以及基质等组成,这些成分组成一个统一体,但若要具有相应的功能则需相互间进行化学和电信号的交换。在这些信息通讯通路中,一个重要途径就是缝隙连接通讯。缝隙连接(gap junction, GJ)是缝隙连接通讯的结构基础,是由缝隙连接蛋白(Connexin, Cx)组成的细胞膜通道,允许离子、小的分子物质以及第二信使在两个相邻细胞间进行交换。近年来人们发现缝隙连接与AS密切相关,但其作用机制尚不清楚。
另外,最近对缝隙连接蛋白37(Connexin 37, Cx37)基因多态与AS及冠心病(coronary heart disease, CHD)、心肌梗死(myocardial infarction, MI)之间进行了大量相关性研究,发现Cx37 C1019T位点是AS的“单基因标志物”,与冠心病、心肌梗死密切相关。而与冠心病和心肌梗死一样以动脉粥样硬化性为病理基础的脑梗死是否与Cx37基因多态相关?目前国内外尚未见报道。
因此我们通过观察氧化型低密度脂蛋白(oxidized low-density lipoprotein, ox-LDL)、高密度脂蛋白(high-densitylipoprotein, HDL)和缝隙连接抑制剂辛醇(octanol)对人脐静脉内皮细胞缝隙连接蛋白表达的影响,从细胞水平研究缝隙连接与AS的关系,并进一步探讨其中的机制。另外还在基因水平研究了Cx37基因多态和动脉粥样硬化性脑梗死的相关性。
目的：体外培养人脐静脉内皮细胞株HUVE-12,用ox-LDL诱导内皮细胞损伤,建立动脉粥样硬化损伤内皮细胞模型,观察其对内皮细胞缝隙连接蛋白表达、细胞凋亡和线粒体凋亡途径的影响,同时用HDL或octanol和ox-LDL共孵育对内皮细胞Cx表达和细胞凋亡的影响并探讨其机制。
方法：无菌培养HUVE-12,实验分为7组：①对照组：普通DMEM培养基；②-④ox-LDL组：培养基中分别加入终浓度为25μg/ml、50μg/ml和100μg/ml ox-LDL孵育24小时；⑤HDL组：培养基中加入终浓度为100μg/mlHDL孵育24小时；⑥HDL+ox-LDL组：培养基中加入终浓度为100μg/mlHDL和50μg/ml ox-LDL共同孵育24小时；⑦octanol+ox-LDL组：培养基中加入终浓度为1mM octanol和50μg/ml ox-LDL共同孵育24小时。分别用免疫细胞化学方法(Immunocytochemistry, ICC)、western blot方法和实时荧光定量RT-PCR (real-time fluorescent quantitative RT-PCR)检测各组细胞缝隙连接蛋白Cx37、Cx40和Cx43以及Bcl-2、Bax和Caspase-3蛋白和相应mRNA的表达；MTT方法检测细胞增殖,台盼蓝拒染法检测细胞活性和存活率,流式细胞仪检测细胞凋亡。
结果：1、与对照组比较,25μg／ml、50μg／ml和100μg／ml ox-LDL组内皮细胞上缝隙连接蛋白Cx37、Cx40蛋白和mRNA的表达水平下调,Cx43蛋白和mRNA表达水平上调,其差异均具有统计学意义(P<0.05)。同时25μg／ml、50μg／ml和100μg／ml ox-LDL组细胞增殖受到明显抑制,细胞凋亡率显著增加,细胞存活率下降,与对照组比较,其差异均具有统计学意义(P<0.05)。25μg／ml、50μg／ml和100μg／ml ox-LDL组线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平下调,促凋亡基因Bax和凋亡蛋白caspase一3蛋白及mRNA表达水平上调,Bcl-2／Bax比值增大,与对照组比较,其差异均有统计学意义(P<0.05)。
2、与对照组比较,HDL组Cx37、Cx40蛋白和mRNA表达水平均上调,Cx43 mRNA表达水平下调,其差异均具统计学意义(P<0.05)；HDL组明显促进细胞增殖,细胞凋亡率显著下降,细胞存活率增加,与对照组比较,其差异均具有统计学意义(P＜0.05)；线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平下调,促凋亡基因Bax和凋亡蛋白caspase-3蛋白及mRNA表达水平上调,Bcl-2／Bax比值增大,与对照组比较,其差异均有统计学意义(P<0.05)。与50μg／ml ox-LDL组比较,HDL+ox-LDL组Cx37、40蛋白和mRNA表达水平上调,Cx43蛋白和mRNA表达水平下调,其差异均具统计学意义(P<0.05)；与50μg／ml ox-LDL组比较,HDL+ox-LDL组细胞增殖并未受抑制,细胞凋亡率下降,细胞存活率增加,其差异均具有统计学意义(P<0.05)；线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平上调,促凋亡基因Bax蛋白和mRNA表达水平下调,凋亡蛋白caspase-3 mRNA表达水平下调,Bcl-2／Bax比值增大,与50μg／ml ox-LDL组比较,其差异均有统计学意义(P<0.05)。
3、与50μg／ml ox-LDL组比较,octanol+ox-LDL组Cx37、Cx40蛋白和mRNA表达水平上调,Cx43蛋白和mRNA表达水平下调,其差异均具统计学意义(P<0.05); octanol+ox-LDL组细胞增殖抑制率下降,细胞凋亡率下降,细胞存活率增加,与50μg/ml ox-LDL组比较,其差异均具有统计学意义(P<0.05)；线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平上调,促凋亡基因Bax、凋亡蛋白caspase-3蛋白和mRNA表达水平下调,Bcl-2/Bax比值增大,与50μg/ml ox-LDL组比较,其差异均有统计学意义(P＜0.05)。
结论：1、ox-LDL可以影响人脐静脉内皮细胞Cx蛋白及mRNA表达,且呈剂量依赖性,表明ox-LDL可能通过内皮细胞Cx的重构参与AS的发生和发展。ox-LDL能明显抑制人脐静脉内皮细胞增殖并促其凋亡,且这种作用与浓度相关；其作用机理可能与线粒体凋亡途径Bcl-2\Bax\ Caspase-3有关,ox-LDL可能通过线粒体凋亡途径导致细胞凋亡而参与AS的发生和发展过程。
2、HDL能逆转ox-LDL对内皮细胞缝隙连接蛋白和线粒体凋亡途径的影响。HDL和ox-LDL在AS中起相反的作用可能与其通过缝隙连接蛋白对线粒体凋亡途径产生不同的影响有关。
3、缝隙连接抑制剂octanol可逆转ox-LDL对人脐静脉内皮细胞缝隙连接蛋白及mRNA的表达水平的影响,阻断缝隙连接后可以抑制ox-LDL对人脐静脉内皮细胞增殖抑制和促凋亡作用,且这种作用可能与线粒体凋亡途径的Bcl-2\Bax\Caspase-3有关。ox-LDL可能通过缝隙连接介导线粒体凋亡途径导致细胞凋亡,促进AS的形成和发展。
目的探讨Cx37 C1019T和I1297D基因多态性与动脉粥样硬化性脑梗死发病的相关性。
方法通过病例-对照研究设计,采用聚合酶链式反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法检测145例健康对照组人群、245例动脉粥样硬化性脑梗死(atherothrombitic cerebral infarction, ACI)患者Cx37基因C1019T和I1297D位点的单核苷酸多态性。
结果1、湖南汉族人群中存在Cx37 C1019T和I1297D基因多态位点,对照组人群中,Cx37 C1019T三种基因型CC、CT和TT频率分别是63.3%、29.0%和9.7%,C和T等位基因频率分别是77.9%和22.1%；Cx37I1297D三种基因型Ⅱ、ID和DD频率分别是47.7%,42.6%和9.7%,I和D等位基因频率分别是69.0%和31.0%。
2、Cx37 C1019T在ACI组三种基因型CC、CT和TT频率分别是70.6%,25.7%和3.7%,C和T等位基因频率分别是83.5%和16.5%,与对照组比较,两组基因型频率和等位基因频率无显著性差异(χ2=3.765,P=0.152和χ2=3.692,P=0.055)。ACI组Cx37 I1297D三种基因型Ⅱ、ID和DD频率是45.3%,42.9%和11.8%,与对照组比较,两组基因型频率和等位基因频率无显著性差异(χ2=0.526,P=0.769和χ2=0.458,P=0.499)。
结论1、湖南汉族人群中存在Cx37 C1019T和I1297D基因多态位点,且以携带C等位基因和工等位基因为主。
2、Cx37 C1019T和I1297D基因多态性可能与湖南汉族人群动脉粥样硬化性脑梗死无关。
Stroke is of great concern because of its high incidence, mutilation and mortality rate.60%-80% of stroke is cerebral infarction of which atherosclerosis is the major cause. Thus, thorough understanding of atherosclerosis mechanism can hopefully reduce the incidence of cerebral infarction.
During the last decade, tremendous researches have been carried out in elucidating the mechanism of atherosclerosis formation, and in spite of encouraging discoveries of its relation with inflammation and hyperlipidemia and etc, the mechanism still remains unclear.
In addition to the endothelium, blood vessel walls are composed of many constituents such as matrix basement, and smooth muscle cells. All these components form a coherent tissue that requires, for proper function, a constant exchange of information via electrical and chemical signals. A key pathway that allows such communication is gap junction (GJ). GJ channels, composed of six connexins to form a channel in the cell membrane, allow the direct exchange of ions small metabolites, and other secondary messengers molecules between cell in contact. Recently, it was found that gap junction was closely related to athereosclerosis, but the mechanism is unclear.
On the other hand, a great deal of studies have been focused on the relationship between the Single-nucleotide polymorphism of Connexin 37 (Cx37) and athereosclerosis, coronary heart disease(CHD), Myocardial infarction(MI). It is found that Cx37 C1019T is a Single-gene marker of athereosclerosis, and it is related with CHD and MI. Similar to CHD and MI, cerebral infarction has the common pathologic manifestation of athereosclerosis. However, the relationship between the Single-nucleotide polymorphism of Connexin 37 (Cx37) and athereosclerosis cerebral infarction is unclear.
Thus, the influence of oxidized low density lipoprotein (ox-LDL), high-density lipoprotein (HDL) and octanol on the expression of connexin of cultured human umbilical vein endothelial cell were observed and its possible mechanism was studied. Moreover, the relationship between the SNP of Connexin 37 (Cx37) and athereosclerosis cerebral infarction was also studied.
Objiective:Our aim was to observe the influence of oxidized low density lipoprotein(ox-LDL) on the expression of connexin and the apotosis of cultured Human umbilical vein endothelial cell (HUVE-12), as well as to investigate the influence and the mechanism of HDL and octanol on the expression of connexin and apotosis of cultured endothelial cells induced by ox-LDL.
Methods:HUVE-12 cells were divided into seven groups and were exposed to different conditions. The groups included:①control group: normal DMEM culture medium;②-④ox-LDL group:HUVE-12 were incubated with 25μg/ml ox-LDL,50μg/ml ox-LDL and 100μg/ml ox-LDL for 24 hours;⑤HDL group:HUVE-12 was incubated with 100μg/ml HDL for 24 hours;⑥HDL and ox-LDL group:HUVE-12 were coincubated with 100μg/ml HDL and 50μg/ml ox-LDL for 24 hours;⑦octanol and ox-LDL group:HUVE-12 was coincubated with 1mm octanol and 50μg/ml ox-LDL for 24 hours. MTT method was carried out to evaluate the proliferation of HUVE-12 while viability of HUVE-12 was detected by Trypan blue staining, cell apotosis was examined through flow-cytometry. The expressions of Cx37,40,43, Bcl-2, Bax and Caspase-3 mRNA were examined by real time RT-PCR, also the proteins expression was examined by immunocy-tochemistry and western blot.
Result:1. Expressions of proteins and mRNA of Cx37 and Cx 40 were decreasing when HUVE-12 incubated with 25μg/ml,50μg/ml and 100μg/ml ox-LDL for 24h. By contrast, expressions of proteins and mRNA of Cx 43 were significantly elevated comparing with the control group (P<0.05). The results showed that after HUVE-12 were exposed to various concentration of ox-LDL for 24h, cell proliferation was downregulated and its viability decreased significantly in a concentration-dependent manner while cell apotosis was increased (P<0.05). Expressions of proteins and mRNA of Bcl-2 were decreased, while expressions of proteins and mRNA of Bax and caspase-3 were increasing. The specific values for Bcl-2/Bax in groups with different ox-LDL concentrations were significantly elevated (P<0.05).
2. Comparing with the 50μg/ml ox-LDL group, expressions of proteins and mRNA of Cx37 and Cx 40 in HDL group were upregulated, when the mRNA expression of Cx43 was downregulated (P＜0.05). Cell proliferation and viability in HDL group were enhanced significantly while cell apotosis was ameliorated (P＜0.05). Expressions of proteins and mRNA of Bcl-2 were upregulated, while the expressions of proteins and mRNA of bax and caspase-3 were downregulated. The specific values for Bcl-2/Bax was elevated (P<0.05). Expressions of proteins and mRNA of Cx37 and Cx 40 in HDL+ox LDL group were upregulated, when expressions of protein and mRNA of Cx43 were downregulated (P<0.05). Cell proliferation and viability in HDL+ ox-LDL group were enhanced significantly while cell apotosis was decreased (P＜0.05). Expressions of proteins and mRNA of Bcl-2 were upregulated, while expressions of proteins and mRNA of bax were downregulated, and mRNA expression of caspase-3 was upregulated. The specific values for Bcl-2/Bax was elevated (P＜0.05).
3. Comparing with the 50μg/ml ox-LDL group, expressions of proteins and mRNA of Cx37 and Cx 40 in octanol+ox-LDL group were upregulated, when expressions of proteins and mRNA of Cx43 were downregualted (P＜0.05). What's more, Cell proliferation and viability in octanol+ox-LDL group were enhanced significantly while cell apotosis was decreased (P<0.05). Expressions of proteins and mRNA of Bcl-2 were increased, while expressions of proteins and mRNA of bax and caspase-3 were decreased. The specific values for Bcl-2/Bax was elevated significantly (P＜0.05).
Conclusion:
1. ox-LDL could induce the remodeling of connexin in HUVE-12 in virto, and the effect was in a concentration-dependent manner. It was suggested that ox-LDL could lead to AS by the remodeling of connexin. HUVE-12 cell proliferation and viability were significantly downregulated in a concentration-dependent manner by ox-LDL while cell apotosis was enhanced. The effect of ox-LDL on cell apotosis of HUVE-12 could be related to mitochondrial apoptosis pathway which could be a mechanism of AS causing by ox-LDL.
2. HDL could prevent the remodeling of connexin in HUVE-12 and decrease cell apotosis of HUVE-12 induced by ox-LDL. It indicated that HDL could play a role in anti-AS by this pathway.
3. Similarly with the effect of HDL, octanol could prevent the remodeling of connexin and decrease cell apotosis in HUVE-12 induced by ox-LDL. The effect of octanol on cell apotosis caused by ox-LDL could also be related to mitochondrial apoptosis pathway. ox-LDL could affect connexins and gap junction in endothelial cells and it could result in the chain of mitochondrial apoptosis pathway which lead to cell apotosis.
Objective:Our aim was to investigate the relationship between connexin 37 gene polymorphisms and atherothrombotic cerebral infarction.
Methods:A case-control study was carried out in which connexin 37 C1019T and I1297D gene polymorphisms in 245 paitents with atherothrombotic cerebral infarction (ACI group) and 145healthy subjects (control group) were analyzed with polymerase chain reaction (PCR)-restriction fragment length polymorphism(RFLP).
Result:
1. The results showed that there were Cx37 C1019T and I1297D single-nucleotide polymorphism (SNP) in han population of Hunan province. In control group Cx37 C1019T CC, CT and TT genotype frequencies were 63.3%、29.0% and 9.7%, while C and T allele frequencies were 77.9% and 22.1%. Cx37 I1297D II, ID and DD genotype frequencies were 47.7%,42.6% and 9.7%, while I and D allele frequencies were 69.0% and 31.0%.
2. In ACI group Cx37 C1019T CC, CT and TT genotype frequencies were 70.6%,25.7% and 3.7%,, while C and T allele frequencies were 83.5% and 16.5%. But no differences were detected of genotypes and allele frequencies among patients with ACI group and control group (x 2=3.765, P=0.152 and x 2=3.692, P=0.055). Cx37 I1297DⅡ, ID and ID genotype frequencies were 45.3%,42.9% and 11.8%, while I and D allele frequencies were 66.7%and 33.3%. But no differences were detected of those genotypes and allele frequencies among patients with ACI group and control group (x 2=0.526,P=0.769 and x 2=0.458,P=0.499).
Conclusion
1. There were Cx37 C1019T and I1297D single-nucleotide polymorphism (SNP) in han population of Hunan Province. The Cx37 C1019T C allele and Cx37 I1297D I allele were dominant respectively in both groups.
2.Cx37gene C1019T和I1297D polymorphism were not associated with an increased risk of CI in Han population of Hunan Province, China, and might not be considered as an independent predictor of atherothrombotic cerebral infarction.
近几十年来人们致力于研究动脉粥样硬化的发病机制,已经发现其与炎症、高血脂等多种因素相关,但其具体作用机制仍不甚明确。血管壁由内皮细胞、平滑肌细胞以及基质等组成,这些成分组成一个统一体,但若要具有相应的功能则需相互间进行化学和电信号的交换。在这些信息通讯通路中,一个重要途径就是缝隙连接通讯。缝隙连接(gap junction, GJ)是缝隙连接通讯的结构基础,是由缝隙连接蛋白(Connexin, Cx)组成的细胞膜通道,允许离子、小的分子物质以及第二信使在两个相邻细胞间进行交换。近年来人们发现缝隙连接与AS密切相关,但其作用机制尚不清楚。
另外,最近对缝隙连接蛋白37(Connexin 37, Cx37)基因多态与AS及冠心病(coronary heart disease, CHD)、心肌梗死(myocardial infarction, MI)之间进行了大量相关性研究,发现Cx37 C1019T位点是AS的“单基因标志物”,与冠心病、心肌梗死密切相关。而与冠心病和心肌梗死一样以动脉粥样硬化性为病理基础的脑梗死是否与Cx37基因多态相关?目前国内外尚未见报道。
因此我们通过观察氧化型低密度脂蛋白(oxidized low-density lipoprotein, ox-LDL)、高密度脂蛋白(high-densitylipoprotein, HDL)和缝隙连接抑制剂辛醇(octanol)对人脐静脉内皮细胞缝隙连接蛋白表达的影响,从细胞水平研究缝隙连接与AS的关系,并进一步探讨其中的机制。另外还在基因水平研究了Cx37基因多态和动脉粥样硬化性脑梗死的相关性。
目的：体外培养人脐静脉内皮细胞株HUVE-12,用ox-LDL诱导内皮细胞损伤,建立动脉粥样硬化损伤内皮细胞模型,观察其对内皮细胞缝隙连接蛋白表达、细胞凋亡和线粒体凋亡途径的影响,同时用HDL或octanol和ox-LDL共孵育对内皮细胞Cx表达和细胞凋亡的影响并探讨其机制。
方法：无菌培养HUVE-12,实验分为7组：①对照组：普通DMEM培养基；②-④ox-LDL组：培养基中分别加入终浓度为25μg/ml、50μg/ml和100μg/ml ox-LDL孵育24小时；⑤HDL组：培养基中加入终浓度为100μg/mlHDL孵育24小时；⑥HDL+ox-LDL组：培养基中加入终浓度为100μg/mlHDL和50μg/ml ox-LDL共同孵育24小时；⑦octanol+ox-LDL组：培养基中加入终浓度为1mM octanol和50μg/ml ox-LDL共同孵育24小时。分别用免疫细胞化学方法(Immunocytochemistry, ICC)、western blot方法和实时荧光定量RT-PCR (real-time fluorescent quantitative RT-PCR)检测各组细胞缝隙连接蛋白Cx37、Cx40和Cx43以及Bcl-2、Bax和Caspase-3蛋白和相应mRNA的表达；MTT方法检测细胞增殖,台盼蓝拒染法检测细胞活性和存活率,流式细胞仪检测细胞凋亡。
结果：1、与对照组比较,25μg／ml、50μg／ml和100μg／ml ox-LDL组内皮细胞上缝隙连接蛋白Cx37、Cx40蛋白和mRNA的表达水平下调,Cx43蛋白和mRNA表达水平上调,其差异均具有统计学意义(P<0.05)。同时25μg／ml、50μg／ml和100μg／ml ox-LDL组细胞增殖受到明显抑制,细胞凋亡率显著增加,细胞存活率下降,与对照组比较,其差异均具有统计学意义(P<0.05)。25μg／ml、50μg／ml和100μg／ml ox-LDL组线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平下调,促凋亡基因Bax和凋亡蛋白caspase一3蛋白及mRNA表达水平上调,Bcl-2／Bax比值增大,与对照组比较,其差异均有统计学意义(P<0.05)。
2、与对照组比较,HDL组Cx37、Cx40蛋白和mRNA表达水平均上调,Cx43 mRNA表达水平下调,其差异均具统计学意义(P<0.05)；HDL组明显促进细胞增殖,细胞凋亡率显著下降,细胞存活率增加,与对照组比较,其差异均具有统计学意义(P＜0.05)；线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平下调,促凋亡基因Bax和凋亡蛋白caspase-3蛋白及mRNA表达水平上调,Bcl-2／Bax比值增大,与对照组比较,其差异均有统计学意义(P<0.05)。与50μg／ml ox-LDL组比较,HDL+ox-LDL组Cx37、40蛋白和mRNA表达水平上调,Cx43蛋白和mRNA表达水平下调,其差异均具统计学意义(P<0.05)；与50μg／ml ox-LDL组比较,HDL+ox-LDL组细胞增殖并未受抑制,细胞凋亡率下降,细胞存活率增加,其差异均具有统计学意义(P<0.05)；线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平上调,促凋亡基因Bax蛋白和mRNA表达水平下调,凋亡蛋白caspase-3 mRNA表达水平下调,Bcl-2／Bax比值增大,与50μg／ml ox-LDL组比较,其差异均有统计学意义(P<0.05)。
3、与50μg／ml ox-LDL组比较,octanol+ox-LDL组Cx37、Cx40蛋白和mRNA表达水平上调,Cx43蛋白和mRNA表达水平下调,其差异均具统计学意义(P<0.05); octanol+ox-LDL组细胞增殖抑制率下降,细胞凋亡率下降,细胞存活率增加,与50μg/ml ox-LDL组比较,其差异均具有统计学意义(P<0.05)；线粒体凋亡途径的抑凋亡基因Bcl-2蛋白和mRNA表达水平上调,促凋亡基因Bax、凋亡蛋白caspase-3蛋白和mRNA表达水平下调,Bcl-2/Bax比值增大,与50μg/ml ox-LDL组比较,其差异均有统计学意义(P＜0.05)。
结论：1、ox-LDL可以影响人脐静脉内皮细胞Cx蛋白及mRNA表达,且呈剂量依赖性,表明ox-LDL可能通过内皮细胞Cx的重构参与AS的发生和发展。ox-LDL能明显抑制人脐静脉内皮细胞增殖并促其凋亡,且这种作用与浓度相关；其作用机理可能与线粒体凋亡途径Bcl-2\Bax\ Caspase-3有关,ox-LDL可能通过线粒体凋亡途径导致细胞凋亡而参与AS的发生和发展过程。
2、HDL能逆转ox-LDL对内皮细胞缝隙连接蛋白和线粒体凋亡途径的影响。HDL和ox-LDL在AS中起相反的作用可能与其通过缝隙连接蛋白对线粒体凋亡途径产生不同的影响有关。
3、缝隙连接抑制剂octanol可逆转ox-LDL对人脐静脉内皮细胞缝隙连接蛋白及mRNA的表达水平的影响,阻断缝隙连接后可以抑制ox-LDL对人脐静脉内皮细胞增殖抑制和促凋亡作用,且这种作用可能与线粒体凋亡途径的Bcl-2\Bax\Caspase-3有关。ox-LDL可能通过缝隙连接介导线粒体凋亡途径导致细胞凋亡,促进AS的形成和发展。
目的探讨Cx37 C1019T和I1297D基因多态性与动脉粥样硬化性脑梗死发病的相关性。
方法通过病例-对照研究设计,采用聚合酶链式反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法检测145例健康对照组人群、245例动脉粥样硬化性脑梗死(atherothrombitic cerebral infarction, ACI)患者Cx37基因C1019T和I1297D位点的单核苷酸多态性。
结果1、湖南汉族人群中存在Cx37 C1019T和I1297D基因多态位点,对照组人群中,Cx37 C1019T三种基因型CC、CT和TT频率分别是63.3%、29.0%和9.7%,C和T等位基因频率分别是77.9%和22.1%；Cx37I1297D三种基因型Ⅱ、ID和DD频率分别是47.7%,42.6%和9.7%,I和D等位基因频率分别是69.0%和31.0%。
2、Cx37 C1019T在ACI组三种基因型CC、CT和TT频率分别是70.6%,25.7%和3.7%,C和T等位基因频率分别是83.5%和16.5%,与对照组比较,两组基因型频率和等位基因频率无显著性差异(χ2=3.765,P=0.152和χ2=3.692,P=0.055)。ACI组Cx37 I1297D三种基因型Ⅱ、ID和DD频率是45.3%,42.9%和11.8%,与对照组比较,两组基因型频率和等位基因频率无显著性差异(χ2=0.526,P=0.769和χ2=0.458,P=0.499)。
结论1、湖南汉族人群中存在Cx37 C1019T和I1297D基因多态位点,且以携带C等位基因和工等位基因为主。
2、Cx37 C1019T和I1297D基因多态性可能与湖南汉族人群动脉粥样硬化性脑梗死无关。
Stroke is of great concern because of its high incidence, mutilation and mortality rate.60%-80% of stroke is cerebral infarction of which atherosclerosis is the major cause. Thus, thorough understanding of atherosclerosis mechanism can hopefully reduce the incidence of cerebral infarction.
During the last decade, tremendous researches have been carried out in elucidating the mechanism of atherosclerosis formation, and in spite of encouraging discoveries of its relation with inflammation and hyperlipidemia and etc, the mechanism still remains unclear.
In addition to the endothelium, blood vessel walls are composed of many constituents such as matrix basement, and smooth muscle cells. All these components form a coherent tissue that requires, for proper function, a constant exchange of information via electrical and chemical signals. A key pathway that allows such communication is gap junction (GJ). GJ channels, composed of six connexins to form a channel in the cell membrane, allow the direct exchange of ions small metabolites, and other secondary messengers molecules between cell in contact. Recently, it was found that gap junction was closely related to athereosclerosis, but the mechanism is unclear.
On the other hand, a great deal of studies have been focused on the relationship between the Single-nucleotide polymorphism of Connexin 37 (Cx37) and athereosclerosis, coronary heart disease(CHD), Myocardial infarction(MI). It is found that Cx37 C1019T is a Single-gene marker of athereosclerosis, and it is related with CHD and MI. Similar to CHD and MI, cerebral infarction has the common pathologic manifestation of athereosclerosis. However, the relationship between the Single-nucleotide polymorphism of Connexin 37 (Cx37) and athereosclerosis cerebral infarction is unclear.
Thus, the influence of oxidized low density lipoprotein (ox-LDL), high-density lipoprotein (HDL) and octanol on the expression of connexin of cultured human umbilical vein endothelial cell were observed and its possible mechanism was studied. Moreover, the relationship between the SNP of Connexin 37 (Cx37) and athereosclerosis cerebral infarction was also studied.
Objiective:Our aim was to observe the influence of oxidized low density lipoprotein(ox-LDL) on the expression of connexin and the apotosis of cultured Human umbilical vein endothelial cell (HUVE-12), as well as to investigate the influence and the mechanism of HDL and octanol on the expression of connexin and apotosis of cultured endothelial cells induced by ox-LDL.
Methods:HUVE-12 cells were divided into seven groups and were exposed to different conditions. The groups included:①control group: normal DMEM culture medium;②-④ox-LDL group:HUVE-12 were incubated with 25μg/ml ox-LDL,50μg/ml ox-LDL and 100μg/ml ox-LDL for 24 hours;⑤HDL group:HUVE-12 was incubated with 100μg/ml HDL for 24 hours;⑥HDL and ox-LDL group:HUVE-12 were coincubated with 100μg/ml HDL and 50μg/ml ox-LDL for 24 hours;⑦octanol and ox-LDL group:HUVE-12 was coincubated with 1mm octanol and 50μg/ml ox-LDL for 24 hours. MTT method was carried out to evaluate the proliferation of HUVE-12 while viability of HUVE-12 was detected by Trypan blue staining, cell apotosis was examined through flow-cytometry. The expressions of Cx37,40,43, Bcl-2, Bax and Caspase-3 mRNA were examined by real time RT-PCR, also the proteins expression was examined by immunocy-tochemistry and western blot.
Result:1. Expressions of proteins and mRNA of Cx37 and Cx 40 were decreasing when HUVE-12 incubated with 25μg/ml,50μg/ml and 100μg/ml ox-LDL for 24h. By contrast, expressions of proteins and mRNA of Cx 43 were significantly elevated comparing with the control group (P<0.05). The results showed that after HUVE-12 were exposed to various concentration of ox-LDL for 24h, cell proliferation was downregulated and its viability decreased significantly in a concentration-dependent manner while cell apotosis was increased (P<0.05). Expressions of proteins and mRNA of Bcl-2 were decreased, while expressions of proteins and mRNA of Bax and caspase-3 were increasing. The specific values for Bcl-2/Bax in groups with different ox-LDL concentrations were significantly elevated (P<0.05).
2. Comparing with the 50μg/ml ox-LDL group, expressions of proteins and mRNA of Cx37 and Cx 40 in HDL group were upregulated, when the mRNA expression of Cx43 was downregulated (P＜0.05). Cell proliferation and viability in HDL group were enhanced significantly while cell apotosis was ameliorated (P＜0.05). Expressions of proteins and mRNA of Bcl-2 were upregulated, while the expressions of proteins and mRNA of bax and caspase-3 were downregulated. The specific values for Bcl-2/Bax was elevated (P<0.05). Expressions of proteins and mRNA of Cx37 and Cx 40 in HDL+ox LDL group were upregulated, when expressions of protein and mRNA of Cx43 were downregulated (P<0.05). Cell proliferation and viability in HDL+ ox-LDL group were enhanced significantly while cell apotosis was decreased (P＜0.05). Expressions of proteins and mRNA of Bcl-2 were upregulated, while expressions of proteins and mRNA of bax were downregulated, and mRNA expression of caspase-3 was upregulated. The specific values for Bcl-2/Bax was elevated (P＜0.05).
3. Comparing with the 50μg/ml ox-LDL group, expressions of proteins and mRNA of Cx37 and Cx 40 in octanol+ox-LDL group were upregulated, when expressions of proteins and mRNA of Cx43 were downregualted (P＜0.05). What's more, Cell proliferation and viability in octanol+ox-LDL group were enhanced significantly while cell apotosis was decreased (P<0.05). Expressions of proteins and mRNA of Bcl-2 were increased, while expressions of proteins and mRNA of bax and caspase-3 were decreased. The specific values for Bcl-2/Bax was elevated significantly (P＜0.05).
Conclusion:
1. ox-LDL could induce the remodeling of connexin in HUVE-12 in virto, and the effect was in a concentration-dependent manner. It was suggested that ox-LDL could lead to AS by the remodeling of connexin. HUVE-12 cell proliferation and viability were significantly downregulated in a concentration-dependent manner by ox-LDL while cell apotosis was enhanced. The effect of ox-LDL on cell apotosis of HUVE-12 could be related to mitochondrial apoptosis pathway which could be a mechanism of AS causing by ox-LDL.
2. HDL could prevent the remodeling of connexin in HUVE-12 and decrease cell apotosis of HUVE-12 induced by ox-LDL. It indicated that HDL could play a role in anti-AS by this pathway.
3. Similarly with the effect of HDL, octanol could prevent the remodeling of connexin and decrease cell apotosis in HUVE-12 induced by ox-LDL. The effect of octanol on cell apotosis caused by ox-LDL could also be related to mitochondrial apoptosis pathway. ox-LDL could affect connexins and gap junction in endothelial cells and it could result in the chain of mitochondrial apoptosis pathway which lead to cell apotosis.
Objective:Our aim was to investigate the relationship between connexin 37 gene polymorphisms and atherothrombotic cerebral infarction.
Methods:A case-control study was carried out in which connexin 37 C1019T and I1297D gene polymorphisms in 245 paitents with atherothrombotic cerebral infarction (ACI group) and 145healthy subjects (control group) were analyzed with polymerase chain reaction (PCR)-restriction fragment length polymorphism(RFLP).
Result:
1. The results showed that there were Cx37 C1019T and I1297D single-nucleotide polymorphism (SNP) in han population of Hunan province. In control group Cx37 C1019T CC, CT and TT genotype frequencies were 63.3%、29.0% and 9.7%, while C and T allele frequencies were 77.9% and 22.1%. Cx37 I1297D II, ID and DD genotype frequencies were 47.7%,42.6% and 9.7%, while I and D allele frequencies were 69.0% and 31.0%.
2. In ACI group Cx37 C1019T CC, CT and TT genotype frequencies were 70.6%,25.7% and 3.7%,, while C and T allele frequencies were 83.5% and 16.5%. But no differences were detected of genotypes and allele frequencies among patients with ACI group and control group (x 2=3.765, P=0.152 and x 2=3.692, P=0.055). Cx37 I1297DⅡ, ID and ID genotype frequencies were 45.3%,42.9% and 11.8%, while I and D allele frequencies were 66.7%and 33.3%. But no differences were detected of those genotypes and allele frequencies among patients with ACI group and control group (x 2=0.526,P=0.769 and x 2=0.458,P=0.499).
Conclusion
1. There were Cx37 C1019T and I1297D single-nucleotide polymorphism (SNP) in han population of Hunan Province. The Cx37 C1019T C allele and Cx37 I1297D I allele were dominant respectively in both groups.
2.Cx37gene C1019T和I1297D polymorphism were not associated with an increased risk of CI in Han population of Hunan Province, China, and might not be considered as an independent predictor of atherothrombotic cerebral infarction.
引文
[1]中华神经病学分会脑血管病学组.中国脑血管病防治指南.人民卫生出版社.2007.1
[2]Fuster V, Ross R, Topol EJ. Atherosclerosis and coronary artery disease. Philadelphia:Lippincott-Raven 1996
[3]Ross R. The pathogensis of atherosclerosis:an update. N Engl J M.1986, 314:488-500.
[4]Ross R. The pathogensis of atherosclerosis:a perspective for the 1990s. Nature. 1993,362:801-809
[5]Benditt EP. Origins of human atherosclerotic plaques, the role of altered gene expression. Arch Pathol Lad Med.1988,112:997-1001.
[6]Ross R. Growth regulatory mechanisms and formation of the lesions of ahterosclerosis.Ann N Y Acad Sci.1995,748:1-6
[7]Dimmeler S, Haendeler J, Galle J, et al.Oxidized Iow-density lipoprotein induees apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanism clue to the'response to injury' hypothesis.Cireulation 1997:95(7): 1760-3.
[8]Imanishi T, Hano T, Sawamura T, et al.Oxidized low density lipoprotein potentiation of Fas-indueed apoptosis through lectin-like oxidized-low Density lipoprotein receptor-1 in human umbilical vaseularendothelial eells.Circ J 2002:66(11):1060-4.
[9]Eseargueil-Blanel, Meilhae O, Pieraggi MT, et al.Oxidized LDLs induce massive apoptosis of cultured human endothelial cells Through a calcium-dependent pathway.Prevention by aurintricathoxylic acid. Arterioscler Thromb Vasc Biol 1997:17(2):331-9.
[10]Sui GZ,Stoek klauser-Farber K, Weiss J, et al.Introduction of apoptosis by high proinsulin and glucose in cultured human umbilical vein endothelial eells is mediated by reaetive oxygen speeies. Diabetologia 1998:41(3):249-56.
[11]Chibber R, Molinatti PA, Wbng JS, et al.The effete ofAminoguanidine and to lrestat on glueose toxicity in bovine retinal capillary pericytes.Diabetes
1994:43(6):758-63.
[12]Napoli C. Oxidation of LDL, atherogenesis, and apoptosis. Ann N Y Acad Sci 2003;1010:698-709.
[13]Colles SM, Maxson JM, Carlson SG, et al Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med 2001; 11(3-4):131-138.
[14]Napoli C.Oxidation of LDL, atherogenesis and apoptosis1 Ann N Y Acad Sci, 2003,1010:698
[15]Salvayre R, Auge N, Benoist H, et al. Oxidized low-density lipoprotein induced apoptosisl Biochim Biophys Acta,2002,1585 (223):213
[16]顾耘.氧化型低密度脂蛋白影响人脐静脉内皮细胞存活率和两种细胞因子的分泌.中华中医药学刊,2008,26(1)：100-101.
[17]Vinken M, Vanhaecke T, Papeleu P, et al. Conexins and their channels in cell growth and cell death. Cell Signal,2005, (Epub ahead of print).
[18]Loewenstein WR,Ross B,The cell-cell channel in the control of growth.Cell Biol,1992,16(1):59
[19]Polacek D,Lal R,Volin MV,et al.Gap junctional communication between vascular cells.Induction of connexin 13 messenger RNA in macrophage foam cells of atherosclerotic lesion.Am J Pathol,1993,142(2):593.
[20]Blackburn JP, Peters NS et al.Upregulation of connexin 43 gap junction during early stages of human coronary atherosclerosis.Arterioscler Thromb Vasc Biol.1995,15(8):1219.
[21]Chadjichristos C E, Kwak B R. Connexins:New Genes in Atherosclerosis[J]. Ann Med,2007,39(6):402-411
[22]Blackburn J P, Peters N S, YehHI, et al. Upregulation of Connexin43 Gap Junctions during Early Stages of Human Coronary Atherosclerosis. Arterioscler Thromb Vasc Biol,1995,15(8):1219-1228.
[23]Isakson B E, Kronke G, Kadl A, et al. Oxidized Phospholipids Alter Vascular Connexin Expression, PhosphorylatiOn, and Heterocellular Communi-cation. Arterioscler Thromb Vasc Biol,2006,26(10):2216-2122.
[24]Kwak B R, Mulhaupt F, Veillard N, et al. Altered Pattern of Vascular Connexin
Expression in AtherOsclerOtic Plaques. Arterioscler Thromb Vasc Biol, 2002,22(2):225-230
[25]Johnson TL,Nerem RM.Endothelial connexin 37,connexin 40,and connexin 43 respond uniquely to substrate and shear stress. Endothelium.2007, 14(4-5):215-26.
[26]Wong CW,Christen T,Roth I,et al.Connexin37 protects against atherosclerosis by regulating monocyte adhesion.Nat Med.2006,12(8):950-954.
[27]Chanson M,Derouette JP,Roth I,et al.Gap junctional communication in tissue inflammation and repair.Biochim Biophys Acta.2005,1711 (2):197-207.
[28]Wong CW,Burger F,Pelli G,et al.Dual benefit of reduced Cx43 on atherosclerosis in LDL receptor-deficient mice.Cell Commun Adhes.2003,10(4-6):395-400.
[29]Ramachandran S,Xie LH,John SA,et al.A novel role for connexin hemichannel in oxidative stress and smoking-induced cell injury.PLoS ONE.2007,2(1):e712.
[30]Libby P,Ridker PM,Mascri A.Inflammation and atherosclerosis. Circulation 2002,105 1135-1143.
[31]Van R H.VanKM.Analbers L J Gap junctions in human umbilical cord endothelial cells contain multiple connexins 1997,272(1 Pt 1):C117-130
[32]Ko YS,Yeh HI,Rotnery S,et al.Connexin make-up of endothelial gap junctions in the rat pulmonary artery as revealed by immunoconfocal microscopy and triple-label immunogold electron microscopy.Dupont EJ Histochem Cytochem.1999 May:47(5):683-92.
[33]Okruhlicova L,Tribulova N,Misejkova M,et al. Gap Junction Remodelling is Involved in the Susceptibility of Diabetic Rats to Hypokalemia induced Ventricular Fibrillation. Acta Histochem,2002,104 (4):387-391
[34]Blackburn JP, Peters NS, Yeh H-I, et al. Upregulation of connexin43 gap junction early stages of human coronary atherosclerosis. Arterioscler Thromb Vase Biol,1995; 15:12191-228.
[35]Yeh H-1, Lupu F, Dupont E, et al. Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vase Biol 1997; 17:3174-3184.
[36]尹力.高脂血症对大鼠主动脉壁连接蛋白37、40和45mRNA表达及内皮功
能影响的实验研究：[博士学位论文].天津：天津医科大学,2005.
[37]Yeh H-I, Lu C-S, Wu Y-J, et al. Reduced expression of connexin37 and.connexin40 in Endothelial hyperlipidemic mice. Arterioscler Thromb Vasc Biol.2003; 23:1391-1397.
[38]Wong CW.Christen T. Foglia B.Eliminating connexin37 enhances atherosclerosis in apolipoprotein Edeficient mice. Cardiovascular Pathology. 2004.13(3)(1):42.
[39]Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res.1998;83:636-643.
[40]Simon AM, Whorter AR. Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin 37 or connexin 40. J Cell Sci 2003;116:2197-2259.
[41]Cottrell GT, Wu Y, Burt JM. Cx40 and Cx43 expression ratio influences heteromeric/heterotypic gap junction channel properties. Am J Physiol 2002;282:C1469-82.
[42]He DS, Jiang JX, Taffet SM, et al. Formation of heteromeric gap junction channels by connexins 40 and 43 in vascular smooth muscle cells. Proc Natl Acad Sci U S A 1999;96:6495-500.
[43]Blackburn JP, Peters NS, Yeh H-I, et al. Upregulation of connexin43 gap junction early stages of human coronary atherosclerosis. Arterioscler Thromb Vase Biol,1995; 15:1219-1228.
[44]Kwak BR,Veillard N,Pelli G,et al.Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. Circulation,2003,107:1033.
[45]Strehlow K, Wemer N, Berweiler J, etal. Estrogen inereases bone marrow-derived endothelial progenitor cell production and diminishes neoiniinia formation.Circulation.2003,107(24):3059-65.
[46]Llevadot J, Murasa S, KureishiY, et al.HMG-CoA reduetase inhibitor mobilizes bone-marrow derived endothelial progenitor cells.J Clin Invest.2001, 108:399-405.
[47]Dirnrneler S, Aieher A, Vasa M, et al.HMG-CoA-reduetase inhibitors(statins) Increase endothelial progenitor cells via the P13 kinase/AktPathway.J Clin Invest2001,108:391-397.
[48]Li DY,Mehta JL.Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells.Circulation,2000,101 (25):2889-2895.
[49]Hastie LE,Paton WF,Hechtman HB,et al.Metabolites of the phospholipase D pathway regulate 1202-induced filam in redisribution in endothelial cells.J Cell Biochem,1998,68(4):511-524.
[50]Werner N, Nickenig G. Influence of cardiovascur risk factors on endothelial progenitor cells:limitations for therapy?. Arterioscler Thromb Vasc Biol,2006, 26(2):257-266.
[51]Brandes,Ralf P.Roads to Dysfunction:Argininase II Contributes to Oxidized Low-Density Lipoprotein-Induced Attenuation of Endothelial NO Production Circulation Research.2006, october,99(9):918-920.
[52]Dimmeler S, Hermann C, Zeiher AM.Apoptosis of endothelial cells. Contribution To the pathophysiology of atherosclerosis? Eur Cytokine Netw 1998:9(4):697-698.
[53]D immeler S, Haendeler J, Galle J, et al. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP3221ike proteases:A mechanistic clue to the "response to injury"hypo thesis. Circulation, 1997; 95 (7):1760
[54]Colles SM, Maxson JM, Carlson SG, et al. Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med 2001; 11(3-4):131-138.
[55]张庆,曾智,任敏等,高密度脂蛋白对氧化型低密度脂蛋白诱导内皮细胞凋亡的影响.四川大学学报(医学版),2003,34(1)：67-69.
[56]高爱社,沈晓君.葛根素对oxLDL诱导的血管内皮细胞凋亡的防护作用.山东中医杂志2008,5.27(5)：334-335
[57]Eskes R,Desagher S,Antonsson B,et al.Bid induces the oligomerization and insertion of Bax into the outermitoch-ondrial membrane.MolCell Biol,2000, 20(3):929-935.
[58]Cain K,Bratton SB,Langlais C,et al.Apaf-1 oligomerizes into-biologically active approximately 700-kDa and inactive approxim-ately 1.4-MDaapoptosome complexes J Biol Chem,2000,275(9):6067-6070.
[59]Basset O, Boittin FX, Cognard C, et at.BCL-2 overexpression prevents calcium Overload and subsequent apoptosis in dystrophie myotubes.Bioehem J,2006 Jan4.
[60]付永锋,樊廷俊,Bcl-2家族蛋白与细胞凋亡。生物化学与生物物理学报2002；34(4)：389-394.
[61]Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked. Science 1997; 275(5303):1129-1132.
[62]Eskes R, Antonsson B, Osen-Sand A, et al. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol 1998; 143(1):217-224.
[63]Kirkin V, Joos S. Zornig M.The role of Bcl-2 family members in tumorigenesis.Biochim Biophys Acta.2004,393(2):226-230.
[64]Kim MR,Tilly JI.Current concepts in Bcl-2 family member regulation of female germ cell development and survival.Biochim Biophys Biophys Acta.2004, 1644(2-3:205-210.
[65]Xia Z, Lundgren B, Bergstrand A, et al. Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X (L). Biochem Pharmacol 1999; 57(10):1199-208.
[66]申晓或,薛丽霞,屈巧芳等.苯扎贝特对ox-LDL诱导内皮细胞凋亡基因Bcl-2/Bax的影响.山西医科大学学报.2008.39(7)：596-599.
[67]Luetjens CM, Bui NT, Sengpie LB. Delayed mitochondrial dysfunction in excitotoxic neuron death:Cytochrome C release and a secondary increase in superoxide production. J Neurosci,2000;20 (15):5715.
[68]Wilson MR.Close Tw, Trosko JE.Cell population dynamics(apoptosis, mitosis, and cell cell communication)during disruption of homeostasis.Cell Res, 2000,25(4):257-268
[69]Nodin C, Nilsson M, Blomstrand F.Gap junction blockage limits intercellular spreading of astrocytic apoptosis induced by metabolic depression. Neuroehem。 2005,94(4):1111-123
[70]Taizen Nakase。 Shinji Fushiki, Christian C, et al. A. strocytie Gap Junctions, Composed of Connexin 43 Reduce Apoptotie Neuronal Damage in Cerebral Isehemia[J]. Stroke,2003,34(9):1987-1993
[71]Wannamethee SG, Shaper AG, Ebrahim S. HDL-cholesterol, Total Cholester01. and the Risk of Stroke in Middle-aged British Men [J]. Stroke(s0039-2499),2000,31:1882-1888.
[72]Curb JD, Abbott RD, Rodriguez BL.et al. High Density Lipoprotein Cholesterol and the Risk of Stroke in Elderly Men:TheHonolulu Heart Program[J]. Am J Epidemiol(S0002-9262)2004,160:150-157.
[73]Simons LA, McCallum J, Friedlander Y, et al. Risk Factors for lschemic Stroke:Dubbo Study of the Elderly[J]. Stroke(S0039-2499).1998,29: 1341-1346.
[74]Nisson SE. Effect of recombinant ApoA-1 Milano on coronery atheroscborsis in p twith a ACS:A randomized controlled trial. JAMA,2003; 290-2921.
[75]梁玉佳,曾智,黄德嘉等.脂蛋白对人血管内皮细胞间隙连接通讯功能的影响.华西医大学报,2000,31(2)：129-132.
[76]Murugesan G, Sa G, Fox PL. High density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor. Circ Res,1994,74：1149-1156.
[77]张秋华、尹洪超、张俊华等.血浆高密度脂蛋白对内皮祖细胞生长特性的影响.中华病理学杂志2006.35(11)：672-676.
[78]Nofer JR, Fobker M, Hobbel G, et al. Activation of phosphatidylinositol specific phospholipase C by HDL-associated lysosphingolipid.Involvement in mitogenesis but not in cholesterol efflux. Biochemistry,2000,39:15199-15207.
[79]Imanishi T, Hano T, Matsuo Y, et al. Oxidized low density lipoprotein inhibits vascular endothelial growth factor induced endothelial progenitor cell differentiation. Clin Exp Pharmacol Physiol,2003,30:665-670.
[80]Mineo C, Yuhanna IS, Quon MJ, et al. High density lipoprotein induced endothelial nitricoxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem,2003,278:9142-9149.
[81]Kimura T, Sato K, Malchinkhuu E,Tomura H,et al. High Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors. Arterioscler Thromb Vasc Biol,2003,23(7):283-288.
[82]McElveen J, Mackness MI, Colley CM, et al. Distribution of paraoxon hydrolytic activity the serum of patients after myocardial infarction. Clin Chem 1986;32:
[83]Parthasarathy S,Barnett J,Fong L G. High density lipoprotein inhibits the oxidative modification of low density lipoprotein. Biochim Biophys Acta 1990; 1044:275.
[84]Sattler W, Stocker R. Greater selective take up by HepG2 cells of high density lipoprotein cholesterylester hydroperoxides than of unoxidised cholesterylesters. Biochem J 1993;294:771.
[85]M I Mackness, C Abbott, S Arrol,et al. The role of high density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low density lipoprotein oxidation.Biochem J 1993;294:829.
[86]王蕾,国汉邦,张小勇等.HDL抑制人脐静脉内皮细胞NADPH氧化酶4表达和活性氧生成.医学分子生物学杂志,2008,5(1)：16-21.
[87]Navab M.,Imes S.S.,Hama S.Y. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein I synthesis and is abolished by high density lipoprotein. J Clin Invest 1991;88:2039.
[88]Suc I, Escargeuil,Blanc I, Troly M, et al. HDL and apoA prevent cell death of endo thelial cells induced by oxidized LDL.Arterioscler Thromb Vasc Bio l, 1997; 17 (10):2158-2166.
[89]Sugano M, Tsuchida K, Makino N. High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis Biochem Biophys Res Commun,2000; 272 (3):872-6.
[90]Pathasarathy S, Barnett J, Fong L G.High density lipo ro tein inhibits the oxidative modification of low density lipoprotein.Bioch im Biphys Acta,1990; 1044 (2):275.
[91]勾蓝图,傅明德.HDL抗动脉粥样硬化的作用.国外医学.心血管疾病分册,2004,31(3)：150-152
[92]张庆,曾智,任敏等,高密度脂蛋白对氧化型低密度脂蛋白诱导内皮细胞凋亡的影响.四川大学学报(医学版),2003,34(1)：67-69.
[93]Nykanen A,Haley B,Zamore PD.ATP requirements and small interfering RNA structure in the RNA interference pathway.Cell,2001,107(3):309-321.
[94]Cecilia M,Hertig,Stefan B.N-cadherin in adult rat cardiomyocytes in cultureJournal of Cell Science,1996,109:11-20.
[95]Wang H, Hong T. Wang H, et al. Altered expression of connexin43 and itspossible role in endothelin-1-inducedcontraction in rabbit basilar artery. Neurol Res,2009,31(1):67-73.
[96]Hong T, Wang H, Wang Y,et al. Effects of gap junctional blockers on cerebral vasospasm after subarachnoid hemorrhage in rabbits. Neurol Res.2009 Apr;31(3):238-44.
[97]陈伟.Cx43蛋白表达在脑血管痉挛细胞模型中的研究：[硕士学位论文].南昌大学,2007.
[98]Derouette J P, Wong C, Bumier L, at al. Molecular role of Cx37 in avanced atherosclerosis:A micro-array study. Atherosclerosis.2009,27[Epub ahead of print].
[99]Christos E Chadjichristos; Ludwig Scheckenbach; Maya Z Richani Sarieddine et al. Endothelial-Specific Deletion of Cx40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion. Circulation.2009;120:S1042
[100]韩冬,冯加纯,邓方,等,缝隙连接对大鼠脑缺血再灌注后血脑屏障通透性的影响.中华神经科杂志,2007.40(7)：447-451.
[101]Ranwanduzy A,Hansen A,Hansen TW,et al.Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke.Neurosurg, 1997,87(6):916-920.
[102]邓方,饶明俐,冯加纯等,缝隙连接胞间通讯对大鼠局灶性脑梗死体积的
影响,中风与神经疾病杂志.2005.22(5)：394-396.
[103]Kalvelyte A, Imbrasaite A, Bukauskiene A, et al. Connexins and apoptotic transformation[J]. Biochemo 2003,66(4):1661-1672.
[104]Cusato K, Ripps H, Zakevicius J, et al. Gap junctions remain open during cytochromec-induced cell death:relationship of conductance to'bystander'cell killing. Cell Deah Differ,2006,17(2):167-172.
[105]邓方,冯加纯,饶明俐等,抑制缝隙连接胞间通讯对大鼠实验性局灶性脑梗死的保护作用.2008,25(3)：285-288.
[106]Huang RP, Hossain MZ, Huang R, et al. Connexin 43(Cx43)enhances chemotherapy. induced apoptosis in human glioblastoma ceils[J]. Cancer,2001, 92(1):130-138.
[107]Brass LM.Isaacohn JL.Merikanga KR,et al.A study of twins and stroke. 1992,23 (2):221-223.
[108]Bak S,Gaist D.Sindrup SH,et al.Genetic liability in stroke:long-term follow-up study of Danish twins.Stoke,2002.3(3):769-774.
[109]Hassan A,Markush S.Genetics and ischemic stroke,Brain,2000,123:1784-1812.
[110]Kiely DK,Wolf PA,Cupples LA.et al.Familial aggregation of stroke.The Franmingha Study.Stroke.1993,24(9):1366-1371.
[111]Thoranvldsen P.Aplund K,Kuulasmaa K,et al.Stroke incidence.case fatality, and mortality in the WHO MONICA project.World Health Organization Monitoring Trends and Determinants in cardiovascular disease.Stroke.1995, 26(3):361-367.
[112]Rastenyte D,Tuomilehto J,Sarti C.Genetics of stroke-review.J of Neurol Sci. 1998,153:132-145.
[113]Van Camp G, Coucke P, Speleman F, et al. The gene for human gap junction protein connexins 37 (GJA4) maps to chromosome 1p35.1,in the vicinity of D1S195. Genomics,1995,30(2):402-403.
[114]Van Camp G,Coucke P,Speleman F,et al. The gene for human gap junction protein connexin37(GJA4)maps to chromosome 1p35.1, in the vicinity of D1S195. Genomics,1995,30:402-403.
[115]Reed KE, Westphale EM, Larson DM, ct al. Molecular cloning and functional expression of human eonnexin37, an endothdial cell gap junction protein. J Clin Invest,1993,91:997-1004.
[116]Cindy W Wong, Thomas Christen, Isabelle Roth, et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. NATURE MEDICINE,2006,12(8):950-954.
[117]Kwak BR,Mulhaupt F,Veillard N,et al.Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vase Biol,2002, 22(2):225-230.
[118]Wong cw,Christen T,Kwak BR. Connexins in leucocytes:shuttling messages?Cardiovasc Res,2004,62:357-367.
[119]Richard G, Lin JP, Smith L,et al. Linkage studies in erythrokeratodermias:fine mapping, genetic heterogeneity,and analysis of candidate genes. J Invest Dermatol 1997; 109:666-71.
[120]Boerma M, Forsberg L, Van Zeal L, et al A genetic polymotphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med.1999.246:211-218.
[121]Yeh HI, Chou Y, Liu HF,et al. Connexin37 gene polymerphism and coronary artery disease in Taiwan [J]. Int J Cardiol,2001,81 (23):251-255.
[122]Wong CW, Christen T, Pfenniger A,et al. Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction [J] Atherosclerosis,2007,191 (2):355-361.
[123]Yamada Y, Izawa H, Ichihara S,,et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes [J]. N Engl J Med,2002, 347 (24):916-923.
[124]杨期东,陆雪芬,谢小玲等.长沙市居民脑血管病危险因素的干预试验.中华医学杂志,1993,73(10)：612-614.
[125]杨期东,周艳宏,刘运海等.长沙市脑血管病社区人群预防研究-死亡率的变化.卒中与神经疾病.2004,4,11(2)：107-110.
[126]Yaling Han,Suya Xi,Xiaolin Zhang et al, Association of Connexin 37 Gene Polymorphisms with Risk of Coronary Artery Disease in Northern Han Chinese.
Cardiology 2008;110:260-265.
[127]章顺荣,徐力辛,张怀勤等.Connexin37基因C1019T多态性与冠心病的关联研究.心脑血管病防治.2007,7(6)：390-392.
[128]Yeh HI, Chou Y, Liu HF, et al. Connexin37 gene polymorphism and coronary artery disease in Taiwan. Int J Cardiol 2001;81:251-255.
[129]Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002,347 (24):1916-1923.
[130]Florinda Listi, Giuseppina Candore, Domenico Lio.et al.Association between C1019T polymorphism of connexin37 and acute myocardial infarction:a study in patients from Sicily. International Journal of Cardiology 102 (2005) 269-271.
[131]Lanfear DE, Marsh S, Gresci S, et al. Genotype associated with myocardial infarction risk are more common in African Americans than in European Americans[刀.J Am Coll Cardiol,2004,44(1):165-167.
[132]Bras LM, Isaacohn JL, Merikanga KR, et al. A study of twins and stroke.Stroke,1992,23(2):221-223.
[133]Liao Y,Day KH, Damon DN, et al. Endothelial cell specific knock out of connexin 43 causes hypotention bradycardiain mice. Proc Natl Acad Sci USA, 2001,98 (17):9989-9994.
[134]Bruzzone R. Learning the language of cell-cell communication through connexin channels. Genome Biol,2001,2 (11):reports4027.12reports4027.5.
[135]Lanfear DE, Jones PG, Marsh S, et al. Connexin37 (GJA4) genotype predicts survival after an acute coronary syndrome. Am Heart J,2007,154(3):561-566.
[136]Wong CW, Christen T, Roth I, Chadjichristos CE,et al.Connexin37 protects against atherosclerosis by regulating monocyte adhesion.Nat Med, 2006;12:950-954.
[1]Vinken M, Vanhaecke T, Papeleu P, et al. Conexins and their channels in cell growth and cell death. Cell Signal,2005, (Epub ahead of print).
[2]Azzam EI,de Toledo SM,Little JB, et al.Evidence for the participation of gap junction mediated intercellular communication in the transmission of damage singals from irradiated to nonirradiated cells.Proc Natl Acad Sci USA,2001,98(2):247
[3]De Leon JR,Buttrick PM, Fishman GI. Functional analysis of the connexin243gene promoter in vivo and in vitro. Mol Cell Cardiol,1994,26: 379-389.
[4]Wei C.J. Wei, X. Xu, C.W. Lo, et al., Connexins and cell signalling in development and disease, Annu. Rev. Cell Dev. Biol.2004 (20),:811-838.
[5]Evans WH,Martin PE.Gap junctions:structure and function (review). Mol Membr Biol 2002 (19):121-136
[6]Sohl G.,Willecke K. Gap junctions and the connexin protein family Cardiovasc Res,2004,62:228-232
[7]Goodenough D.A.,Goliger J.A.,Paul D.L. Connexins,connexons,and intercellular communication (review) Annu.Rev.Biochem.1996,65,:.475-502;
[8]GE.Sosinsky,B.J.Nicholson, Structural organization of gapjunction channels, Biochim. Biophys. Acta 2005,1711:99-125.
[9]Bruzzone R. Learning the language of cell-cell communication through connexin channels[J]. Genom e B iol,2001,2 (11):reports 4027. 1-reports4027.5.
[10]Vaidya D, Morley GE, Samie FH, Jalife J. Reentry and fibrillation in the mouse heart:a challenge to the critical mass hypothesis. Circ Res,1999,85:174-181
[11]Christ GJ, Sprdy DC. Marwan ES, et al. Gap Junctions in vascular tissues. Circ Res.1996,79:631-646.
[12]Stains J.P.,Civitelli R. et al. Gap junctions in skeletal development and function Biochim Biophys Acta,2005,1719,:.69-81;
[13]K Dorshkind, L Green, A Godwin and WH Fletcher, Connexin-43-type gap junctions mediate communication between bone marrow stromal cells.Blood,
1993,82,(1):38-45.
[14]Bernd Sutor, Timothy Hagerty.Involvement of gap junctions in the development of the neocortex, Biochim Biophys Acta 2005,1719:59-68.
[15]Iacobas D.A., Iacobas S.,Urban-Maldonado M., et al. Sensitivity of the brain transcriptome to connexin ablation Biochim.Biophys.Acta,2005,1711:.183-196.
[16]Herve JC, Sarreuilhe D. Connexin. made channels as pharmacological targets. Curt Pharm Des,2005,11:1941-958.
[17]Morley, G.E., Vaidya, D., Samie, F.H., et al. Characterization of conduction in the ventricles of normal and heterozygousCx43 knockout mice using optical mapping. J. Cardiovasc. Electrophysiol.1999.10,1361-1375.
[18]Dora, K.A.,2001. Cell-cell communication in the vessel wall. Vasc. Med. 6,43-50.
[19]Nagy, J.I., Dudek, F.E., Rash, J.E.,2004. Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res. Brain Res.Rev. 47,191-215.
[20]Michon, L., Nlend Nlend, R., Bavamian, S., et al. Involvement of gap junctional communication in secretion. Biochim. Biophys. Acta 2005.1719,82-101
[21]Montecino-Rodriguez, E., Leathers, H., Dorshkind, K.,2000. Expression of connexin 43 (Cx43) is critical for normal hematopoiesis. Blood 96,917-924.
[22]Ehrlich, H.P., Diez, T.,2003. Role for gap junctional intercellular communications in wound repair. Wound Repair Regen.11,481-489.
[23]King, T.J., Lampe, P.D.,2005. Temporal regulation of connexin phosphorylation in embryonic and adult tissues. Biochim. Biophys. Acta 1719,24-35 (Epub 2005 August 8).
[24]Buzhynskyy N,Hite RK,Walz T,Scheuring S. The supramolecular architecture of junctional microdomains in native lens membranes. EMBO Rep 2007.8:51-55
[25]Chanson, M., Derouette, J.P., Roth, I., et al. Gap junctional communication in tissue inflammation and repair.Biochim. Biophys. Acta 1711,197-207 (Epub 2004 October 30).
[26]Krutovskikh, V.A., Piccoli, C., Yamasaki, H., Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene 2002.
21,1989-1999.
[27]Wilson, M.R., Close, T.W., Trosko, J.E..Cell population dynamics (apoptosis, mitosis, and cell-cell communication) during disruption ofhomeostasis. Exp. Cell Res.254,257-268.
[28]Lin, J.H., Weigel, H., Cotrina, M.L., et al, Gap-junction-mediated propagation and amplification of cell injury. Nat. Neurosci.1998.1,494-500.
[29]Van Camp G, Coucke P, Speleman F, et al. The gene for human gap junction protein connexins 37 (GJA4) maps to chromosome 1p35.1,in the vicinity of D1S195 [J]. Genomics,1995,30(2):402-403.
[30]Reed,K.E., Westphale,E.M., Larson.D.M., et al. Molecular cloning and functional expression of human connexin 37, an endothelial cell gap junction protein./. Clin. Invest.,1993,91,997-1004.
[31]HaefligerJ.A., Bruzzone.R., Jenkins.N.A., et al. Four novel members of the connexin family ofgap junction proteins. Molecular cloning, expression, and chromosome mapping. J. Biol. Chem.,1992,161,2057-2064.
[32]Yin BY, Zhang Y, Sun JH, et al. Connexin37 mRNA expression in in vivo and in vitro mouse oocyte. Zygote.2009,17(2):163-8.
[33]Willecke K, Heynes R, Dahl E, et al. Mouse Connexin37:Cloning and functional expression of a gap junction gene highlyexpressed in lung. J Cell Biol 1991. 114; 1049-1057
[34]Haefliger J-A, Castillo E, Waeber G, et al Hypertension differentially affects the expression ofthe gap junctional protein connexin43 in cardiac myocytes andaortic smoth muscle cells. Adv Exp Med Biol 1997,.432;71-82.
[35]Davis LM, Rodefeld ME, Green K,et al. Gap junction protein phenotypes of the human heart and conduction system.J Cardiovasc Electrophysiol 10;813-822.
[36]Delorme B, Dahl E, Jarry-Guichard T, et al Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system. Dev Dyn 1995.204;358-371.
[37]Vozzi C, Dupont E, Coppen SR, et al Chamberrelated differences in connexin expression in the human heart. J Mol Cell Cardiol 1999.31;991-1003.
[38]Davis LM, Rodefeld ME, Green K, et al. Gap junction protein phenotypes of the
human heart and conduction system. J Cardiovasc Electrophysiol 1995.10;813-822.
[39]Traub O, Hertlein B, Kasper M, et al Characterization of the gap junction protein connexin37 in murine endothelium, respiratory epithelium, and after transfection in HeLa cells. Eur J Cell Biol,1998.77;313-322.
[40]Haefliger JA, Polikar R, Schnyder G et al. Connexin37 in Normal and Pathological Development of Mouse Heart and Great Arteries. Dev Dyn.2000 Jun;218(2):331-344
[41]Reed, K. E., Westphale, E. M., Larson, D. M., et al.. Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein. J. Clin. Invest.1993 91,997-1004.
[42]Veenstra, R. D., Wang, H. Z., Beyer, E. C. et al. Connexin37 forms high conductance gap junction channels with subconductance state activity and selective dye and ionic permeabilities. Biophys. J.1994,66,1915-1928.
[43]Haefliger JA, Castillo E, Waeber G, et al. Hypertension increases connexin43 in a tissue specific manner. Circulation.1997;95:1007-1014.
[44]Polacek D, Bech F, McKinsey JF, et al. Connexin43 gene expression in the rabbit arterial wall:effects of hypercholesterolemia, balloon injury and their combination. J Vasc Res.1996;34:19-30.
[45]Yeh HI, Lupu F, Dupont E, et al. Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vasc Biol.1997; 17:3174-3184.
[46]Boerma M, Forsberg L, Van Zeijl L, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. Journal of Internal Medicine 1999; 246:211-218
[47]Powell RJ, Cronenwett JL, Fillinger MF, et al.. Endothelial cell modulation of smooth muscle cell morphology and organizational growth pattern. Ann Vasc Surg 1996; 10:4-10.
[48]Richard G, Lin JP, Smith L,et al. Linkage studies in erythrokeratodermias:fine mapping, genetic heterogeneity, and analysis of candidate genes. J Invest Dermatol 1997; 109:666-71
[49]Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and plaque in borderline hypertension. Stroke 1995; 26:34±9.
[50]Mercuri M, Tang R, Phillips M, et al. Ultrasound protocol and quality control procedures in the European Lacidipine Study on Atherosclerosis (ELSA). Blood Pressure 1996; 4 s:20-3.
[51]Eran Gershon,Vicki Plaks,Nava Dekel.Gap junctions in the ovary: Expression,localization and function. Molecular and Cellular Endocrinology 282 (2008) 18-25
[52]V.Krutovskikh, N.Mironov and H.Yamasakil. Human connexin 37 is polymorphic but not mutated in tumours. Cardnogenesis vol.17 no.8 pp. 1761-1763,1996
[53]Cai WJ.Kocsis E.Scholz D Presence of Cx37 and lack of desmin in smooth muscle cells are early markers for anteriogenesis.Mol cell Biochem.2004, 262(1-2):17-23
[54]Van Rijen HVM, Van Kempen MJA, Analbers LJS et al. Gap junctions in human umbilical cord endothelial cells contain multiple. connexins. Am J Physiol Cell Physiol 1997;272:C117-30.
[55]Yeh HI, Dupont E, Coppen S, et al. Gap junction localization and connexin expression in cytochemically identified endothelial cells from arterial tissue. J Histochem Cytochem 1997;45:539-50.
[56]Yeh HI, Rothery S, Dupont E, et al. Individual gap junction plaques contain multiple connexins in arterial endothelium. Circ Res 1998;83:1248-63.
[57]Xie H, Laird DW, Chang TH, et al. A mitosis-specific phosphorylation of the gap junction protein connexin43 in human vascular cells:biochemical characterization and localization. J Cell Biol.1997; 137:203-210.
[58]Kwak BR, Pepper MS, Gros DB, et al. Inhibition of endothelial wound repair by dominant negative connexin inhibitors. Mol Biol Cell.2001; 12:831-845
[59]Gabriels JE and Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res 1998.83:636-643.
[60]Yasuo Kansui, Koji Fujii, Keiichiro Nakamura.et al. Angiotensin Ⅱ receptor
blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats.Am J Physiol Heart Circ Physiol,2004.287:H216-H224,
[61]Brenda R. Kwak, Flore Mulhaupt, Niels Veillard, et al. Altered Pattern of Vascular Connexin Expression in Atherosclerotic Plaques. Arterioscler. Thromb. Vasc. Biol.2002;22;225-230
[62]Wong CW.Christen T. Foglia B.Eliminating connexin37 enhances atherosclerosis in apolipoprotein Edeficient mice. Cardiovascular Pathology.2004.13(3)(1):42.
[63]Yeh H-1, Lupu F, Dupont E, et al. Upregulation of connexin43 gap junctions between smooth mus cle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vase Biol1997; 17:3174-3184.
[64]Wong CW.Christen T. Foglia B.Eliminating connexin37 enhances atherosclerosis in apolipoprotein Edeficient mice. Cardiovascular Pathology.2004.13(3)(1):42.
[65]Cindy W. Wong, Thomas Christen. et al. Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction?.Atherosclerosis 191 (2007) 355-361
[66]VanRijen HVM, VanKempen MJA, Postma S, et al. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine.1998; 10:258-264.
[67]Li H, Brodsky S, Kumari S, et al. Paradoxical overexpression and translocation of connexin43 in homocysteine-treated endothelial cells.Am J Physiol Heart Circ Physiol 2002;282:H2124-33.
[68]Hu J, Cotgreave IA. Differential regulation of gap junctions by proinflammatory mediators in vitro. J Clin Invest 1997;99:2312-6.
[69]Locke D, Liu J, Harris AL. Lipid rafts prepared by different methods contain different connexin channels, but gap junctions are not lipid rafts. Biochemistry. 2005;44:13027-13042.
[70]Kwak BR, Mulhaupt F, Veillard N, et al. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2002;22:225-230.
[71]Davies PF, Shi C, Depaola N, et al. Hemodynamics and the focal origin of atherosclerosis:a spatial approach to endothelial structure, gene expression, and
function. Ann N Y Acad Sci.2001;947:7-16.
[72]Ross R. Atherosclerosis:an inflammatory disease. N Engl J Med 1999;340:115-26.
[73]Kumar NM, Gilula NB. The gap junction communication channel. Cell 1996;84:381-8.
[74]Yeh HI, Chang HM, Lu WW, et al. Age-related alteration of gap junction distribution and connexin expression in rat aortic endothelium. Histochem Cytochem 2000;48:1377-89.
[75]Stone PH.Coskun AU.Kinlay S.Effect of endothelial shear stress on the progression of coronary artery disease,vascular remodeling,and in-stent restenosis in humons:in vivo 6-month follow-up study.Circulation,2003,108,(4):438-444
[76]Cheng C.Tempel D.van Heperen R Atherosclerotic lesion size and vulnerability are detemined by patterns of fluid shear stress. Circulation,2006,113(23):2 744-753
[77]Ebong EE.Kim S.DePsola N.Flow regulates intercllular communication in HAEC by assembling functional Cx40 and Cx37 gap junctional channels.Am J Physiol Heart Circ Physiol.2006,290(5):H2015-023
[78]Dai G,Kaazempur-Morfrd MR.Natarajan S.Distinct endothelial phemotypes evoked by arterial waveforms derived form atherosclerosis-susceptible and-resistant regions of human vasculature. Proc Natl Acad Sci,2004,101 (41):14 871-876.
[79]Kwak BR.Mulhsupt F.Veillard N Altered pattern of vascular connexin expression in atherosclerotic plaques.Arterioscler Thromb Vasc Biol.2002,22(2):225-230.
[80]Jean-Paul Derouettea, Cindy Wonga, Laurent Burniera, Molecular role of Cx37 in advanced atherosclerosis:A micro-array study. Atherosclerosis 206 (2009) 69-76
[81]Itahana K。 Takeya T.Morikazu Y, et al. Isolation and characterization of a novel connexin gene. Cx 60. in porcine ovarian follicles. Endocrinology,1998, 139(1):320-329
[82]Simon AM. Goodenough DA. Li E。 et al. Female fertility in mice lacking connexin37. Nature,1997,585(6616):525-529
[83]Veitch GI。 Gittens JE. Shao O,et al. Selective assembly of connexin37 into
heterocellular gap junctions at the oocyte/granulosa cell interface. J Cell Sci.2004.117(pt 13):2699-2707
[84]Carabatsos MJ, Sellitto C, Goodenough DA, et al. Oocyte-granulosa ell heterologous gap junctions are required for the coordination of uclear and cytoplasmic meiotic competence. Dev Biol,2000,226(2):167-179
[85]Simon AM, Godenough DA, Li E, et al. Female infemlity in mice lacking connexin37[J]. Nature。 1997,585(6616):525-529.
[86]Carabatsos MJ, Selitto C, Godenough DA, et al. Oocyte-granulosa cell heterologous gap junction are required for the coordination of nuclear and cytoplasmic meiotic competence[J]. Dev Biol,2000,226(2):167-179
[87]Simon AM, Godenough DA, Li E, et al. Female infemlity in mice lacking connexin37[J]. Nature。1997,585(6616):525-529.
[88]van Rijen HV, van Kempen MJ, Postma S, et al.. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine.1998; 10:258-264.
[89]V.Krutovskikh, N.Mironov and H.Yamasakil., Human connexin 37 is polymorphic but not mutated in tumours. Cardnogenesis vol.17 no.8 pp. 1761-1763,1996
[90]Britz-Cunningham SH, Shah MM, Zuppan CW, Fletcher WH. Mutations of the connexin43 gap-junction gene in patients with heart malformations and defects of laterality. New England J Med 1995; 332:1323-9.
[91]Marc Chanson, Brenda R Kwak Cormexin37:a potential modifier gene of Inflammatory disease， J Mol Med,2007.85:787-795.147 Chard G. Connexin gene pathology. Clin Exp Dennatol,2003,28; 397-409
[92]Van Camp G, Coucke P, Speleman F, et al. The gene for human gap junction protein connexins 37 (GJA4) maps to chromosome 1p35.1,in the vicinity of D1S195. Genomics,1995,30(2):402-403
[93]Krutovskikh V, Mironov N, Yamasaki H. Human connexin 37 is polymorphic but not mutated in tumours. Carcinogenesis 1996; 17:1761-3.
[94]Yamada, Y., Ando, F., Shimokata, H. Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese
women and men. Int J Mol Med.2007 May;19(5):791-801.
[95]Richard G, Lin JP, Smith L et al. Linkage studies in erythrokeratodermias:fine mapping, genetic heterogeneity, and analysis of candidate genes. J Invest Dermatol 1997; 109:666-71.
[96]Wong CW, Christen T, Roth I, et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med 2006; 12:950-4.
[97]Boerma M, Forsberg L, Van Zeal L, et al.A genetic polymotphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med.1999.246:211-218
[98]Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002,347 (24):916-923.
[99]Yamada Y, lzawa H, Ichihara S, et al Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002.347(24): 1916-1923
[100]Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002,347 (24):1916-1923
[101]Yoshiji,Yamada, Sahoko,et al. Genetic risk for coronary artery disease in individuals with or without type 2 diabetes. Molecular Genetics and Metabolism 81(2004)282-290
[102]Akihiro Hirashiki, Yoshiji Yamada, Yosuke Murase. et al.Association of Gene Polymorphisms With Coronary Artery Disease in Low-or High-Risk Subjects Defined by Conventional Risk Factors. Journal of the American College of Cardiology. Vol.42, No.8,2003
[103]Katugampola S, Davenport, A. Emerging roles for orphan G protein coupled receptors in the cardiovascular system. Trends Pharmacol Sci,2003,24 (1):30-35.
[104]Boerma M, Forsberg L, Van Zeijl L, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med 1999;246:211-8.
[105]Yeh HI, Chou Y, Liu HF, Chang SC, et al. Connexin37 gene polymorphism and coronary artery disease in Taiwan. Int J Cardiol 2001;81:251-5.
[106]Yaling Han, Suya Xi, Xiaolin Zhang,et al. Association of Connexin 37 Gene Polymorphisms with Risk of Coronary Artery Disease in Northern Han Chinese. Cardiology 2008; 110:260-265
[107]Florinda Listi,Giuseppina Candore,Domenico Lio,et al. Association between C1019T polymorphism of connexin37 and acute myocardial infarction:a study in patients from Sicily. International Journal of Cardiology 102 (2005) 269-271
[108]Yamada, Y,Izawa,H,Ichihara,S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. New Engl J Med,2002,Vol. 347, No.24.
[109]Kato T, yamada A, Mumse Y, et al Specific gene polymorphisms could be risk factors for coronary artery disease in individuals with or without hypertension. Circulation,2003.108:VI-712.
[110]Yamada Y, Ichiham S, lzawaH, et al Genetic risk for coronary artery diseasein individuals with or without type 2 diabetes Mol Genet Metab,2004,81:282-290.
[111]Shimokata K, Yamada Y, Kondo T, et al.Association of genepolymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. Atherosclerosis,2004,172:167-173.
[112]Listi F, Candore G, Balistreri CR, et al.Connexin37 1019 gene polymoqohism in myocardial infarction patients and centenarians.Atherosclerosis,2007,191(2): 460-461.
[113]Wong, C.W., Christen, T., Roth, I., et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med.2006 Aug;12(8):950-4.
[114]Wong CW, Christen T, Pfenniger A, et al. Do allelic vmiants of the connexin37 1019 gene polymorphism differentially predict foreoronary artery disease and myocardialinfarction?Atherosclerosis,2006,178:441-442
[115]Auni Collings Md. Shaheenul Islam, Markus Juonala.et al. Associations between connexin37 gene polymorphism and markers of subclinical atherosclerosis:The Cardiovascular Risk in Young Finns study. Atherosclerosis
195(2007)379-384
[116]Horan PG, Alien AR, Patterson CC,et al The eollnexill 37 gene polymorphism and coronary artery disease in ireland. Heart,2006,92(3):395-396.
[117]Collings A, Islam MS, Juonala M, etal Associations between connexin 37 gene polymorphism and markers of subclinical atherosclerosis:the Cardiovascular Risk in Young Finns study.Atherosclerosis,2007,195(2):379-384
[118]Cooper CD, Solan JL, Dolejsi MK, et al. Analysis of connexin phosphorylation sites. Methods 2000;20:196-204
[119]Iwai N.Association analyses between polymorphisms in the GJA4 gene cluster and myocardial infamtion in Japanese.Thromb Haemost,2003,90(6):122.
[2]Fuster V, Ross R, Topol EJ. Atherosclerosis and coronary artery disease. Philadelphia:Lippincott-Raven 1996
[3]Ross R. The pathogensis of atherosclerosis:an update. N Engl J M.1986, 314:488-500.
[4]Ross R. The pathogensis of atherosclerosis:a perspective for the 1990s. Nature. 1993,362:801-809
[5]Benditt EP. Origins of human atherosclerotic plaques, the role of altered gene expression. Arch Pathol Lad Med.1988,112:997-1001.
[6]Ross R. Growth regulatory mechanisms and formation of the lesions of ahterosclerosis.Ann N Y Acad Sci.1995,748:1-6
[7]Dimmeler S, Haendeler J, Galle J, et al.Oxidized Iow-density lipoprotein induees apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanism clue to the'response to injury' hypothesis.Cireulation 1997:95(7): 1760-3.
[8]Imanishi T, Hano T, Sawamura T, et al.Oxidized low density lipoprotein potentiation of Fas-indueed apoptosis through lectin-like oxidized-low Density lipoprotein receptor-1 in human umbilical vaseularendothelial eells.Circ J 2002:66(11):1060-4.
[9]Eseargueil-Blanel, Meilhae O, Pieraggi MT, et al.Oxidized LDLs induce massive apoptosis of cultured human endothelial cells Through a calcium-dependent pathway.Prevention by aurintricathoxylic acid. Arterioscler Thromb Vasc Biol 1997:17(2):331-9.
[10]Sui GZ,Stoek klauser-Farber K, Weiss J, et al.Introduction of apoptosis by high proinsulin and glucose in cultured human umbilical vein endothelial eells is mediated by reaetive oxygen speeies. Diabetologia 1998:41(3):249-56.
[11]Chibber R, Molinatti PA, Wbng JS, et al.The effete ofAminoguanidine and to lrestat on glueose toxicity in bovine retinal capillary pericytes.Diabetes
1994:43(6):758-63.
[12]Napoli C. Oxidation of LDL, atherogenesis, and apoptosis. Ann N Y Acad Sci 2003;1010:698-709.
[13]Colles SM, Maxson JM, Carlson SG, et al Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med 2001; 11(3-4):131-138.
[14]Napoli C.Oxidation of LDL, atherogenesis and apoptosis1 Ann N Y Acad Sci, 2003,1010:698
[15]Salvayre R, Auge N, Benoist H, et al. Oxidized low-density lipoprotein induced apoptosisl Biochim Biophys Acta,2002,1585 (223):213
[16]顾耘.氧化型低密度脂蛋白影响人脐静脉内皮细胞存活率和两种细胞因子的分泌.中华中医药学刊,2008,26(1)：100-101.
[17]Vinken M, Vanhaecke T, Papeleu P, et al. Conexins and their channels in cell growth and cell death. Cell Signal,2005, (Epub ahead of print).
[18]Loewenstein WR,Ross B,The cell-cell channel in the control of growth.Cell Biol,1992,16(1):59
[19]Polacek D,Lal R,Volin MV,et al.Gap junctional communication between vascular cells.Induction of connexin 13 messenger RNA in macrophage foam cells of atherosclerotic lesion.Am J Pathol,1993,142(2):593.
[20]Blackburn JP, Peters NS et al.Upregulation of connexin 43 gap junction during early stages of human coronary atherosclerosis.Arterioscler Thromb Vasc Biol.1995,15(8):1219.
[21]Chadjichristos C E, Kwak B R. Connexins:New Genes in Atherosclerosis[J]. Ann Med,2007,39(6):402-411
[22]Blackburn J P, Peters N S, YehHI, et al. Upregulation of Connexin43 Gap Junctions during Early Stages of Human Coronary Atherosclerosis. Arterioscler Thromb Vasc Biol,1995,15(8):1219-1228.
[23]Isakson B E, Kronke G, Kadl A, et al. Oxidized Phospholipids Alter Vascular Connexin Expression, PhosphorylatiOn, and Heterocellular Communi-cation. Arterioscler Thromb Vasc Biol,2006,26(10):2216-2122.
[24]Kwak B R, Mulhaupt F, Veillard N, et al. Altered Pattern of Vascular Connexin
Expression in AtherOsclerOtic Plaques. Arterioscler Thromb Vasc Biol, 2002,22(2):225-230
[25]Johnson TL,Nerem RM.Endothelial connexin 37,connexin 40,and connexin 43 respond uniquely to substrate and shear stress. Endothelium.2007, 14(4-5):215-26.
[26]Wong CW,Christen T,Roth I,et al.Connexin37 protects against atherosclerosis by regulating monocyte adhesion.Nat Med.2006,12(8):950-954.
[27]Chanson M,Derouette JP,Roth I,et al.Gap junctional communication in tissue inflammation and repair.Biochim Biophys Acta.2005,1711 (2):197-207.
[28]Wong CW,Burger F,Pelli G,et al.Dual benefit of reduced Cx43 on atherosclerosis in LDL receptor-deficient mice.Cell Commun Adhes.2003,10(4-6):395-400.
[29]Ramachandran S,Xie LH,John SA,et al.A novel role for connexin hemichannel in oxidative stress and smoking-induced cell injury.PLoS ONE.2007,2(1):e712.
[30]Libby P,Ridker PM,Mascri A.Inflammation and atherosclerosis. Circulation 2002,105 1135-1143.
[31]Van R H.VanKM.Analbers L J Gap junctions in human umbilical cord endothelial cells contain multiple connexins 1997,272(1 Pt 1):C117-130
[32]Ko YS,Yeh HI,Rotnery S,et al.Connexin make-up of endothelial gap junctions in the rat pulmonary artery as revealed by immunoconfocal microscopy and triple-label immunogold electron microscopy.Dupont EJ Histochem Cytochem.1999 May:47(5):683-92.
[33]Okruhlicova L,Tribulova N,Misejkova M,et al. Gap Junction Remodelling is Involved in the Susceptibility of Diabetic Rats to Hypokalemia induced Ventricular Fibrillation. Acta Histochem,2002,104 (4):387-391
[34]Blackburn JP, Peters NS, Yeh H-I, et al. Upregulation of connexin43 gap junction early stages of human coronary atherosclerosis. Arterioscler Thromb Vase Biol,1995; 15:12191-228.
[35]Yeh H-1, Lupu F, Dupont E, et al. Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vase Biol 1997; 17:3174-3184.
[36]尹力.高脂血症对大鼠主动脉壁连接蛋白37、40和45mRNA表达及内皮功
能影响的实验研究：[博士学位论文].天津：天津医科大学,2005.
[37]Yeh H-I, Lu C-S, Wu Y-J, et al. Reduced expression of connexin37 and.connexin40 in Endothelial hyperlipidemic mice. Arterioscler Thromb Vasc Biol.2003; 23:1391-1397.
[38]Wong CW.Christen T. Foglia B.Eliminating connexin37 enhances atherosclerosis in apolipoprotein Edeficient mice. Cardiovascular Pathology. 2004.13(3)(1):42.
[39]Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res.1998;83:636-643.
[40]Simon AM, Whorter AR. Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin 37 or connexin 40. J Cell Sci 2003;116:2197-2259.
[41]Cottrell GT, Wu Y, Burt JM. Cx40 and Cx43 expression ratio influences heteromeric/heterotypic gap junction channel properties. Am J Physiol 2002;282:C1469-82.
[42]He DS, Jiang JX, Taffet SM, et al. Formation of heteromeric gap junction channels by connexins 40 and 43 in vascular smooth muscle cells. Proc Natl Acad Sci U S A 1999;96:6495-500.
[43]Blackburn JP, Peters NS, Yeh H-I, et al. Upregulation of connexin43 gap junction early stages of human coronary atherosclerosis. Arterioscler Thromb Vase Biol,1995; 15:1219-1228.
[44]Kwak BR,Veillard N,Pelli G,et al.Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. Circulation,2003,107:1033.
[45]Strehlow K, Wemer N, Berweiler J, etal. Estrogen inereases bone marrow-derived endothelial progenitor cell production and diminishes neoiniinia formation.Circulation.2003,107(24):3059-65.
[46]Llevadot J, Murasa S, KureishiY, et al.HMG-CoA reduetase inhibitor mobilizes bone-marrow derived endothelial progenitor cells.J Clin Invest.2001, 108:399-405.
[47]Dirnrneler S, Aieher A, Vasa M, et al.HMG-CoA-reduetase inhibitors(statins) Increase endothelial progenitor cells via the P13 kinase/AktPathway.J Clin Invest2001,108:391-397.
[48]Li DY,Mehta JL.Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells.Circulation,2000,101 (25):2889-2895.
[49]Hastie LE,Paton WF,Hechtman HB,et al.Metabolites of the phospholipase D pathway regulate 1202-induced filam in redisribution in endothelial cells.J Cell Biochem,1998,68(4):511-524.
[50]Werner N, Nickenig G. Influence of cardiovascur risk factors on endothelial progenitor cells:limitations for therapy?. Arterioscler Thromb Vasc Biol,2006, 26(2):257-266.
[51]Brandes,Ralf P.Roads to Dysfunction:Argininase II Contributes to Oxidized Low-Density Lipoprotein-Induced Attenuation of Endothelial NO Production Circulation Research.2006, october,99(9):918-920.
[52]Dimmeler S, Hermann C, Zeiher AM.Apoptosis of endothelial cells. Contribution To the pathophysiology of atherosclerosis? Eur Cytokine Netw 1998:9(4):697-698.
[53]D immeler S, Haendeler J, Galle J, et al. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP3221ike proteases:A mechanistic clue to the "response to injury"hypo thesis. Circulation, 1997; 95 (7):1760
[54]Colles SM, Maxson JM, Carlson SG, et al. Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med 2001; 11(3-4):131-138.
[55]张庆,曾智,任敏等,高密度脂蛋白对氧化型低密度脂蛋白诱导内皮细胞凋亡的影响.四川大学学报(医学版),2003,34(1)：67-69.
[56]高爱社,沈晓君.葛根素对oxLDL诱导的血管内皮细胞凋亡的防护作用.山东中医杂志2008,5.27(5)：334-335
[57]Eskes R,Desagher S,Antonsson B,et al.Bid induces the oligomerization and insertion of Bax into the outermitoch-ondrial membrane.MolCell Biol,2000, 20(3):929-935.
[58]Cain K,Bratton SB,Langlais C,et al.Apaf-1 oligomerizes into-biologically active approximately 700-kDa and inactive approxim-ately 1.4-MDaapoptosome complexes J Biol Chem,2000,275(9):6067-6070.
[59]Basset O, Boittin FX, Cognard C, et at.BCL-2 overexpression prevents calcium Overload and subsequent apoptosis in dystrophie myotubes.Bioehem J,2006 Jan4.
[60]付永锋,樊廷俊,Bcl-2家族蛋白与细胞凋亡。生物化学与生物物理学报2002；34(4)：389-394.
[61]Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked. Science 1997; 275(5303):1129-1132.
[62]Eskes R, Antonsson B, Osen-Sand A, et al. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol 1998; 143(1):217-224.
[63]Kirkin V, Joos S. Zornig M.The role of Bcl-2 family members in tumorigenesis.Biochim Biophys Acta.2004,393(2):226-230.
[64]Kim MR,Tilly JI.Current concepts in Bcl-2 family member regulation of female germ cell development and survival.Biochim Biophys Biophys Acta.2004, 1644(2-3:205-210.
[65]Xia Z, Lundgren B, Bergstrand A, et al. Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X (L). Biochem Pharmacol 1999; 57(10):1199-208.
[66]申晓或,薛丽霞,屈巧芳等.苯扎贝特对ox-LDL诱导内皮细胞凋亡基因Bcl-2/Bax的影响.山西医科大学学报.2008.39(7)：596-599.
[67]Luetjens CM, Bui NT, Sengpie LB. Delayed mitochondrial dysfunction in excitotoxic neuron death:Cytochrome C release and a secondary increase in superoxide production. J Neurosci,2000;20 (15):5715.
[68]Wilson MR.Close Tw, Trosko JE.Cell population dynamics(apoptosis, mitosis, and cell cell communication)during disruption of homeostasis.Cell Res, 2000,25(4):257-268
[69]Nodin C, Nilsson M, Blomstrand F.Gap junction blockage limits intercellular spreading of astrocytic apoptosis induced by metabolic depression. Neuroehem。 2005,94(4):1111-123
[70]Taizen Nakase。 Shinji Fushiki, Christian C, et al. A. strocytie Gap Junctions, Composed of Connexin 43 Reduce Apoptotie Neuronal Damage in Cerebral Isehemia[J]. Stroke,2003,34(9):1987-1993
[71]Wannamethee SG, Shaper AG, Ebrahim S. HDL-cholesterol, Total Cholester01. and the Risk of Stroke in Middle-aged British Men [J]. Stroke(s0039-2499),2000,31:1882-1888.
[72]Curb JD, Abbott RD, Rodriguez BL.et al. High Density Lipoprotein Cholesterol and the Risk of Stroke in Elderly Men:TheHonolulu Heart Program[J]. Am J Epidemiol(S0002-9262)2004,160:150-157.
[73]Simons LA, McCallum J, Friedlander Y, et al. Risk Factors for lschemic Stroke:Dubbo Study of the Elderly[J]. Stroke(S0039-2499).1998,29: 1341-1346.
[74]Nisson SE. Effect of recombinant ApoA-1 Milano on coronery atheroscborsis in p twith a ACS:A randomized controlled trial. JAMA,2003; 290-2921.
[75]梁玉佳,曾智,黄德嘉等.脂蛋白对人血管内皮细胞间隙连接通讯功能的影响.华西医大学报,2000,31(2)：129-132.
[76]Murugesan G, Sa G, Fox PL. High density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor. Circ Res,1994,74：1149-1156.
[77]张秋华、尹洪超、张俊华等.血浆高密度脂蛋白对内皮祖细胞生长特性的影响.中华病理学杂志2006.35(11)：672-676.
[78]Nofer JR, Fobker M, Hobbel G, et al. Activation of phosphatidylinositol specific phospholipase C by HDL-associated lysosphingolipid.Involvement in mitogenesis but not in cholesterol efflux. Biochemistry,2000,39:15199-15207.
[79]Imanishi T, Hano T, Matsuo Y, et al. Oxidized low density lipoprotein inhibits vascular endothelial growth factor induced endothelial progenitor cell differentiation. Clin Exp Pharmacol Physiol,2003,30:665-670.
[80]Mineo C, Yuhanna IS, Quon MJ, et al. High density lipoprotein induced endothelial nitricoxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem,2003,278:9142-9149.
[81]Kimura T, Sato K, Malchinkhuu E,Tomura H,et al. High Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors. Arterioscler Thromb Vasc Biol,2003,23(7):283-288.
[82]McElveen J, Mackness MI, Colley CM, et al. Distribution of paraoxon hydrolytic activity the serum of patients after myocardial infarction. Clin Chem 1986;32:
[83]Parthasarathy S,Barnett J,Fong L G. High density lipoprotein inhibits the oxidative modification of low density lipoprotein. Biochim Biophys Acta 1990; 1044:275.
[84]Sattler W, Stocker R. Greater selective take up by HepG2 cells of high density lipoprotein cholesterylester hydroperoxides than of unoxidised cholesterylesters. Biochem J 1993;294:771.
[85]M I Mackness, C Abbott, S Arrol,et al. The role of high density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low density lipoprotein oxidation.Biochem J 1993;294:829.
[86]王蕾,国汉邦,张小勇等.HDL抑制人脐静脉内皮细胞NADPH氧化酶4表达和活性氧生成.医学分子生物学杂志,2008,5(1)：16-21.
[87]Navab M.,Imes S.S.,Hama S.Y. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein I synthesis and is abolished by high density lipoprotein. J Clin Invest 1991;88:2039.
[88]Suc I, Escargeuil,Blanc I, Troly M, et al. HDL and apoA prevent cell death of endo thelial cells induced by oxidized LDL.Arterioscler Thromb Vasc Bio l, 1997; 17 (10):2158-2166.
[89]Sugano M, Tsuchida K, Makino N. High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis Biochem Biophys Res Commun,2000; 272 (3):872-6.
[90]Pathasarathy S, Barnett J, Fong L G.High density lipo ro tein inhibits the oxidative modification of low density lipoprotein.Bioch im Biphys Acta,1990; 1044 (2):275.
[91]勾蓝图,傅明德.HDL抗动脉粥样硬化的作用.国外医学.心血管疾病分册,2004,31(3)：150-152
[92]张庆,曾智,任敏等,高密度脂蛋白对氧化型低密度脂蛋白诱导内皮细胞凋亡的影响.四川大学学报(医学版),2003,34(1)：67-69.
[93]Nykanen A,Haley B,Zamore PD.ATP requirements and small interfering RNA structure in the RNA interference pathway.Cell,2001,107(3):309-321.
[94]Cecilia M,Hertig,Stefan B.N-cadherin in adult rat cardiomyocytes in cultureJournal of Cell Science,1996,109:11-20.
[95]Wang H, Hong T. Wang H, et al. Altered expression of connexin43 and itspossible role in endothelin-1-inducedcontraction in rabbit basilar artery. Neurol Res,2009,31(1):67-73.
[96]Hong T, Wang H, Wang Y,et al. Effects of gap junctional blockers on cerebral vasospasm after subarachnoid hemorrhage in rabbits. Neurol Res.2009 Apr;31(3):238-44.
[97]陈伟.Cx43蛋白表达在脑血管痉挛细胞模型中的研究：[硕士学位论文].南昌大学,2007.
[98]Derouette J P, Wong C, Bumier L, at al. Molecular role of Cx37 in avanced atherosclerosis:A micro-array study. Atherosclerosis.2009,27[Epub ahead of print].
[99]Christos E Chadjichristos; Ludwig Scheckenbach; Maya Z Richani Sarieddine et al. Endothelial-Specific Deletion of Cx40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion. Circulation.2009;120:S1042
[100]韩冬,冯加纯,邓方,等,缝隙连接对大鼠脑缺血再灌注后血脑屏障通透性的影响.中华神经科杂志,2007.40(7)：447-451.
[101]Ranwanduzy A,Hansen A,Hansen TW,et al.Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke.Neurosurg, 1997,87(6):916-920.
[102]邓方,饶明俐,冯加纯等,缝隙连接胞间通讯对大鼠局灶性脑梗死体积的
影响,中风与神经疾病杂志.2005.22(5)：394-396.
[103]Kalvelyte A, Imbrasaite A, Bukauskiene A, et al. Connexins and apoptotic transformation[J]. Biochemo 2003,66(4):1661-1672.
[104]Cusato K, Ripps H, Zakevicius J, et al. Gap junctions remain open during cytochromec-induced cell death:relationship of conductance to'bystander'cell killing. Cell Deah Differ,2006,17(2):167-172.
[105]邓方,冯加纯,饶明俐等,抑制缝隙连接胞间通讯对大鼠实验性局灶性脑梗死的保护作用.2008,25(3)：285-288.
[106]Huang RP, Hossain MZ, Huang R, et al. Connexin 43(Cx43)enhances chemotherapy. induced apoptosis in human glioblastoma ceils[J]. Cancer,2001, 92(1):130-138.
[107]Brass LM.Isaacohn JL.Merikanga KR,et al.A study of twins and stroke. 1992,23 (2):221-223.
[108]Bak S,Gaist D.Sindrup SH,et al.Genetic liability in stroke:long-term follow-up study of Danish twins.Stoke,2002.3(3):769-774.
[109]Hassan A,Markush S.Genetics and ischemic stroke,Brain,2000,123:1784-1812.
[110]Kiely DK,Wolf PA,Cupples LA.et al.Familial aggregation of stroke.The Franmingha Study.Stroke.1993,24(9):1366-1371.
[111]Thoranvldsen P.Aplund K,Kuulasmaa K,et al.Stroke incidence.case fatality, and mortality in the WHO MONICA project.World Health Organization Monitoring Trends and Determinants in cardiovascular disease.Stroke.1995, 26(3):361-367.
[112]Rastenyte D,Tuomilehto J,Sarti C.Genetics of stroke-review.J of Neurol Sci. 1998,153:132-145.
[113]Van Camp G, Coucke P, Speleman F, et al. The gene for human gap junction protein connexins 37 (GJA4) maps to chromosome 1p35.1,in the vicinity of D1S195. Genomics,1995,30(2):402-403.
[114]Van Camp G,Coucke P,Speleman F,et al. The gene for human gap junction protein connexin37(GJA4)maps to chromosome 1p35.1, in the vicinity of D1S195. Genomics,1995,30:402-403.
[115]Reed KE, Westphale EM, Larson DM, ct al. Molecular cloning and functional expression of human eonnexin37, an endothdial cell gap junction protein. J Clin Invest,1993,91:997-1004.
[116]Cindy W Wong, Thomas Christen, Isabelle Roth, et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. NATURE MEDICINE,2006,12(8):950-954.
[117]Kwak BR,Mulhaupt F,Veillard N,et al.Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vase Biol,2002, 22(2):225-230.
[118]Wong cw,Christen T,Kwak BR. Connexins in leucocytes:shuttling messages?Cardiovasc Res,2004,62:357-367.
[119]Richard G, Lin JP, Smith L,et al. Linkage studies in erythrokeratodermias:fine mapping, genetic heterogeneity,and analysis of candidate genes. J Invest Dermatol 1997; 109:666-71.
[120]Boerma M, Forsberg L, Van Zeal L, et al A genetic polymotphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med.1999.246:211-218.
[121]Yeh HI, Chou Y, Liu HF,et al. Connexin37 gene polymerphism and coronary artery disease in Taiwan [J]. Int J Cardiol,2001,81 (23):251-255.
[122]Wong CW, Christen T, Pfenniger A,et al. Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction [J] Atherosclerosis,2007,191 (2):355-361.
[123]Yamada Y, Izawa H, Ichihara S,,et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes [J]. N Engl J Med,2002, 347 (24):916-923.
[124]杨期东,陆雪芬,谢小玲等.长沙市居民脑血管病危险因素的干预试验.中华医学杂志,1993,73(10)：612-614.
[125]杨期东,周艳宏,刘运海等.长沙市脑血管病社区人群预防研究-死亡率的变化.卒中与神经疾病.2004,4,11(2)：107-110.
[126]Yaling Han,Suya Xi,Xiaolin Zhang et al, Association of Connexin 37 Gene Polymorphisms with Risk of Coronary Artery Disease in Northern Han Chinese.
Cardiology 2008;110:260-265.
[127]章顺荣,徐力辛,张怀勤等.Connexin37基因C1019T多态性与冠心病的关联研究.心脑血管病防治.2007,7(6)：390-392.
[128]Yeh HI, Chou Y, Liu HF, et al. Connexin37 gene polymorphism and coronary artery disease in Taiwan. Int J Cardiol 2001;81:251-255.
[129]Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002,347 (24):1916-1923.
[130]Florinda Listi, Giuseppina Candore, Domenico Lio.et al.Association between C1019T polymorphism of connexin37 and acute myocardial infarction:a study in patients from Sicily. International Journal of Cardiology 102 (2005) 269-271.
[131]Lanfear DE, Marsh S, Gresci S, et al. Genotype associated with myocardial infarction risk are more common in African Americans than in European Americans[刀.J Am Coll Cardiol,2004,44(1):165-167.
[132]Bras LM, Isaacohn JL, Merikanga KR, et al. A study of twins and stroke.Stroke,1992,23(2):221-223.
[133]Liao Y,Day KH, Damon DN, et al. Endothelial cell specific knock out of connexin 43 causes hypotention bradycardiain mice. Proc Natl Acad Sci USA, 2001,98 (17):9989-9994.
[134]Bruzzone R. Learning the language of cell-cell communication through connexin channels. Genome Biol,2001,2 (11):reports4027.12reports4027.5.
[135]Lanfear DE, Jones PG, Marsh S, et al. Connexin37 (GJA4) genotype predicts survival after an acute coronary syndrome. Am Heart J,2007,154(3):561-566.
[136]Wong CW, Christen T, Roth I, Chadjichristos CE,et al.Connexin37 protects against atherosclerosis by regulating monocyte adhesion.Nat Med, 2006;12:950-954.
[1]Vinken M, Vanhaecke T, Papeleu P, et al. Conexins and their channels in cell growth and cell death. Cell Signal,2005, (Epub ahead of print).
[2]Azzam EI,de Toledo SM,Little JB, et al.Evidence for the participation of gap junction mediated intercellular communication in the transmission of damage singals from irradiated to nonirradiated cells.Proc Natl Acad Sci USA,2001,98(2):247
[3]De Leon JR,Buttrick PM, Fishman GI. Functional analysis of the connexin243gene promoter in vivo and in vitro. Mol Cell Cardiol,1994,26: 379-389.
[4]Wei C.J. Wei, X. Xu, C.W. Lo, et al., Connexins and cell signalling in development and disease, Annu. Rev. Cell Dev. Biol.2004 (20),:811-838.
[5]Evans WH,Martin PE.Gap junctions:structure and function (review). Mol Membr Biol 2002 (19):121-136
[6]Sohl G.,Willecke K. Gap junctions and the connexin protein family Cardiovasc Res,2004,62:228-232
[7]Goodenough D.A.,Goliger J.A.,Paul D.L. Connexins,connexons,and intercellular communication (review) Annu.Rev.Biochem.1996,65,:.475-502;
[8]GE.Sosinsky,B.J.Nicholson, Structural organization of gapjunction channels, Biochim. Biophys. Acta 2005,1711:99-125.
[9]Bruzzone R. Learning the language of cell-cell communication through connexin channels[J]. Genom e B iol,2001,2 (11):reports 4027. 1-reports4027.5.
[10]Vaidya D, Morley GE, Samie FH, Jalife J. Reentry and fibrillation in the mouse heart:a challenge to the critical mass hypothesis. Circ Res,1999,85:174-181
[11]Christ GJ, Sprdy DC. Marwan ES, et al. Gap Junctions in vascular tissues. Circ Res.1996,79:631-646.
[12]Stains J.P.,Civitelli R. et al. Gap junctions in skeletal development and function Biochim Biophys Acta,2005,1719,:.69-81;
[13]K Dorshkind, L Green, A Godwin and WH Fletcher, Connexin-43-type gap junctions mediate communication between bone marrow stromal cells.Blood,
1993,82,(1):38-45.
[14]Bernd Sutor, Timothy Hagerty.Involvement of gap junctions in the development of the neocortex, Biochim Biophys Acta 2005,1719:59-68.
[15]Iacobas D.A., Iacobas S.,Urban-Maldonado M., et al. Sensitivity of the brain transcriptome to connexin ablation Biochim.Biophys.Acta,2005,1711:.183-196.
[16]Herve JC, Sarreuilhe D. Connexin. made channels as pharmacological targets. Curt Pharm Des,2005,11:1941-958.
[17]Morley, G.E., Vaidya, D., Samie, F.H., et al. Characterization of conduction in the ventricles of normal and heterozygousCx43 knockout mice using optical mapping. J. Cardiovasc. Electrophysiol.1999.10,1361-1375.
[18]Dora, K.A.,2001. Cell-cell communication in the vessel wall. Vasc. Med. 6,43-50.
[19]Nagy, J.I., Dudek, F.E., Rash, J.E.,2004. Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res. Brain Res.Rev. 47,191-215.
[20]Michon, L., Nlend Nlend, R., Bavamian, S., et al. Involvement of gap junctional communication in secretion. Biochim. Biophys. Acta 2005.1719,82-101
[21]Montecino-Rodriguez, E., Leathers, H., Dorshkind, K.,2000. Expression of connexin 43 (Cx43) is critical for normal hematopoiesis. Blood 96,917-924.
[22]Ehrlich, H.P., Diez, T.,2003. Role for gap junctional intercellular communications in wound repair. Wound Repair Regen.11,481-489.
[23]King, T.J., Lampe, P.D.,2005. Temporal regulation of connexin phosphorylation in embryonic and adult tissues. Biochim. Biophys. Acta 1719,24-35 (Epub 2005 August 8).
[24]Buzhynskyy N,Hite RK,Walz T,Scheuring S. The supramolecular architecture of junctional microdomains in native lens membranes. EMBO Rep 2007.8:51-55
[25]Chanson, M., Derouette, J.P., Roth, I., et al. Gap junctional communication in tissue inflammation and repair.Biochim. Biophys. Acta 1711,197-207 (Epub 2004 October 30).
[26]Krutovskikh, V.A., Piccoli, C., Yamasaki, H., Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene 2002.
21,1989-1999.
[27]Wilson, M.R., Close, T.W., Trosko, J.E..Cell population dynamics (apoptosis, mitosis, and cell-cell communication) during disruption ofhomeostasis. Exp. Cell Res.254,257-268.
[28]Lin, J.H., Weigel, H., Cotrina, M.L., et al, Gap-junction-mediated propagation and amplification of cell injury. Nat. Neurosci.1998.1,494-500.
[29]Van Camp G, Coucke P, Speleman F, et al. The gene for human gap junction protein connexins 37 (GJA4) maps to chromosome 1p35.1,in the vicinity of D1S195 [J]. Genomics,1995,30(2):402-403.
[30]Reed,K.E., Westphale,E.M., Larson.D.M., et al. Molecular cloning and functional expression of human connexin 37, an endothelial cell gap junction protein./. Clin. Invest.,1993,91,997-1004.
[31]HaefligerJ.A., Bruzzone.R., Jenkins.N.A., et al. Four novel members of the connexin family ofgap junction proteins. Molecular cloning, expression, and chromosome mapping. J. Biol. Chem.,1992,161,2057-2064.
[32]Yin BY, Zhang Y, Sun JH, et al. Connexin37 mRNA expression in in vivo and in vitro mouse oocyte. Zygote.2009,17(2):163-8.
[33]Willecke K, Heynes R, Dahl E, et al. Mouse Connexin37:Cloning and functional expression of a gap junction gene highlyexpressed in lung. J Cell Biol 1991. 114; 1049-1057
[34]Haefliger J-A, Castillo E, Waeber G, et al Hypertension differentially affects the expression ofthe gap junctional protein connexin43 in cardiac myocytes andaortic smoth muscle cells. Adv Exp Med Biol 1997,.432;71-82.
[35]Davis LM, Rodefeld ME, Green K,et al. Gap junction protein phenotypes of the human heart and conduction system.J Cardiovasc Electrophysiol 10;813-822.
[36]Delorme B, Dahl E, Jarry-Guichard T, et al Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system. Dev Dyn 1995.204;358-371.
[37]Vozzi C, Dupont E, Coppen SR, et al Chamberrelated differences in connexin expression in the human heart. J Mol Cell Cardiol 1999.31;991-1003.
[38]Davis LM, Rodefeld ME, Green K, et al. Gap junction protein phenotypes of the
human heart and conduction system. J Cardiovasc Electrophysiol 1995.10;813-822.
[39]Traub O, Hertlein B, Kasper M, et al Characterization of the gap junction protein connexin37 in murine endothelium, respiratory epithelium, and after transfection in HeLa cells. Eur J Cell Biol,1998.77;313-322.
[40]Haefliger JA, Polikar R, Schnyder G et al. Connexin37 in Normal and Pathological Development of Mouse Heart and Great Arteries. Dev Dyn.2000 Jun;218(2):331-344
[41]Reed, K. E., Westphale, E. M., Larson, D. M., et al.. Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein. J. Clin. Invest.1993 91,997-1004.
[42]Veenstra, R. D., Wang, H. Z., Beyer, E. C. et al. Connexin37 forms high conductance gap junction channels with subconductance state activity and selective dye and ionic permeabilities. Biophys. J.1994,66,1915-1928.
[43]Haefliger JA, Castillo E, Waeber G, et al. Hypertension increases connexin43 in a tissue specific manner. Circulation.1997;95:1007-1014.
[44]Polacek D, Bech F, McKinsey JF, et al. Connexin43 gene expression in the rabbit arterial wall:effects of hypercholesterolemia, balloon injury and their combination. J Vasc Res.1996;34:19-30.
[45]Yeh HI, Lupu F, Dupont E, et al. Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vasc Biol.1997; 17:3174-3184.
[46]Boerma M, Forsberg L, Van Zeijl L, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. Journal of Internal Medicine 1999; 246:211-218
[47]Powell RJ, Cronenwett JL, Fillinger MF, et al.. Endothelial cell modulation of smooth muscle cell morphology and organizational growth pattern. Ann Vasc Surg 1996; 10:4-10.
[48]Richard G, Lin JP, Smith L,et al. Linkage studies in erythrokeratodermias:fine mapping, genetic heterogeneity, and analysis of candidate genes. J Invest Dermatol 1997; 109:666-71
[49]Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and plaque in borderline hypertension. Stroke 1995; 26:34±9.
[50]Mercuri M, Tang R, Phillips M, et al. Ultrasound protocol and quality control procedures in the European Lacidipine Study on Atherosclerosis (ELSA). Blood Pressure 1996; 4 s:20-3.
[51]Eran Gershon,Vicki Plaks,Nava Dekel.Gap junctions in the ovary: Expression,localization and function. Molecular and Cellular Endocrinology 282 (2008) 18-25
[52]V.Krutovskikh, N.Mironov and H.Yamasakil. Human connexin 37 is polymorphic but not mutated in tumours. Cardnogenesis vol.17 no.8 pp. 1761-1763,1996
[53]Cai WJ.Kocsis E.Scholz D Presence of Cx37 and lack of desmin in smooth muscle cells are early markers for anteriogenesis.Mol cell Biochem.2004, 262(1-2):17-23
[54]Van Rijen HVM, Van Kempen MJA, Analbers LJS et al. Gap junctions in human umbilical cord endothelial cells contain multiple. connexins. Am J Physiol Cell Physiol 1997;272:C117-30.
[55]Yeh HI, Dupont E, Coppen S, et al. Gap junction localization and connexin expression in cytochemically identified endothelial cells from arterial tissue. J Histochem Cytochem 1997;45:539-50.
[56]Yeh HI, Rothery S, Dupont E, et al. Individual gap junction plaques contain multiple connexins in arterial endothelium. Circ Res 1998;83:1248-63.
[57]Xie H, Laird DW, Chang TH, et al. A mitosis-specific phosphorylation of the gap junction protein connexin43 in human vascular cells:biochemical characterization and localization. J Cell Biol.1997; 137:203-210.
[58]Kwak BR, Pepper MS, Gros DB, et al. Inhibition of endothelial wound repair by dominant negative connexin inhibitors. Mol Biol Cell.2001; 12:831-845
[59]Gabriels JE and Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res 1998.83:636-643.
[60]Yasuo Kansui, Koji Fujii, Keiichiro Nakamura.et al. Angiotensin Ⅱ receptor
blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats.Am J Physiol Heart Circ Physiol,2004.287:H216-H224,
[61]Brenda R. Kwak, Flore Mulhaupt, Niels Veillard, et al. Altered Pattern of Vascular Connexin Expression in Atherosclerotic Plaques. Arterioscler. Thromb. Vasc. Biol.2002;22;225-230
[62]Wong CW.Christen T. Foglia B.Eliminating connexin37 enhances atherosclerosis in apolipoprotein Edeficient mice. Cardiovascular Pathology.2004.13(3)(1):42.
[63]Yeh H-1, Lupu F, Dupont E, et al. Upregulation of connexin43 gap junctions between smooth mus cle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vase Biol1997; 17:3174-3184.
[64]Wong CW.Christen T. Foglia B.Eliminating connexin37 enhances atherosclerosis in apolipoprotein Edeficient mice. Cardiovascular Pathology.2004.13(3)(1):42.
[65]Cindy W. Wong, Thomas Christen. et al. Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction?.Atherosclerosis 191 (2007) 355-361
[66]VanRijen HVM, VanKempen MJA, Postma S, et al. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine.1998; 10:258-264.
[67]Li H, Brodsky S, Kumari S, et al. Paradoxical overexpression and translocation of connexin43 in homocysteine-treated endothelial cells.Am J Physiol Heart Circ Physiol 2002;282:H2124-33.
[68]Hu J, Cotgreave IA. Differential regulation of gap junctions by proinflammatory mediators in vitro. J Clin Invest 1997;99:2312-6.
[69]Locke D, Liu J, Harris AL. Lipid rafts prepared by different methods contain different connexin channels, but gap junctions are not lipid rafts. Biochemistry. 2005;44:13027-13042.
[70]Kwak BR, Mulhaupt F, Veillard N, et al. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2002;22:225-230.
[71]Davies PF, Shi C, Depaola N, et al. Hemodynamics and the focal origin of atherosclerosis:a spatial approach to endothelial structure, gene expression, and
function. Ann N Y Acad Sci.2001;947:7-16.
[72]Ross R. Atherosclerosis:an inflammatory disease. N Engl J Med 1999;340:115-26.
[73]Kumar NM, Gilula NB. The gap junction communication channel. Cell 1996;84:381-8.
[74]Yeh HI, Chang HM, Lu WW, et al. Age-related alteration of gap junction distribution and connexin expression in rat aortic endothelium. Histochem Cytochem 2000;48:1377-89.
[75]Stone PH.Coskun AU.Kinlay S.Effect of endothelial shear stress on the progression of coronary artery disease,vascular remodeling,and in-stent restenosis in humons:in vivo 6-month follow-up study.Circulation,2003,108,(4):438-444
[76]Cheng C.Tempel D.van Heperen R Atherosclerotic lesion size and vulnerability are detemined by patterns of fluid shear stress. Circulation,2006,113(23):2 744-753
[77]Ebong EE.Kim S.DePsola N.Flow regulates intercllular communication in HAEC by assembling functional Cx40 and Cx37 gap junctional channels.Am J Physiol Heart Circ Physiol.2006,290(5):H2015-023
[78]Dai G,Kaazempur-Morfrd MR.Natarajan S.Distinct endothelial phemotypes evoked by arterial waveforms derived form atherosclerosis-susceptible and-resistant regions of human vasculature. Proc Natl Acad Sci,2004,101 (41):14 871-876.
[79]Kwak BR.Mulhsupt F.Veillard N Altered pattern of vascular connexin expression in atherosclerotic plaques.Arterioscler Thromb Vasc Biol.2002,22(2):225-230.
[80]Jean-Paul Derouettea, Cindy Wonga, Laurent Burniera, Molecular role of Cx37 in advanced atherosclerosis:A micro-array study. Atherosclerosis 206 (2009) 69-76
[81]Itahana K。 Takeya T.Morikazu Y, et al. Isolation and characterization of a novel connexin gene. Cx 60. in porcine ovarian follicles. Endocrinology,1998, 139(1):320-329
[82]Simon AM. Goodenough DA. Li E。 et al. Female fertility in mice lacking connexin37. Nature,1997,585(6616):525-529
[83]Veitch GI。 Gittens JE. Shao O,et al. Selective assembly of connexin37 into
heterocellular gap junctions at the oocyte/granulosa cell interface. J Cell Sci.2004.117(pt 13):2699-2707
[84]Carabatsos MJ, Sellitto C, Goodenough DA, et al. Oocyte-granulosa ell heterologous gap junctions are required for the coordination of uclear and cytoplasmic meiotic competence. Dev Biol,2000,226(2):167-179
[85]Simon AM, Godenough DA, Li E, et al. Female infemlity in mice lacking connexin37[J]. Nature。 1997,585(6616):525-529.
[86]Carabatsos MJ, Selitto C, Godenough DA, et al. Oocyte-granulosa cell heterologous gap junction are required for the coordination of nuclear and cytoplasmic meiotic competence[J]. Dev Biol,2000,226(2):167-179
[87]Simon AM, Godenough DA, Li E, et al. Female infemlity in mice lacking connexin37[J]. Nature。1997,585(6616):525-529.
[88]van Rijen HV, van Kempen MJ, Postma S, et al.. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine.1998; 10:258-264.
[89]V.Krutovskikh, N.Mironov and H.Yamasakil., Human connexin 37 is polymorphic but not mutated in tumours. Cardnogenesis vol.17 no.8 pp. 1761-1763,1996
[90]Britz-Cunningham SH, Shah MM, Zuppan CW, Fletcher WH. Mutations of the connexin43 gap-junction gene in patients with heart malformations and defects of laterality. New England J Med 1995; 332:1323-9.
[91]Marc Chanson, Brenda R Kwak Cormexin37:a potential modifier gene of Inflammatory disease， J Mol Med,2007.85:787-795.147 Chard G. Connexin gene pathology. Clin Exp Dennatol,2003,28; 397-409
[92]Van Camp G, Coucke P, Speleman F, et al. The gene for human gap junction protein connexins 37 (GJA4) maps to chromosome 1p35.1,in the vicinity of D1S195. Genomics,1995,30(2):402-403
[93]Krutovskikh V, Mironov N, Yamasaki H. Human connexin 37 is polymorphic but not mutated in tumours. Carcinogenesis 1996; 17:1761-3.
[94]Yamada, Y., Ando, F., Shimokata, H. Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese
women and men. Int J Mol Med.2007 May;19(5):791-801.
[95]Richard G, Lin JP, Smith L et al. Linkage studies in erythrokeratodermias:fine mapping, genetic heterogeneity, and analysis of candidate genes. J Invest Dermatol 1997; 109:666-71.
[96]Wong CW, Christen T, Roth I, et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med 2006; 12:950-4.
[97]Boerma M, Forsberg L, Van Zeal L, et al.A genetic polymotphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med.1999.246:211-218
[98]Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002,347 (24):916-923.
[99]Yamada Y, lzawa H, Ichihara S, et al Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002.347(24): 1916-1923
[100]Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med,2002,347 (24):1916-1923
[101]Yoshiji,Yamada, Sahoko,et al. Genetic risk for coronary artery disease in individuals with or without type 2 diabetes. Molecular Genetics and Metabolism 81(2004)282-290
[102]Akihiro Hirashiki, Yoshiji Yamada, Yosuke Murase. et al.Association of Gene Polymorphisms With Coronary Artery Disease in Low-or High-Risk Subjects Defined by Conventional Risk Factors. Journal of the American College of Cardiology. Vol.42, No.8,2003
[103]Katugampola S, Davenport, A. Emerging roles for orphan G protein coupled receptors in the cardiovascular system. Trends Pharmacol Sci,2003,24 (1):30-35.
[104]Boerma M, Forsberg L, Van Zeijl L, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med 1999;246:211-8.
[105]Yeh HI, Chou Y, Liu HF, Chang SC, et al. Connexin37 gene polymorphism and coronary artery disease in Taiwan. Int J Cardiol 2001;81:251-5.
[106]Yaling Han, Suya Xi, Xiaolin Zhang,et al. Association of Connexin 37 Gene Polymorphisms with Risk of Coronary Artery Disease in Northern Han Chinese. Cardiology 2008; 110:260-265
[107]Florinda Listi,Giuseppina Candore,Domenico Lio,et al. Association between C1019T polymorphism of connexin37 and acute myocardial infarction:a study in patients from Sicily. International Journal of Cardiology 102 (2005) 269-271
[108]Yamada, Y,Izawa,H,Ichihara,S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. New Engl J Med,2002,Vol. 347, No.24.
[109]Kato T, yamada A, Mumse Y, et al Specific gene polymorphisms could be risk factors for coronary artery disease in individuals with or without hypertension. Circulation,2003.108:VI-712.
[110]Yamada Y, Ichiham S, lzawaH, et al Genetic risk for coronary artery diseasein individuals with or without type 2 diabetes Mol Genet Metab,2004,81:282-290.
[111]Shimokata K, Yamada Y, Kondo T, et al.Association of genepolymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. Atherosclerosis,2004,172:167-173.
[112]Listi F, Candore G, Balistreri CR, et al.Connexin37 1019 gene polymoqohism in myocardial infarction patients and centenarians.Atherosclerosis,2007,191(2): 460-461.
[113]Wong, C.W., Christen, T., Roth, I., et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med.2006 Aug;12(8):950-4.
[114]Wong CW, Christen T, Pfenniger A, et al. Do allelic vmiants of the connexin37 1019 gene polymorphism differentially predict foreoronary artery disease and myocardialinfarction?Atherosclerosis,2006,178:441-442
[115]Auni Collings Md. Shaheenul Islam, Markus Juonala.et al. Associations between connexin37 gene polymorphism and markers of subclinical atherosclerosis:The Cardiovascular Risk in Young Finns study. Atherosclerosis
195(2007)379-384
[116]Horan PG, Alien AR, Patterson CC,et al The eollnexill 37 gene polymorphism and coronary artery disease in ireland. Heart,2006,92(3):395-396.
[117]Collings A, Islam MS, Juonala M, etal Associations between connexin 37 gene polymorphism and markers of subclinical atherosclerosis:the Cardiovascular Risk in Young Finns study.Atherosclerosis,2007,195(2):379-384
[118]Cooper CD, Solan JL, Dolejsi MK, et al. Analysis of connexin phosphorylation sites. Methods 2000;20:196-204
[119]Iwai N.Association analyses between polymorphisms in the GJA4 gene cluster and myocardial infamtion in Japanese.Thromb Haemost,2003,90(6):122.