2型糖尿病患者血浆及其高密度脂蛋白对细胞内胆固醇外流的影响&不同剂量雌激素对小鼠心脏和肾脏结构和功能的影响
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摘要
背景:
2型糖尿病患者常有血脂异常。已证实2型糖尿病患者的胆固醇逆转运途径存在异常,而细胞内胆固醇外流是胆固醇逆转运途径的重要的初始步骤,本研究主要针对胆固醇外流这一步骤进行探讨。
以往的研究证实,2型糖尿病患者细胞内的胆固醇外流的能力可能是降低的。如:从培养的纤维母细胞到含高糖的血浆的胆固醇转运是降低的[1],胆固醇从Fu5Ah细胞流出到糖尿病血浆的能力也是受损的[2]。但近期也有研究显示,1型糖尿病血浆诱导Fu5AH细胞和高表达ABCA1的HSF细胞的胆固醇外流的能力反而是升高的[3]。糖尿病患者血浆成分变化较为复杂,许多因素可以影响胆固醇外流。如血浆中胰岛素含量[4],血糖水平,细胞因子水平[5],脂蛋白糖化情况[7]等,胆固醇外流率并不能完全取决于HDL。因此,糖尿病患者血浆中非脂质成分的异常,还是HDL质或量的异常在影响细胞内胆固醇流出方面起主要作用,至今仍不明确。
在胆固醇逆转运的第一步一胆固醇从外周细胞流出中,ABCA1,SR-BI是迄今为止研究最多的促进胆固醇流出的细胞表面蛋白[8]。近期发现的ABCG1也是在胆固醇流出和流入途径中均起到重要作用的半转运体。除了通过ABCA1,ABCG1,SR-BI途径外,细胞内的胆固醇还可以通过ABCG4、ABCG5、自由扩散等多种方式流出。多个文献显示,有些细胞可以表达相对单一的介导胆固醇转运的细胞表面蛋白,因而可以利用这些细胞相对专一地研究某个细胞表面蛋白对胆固醇外流的作用。
文献显示[7],体外的细胞胆固醇流出实验能够预测糖尿病和非糖尿病患者动脉粥样硬化的病变程度。因此,通过对细胞内胆固醇外流的体外实验研究,我们希望能够间接了解2型糖尿病患者体内外周细胞胆固醇外流的情况。
研究目的:
1.了解HepG2、HSF、HUVEC细胞SR-BI、ABCA1、ABCG1表达的情况。
2.通过对2型糖尿病患者的HDL、无脂血浆及全血血清对经由ABCA1,SR-BI胆固醇流出途径的研究,并与非2型糖尿病组比较,了解2型糖尿病患者血清及其HDL影响细胞内胆固醇外流的特点。
方法:
1.原代分离和培养HSF和HUVEC细胞。
2.RT-PCR和Western Blot方法鉴定三种HepG2、HSF、HUVEC细胞上ABCA1、SR-BI、ABCG1含量。
3.使用超速离心方法分离非2型糖尿病组(对照组)和2型糖尿病组患者血浆中HDL和LPDS,并用苏丹黑染色鉴定。
4.给实验细胞负载H~3标记的胆固醇,分别用非2型糖尿病组和2型糖尿病组的血清、LPDS、HDL诱导HepG2和HSF细胞内胆固醇外流,测定胆固醇流出率。
5.将22-OH胆固醇刺激前后的HSF的胆固醇流出率之差作为经由ABCA1途径的胆固醇流出率。HepG2的胆固醇流出率作为经由SR-BI途径的胆固醇流出率。
6.用荧光标记的方法测定两组PLTP和CETP的活性。
7.将胆固醇流出率与患者的基础资料、PLTP、CETP活性等进行相关性分析。
8.统计分析:采用SPSS 13.0软件进行统计分析。
结果:
1.使用组织贴块培养法可成功分离培养HSF细胞。
2.使用胶原酶灌注分离法可快速成功分离培养HUVEC细胞,培养过程须添加生长因子复合物。
3.用RT-PCR和Western Blot方法证实,HepG2细胞可高表达SR-BI,而HSF和HUVEC细胞在22-OH胆固醇刺激后可分别高表达ABCA1和ABCG1。
4.超速离心分离法可较好的分离出纯度较高的HDL和LPDS。
5.2型糖尿病组的HDL诱导HepG2细胞胆固醇外流能力较对照组明显减弱(P=0.0015)。
6.2型糖尿病组的血清诱导HepG2细胞胆固醇外流的能力较对照组无明显差异(P=0.19)。
7.2型糖尿病与对照组相比的HDL诱导22-OH胆固醇刺激ABCA1高表达前后的胆固醇流出率差值,在两组之间没有明显差异。
8.全血血清诱导的22-OH胆固醇刺激前后的胆固醇流出率差值在2型糖尿病组较对照组差异无显著性(对照组VS 2型糖尿病组,5.7±4.4%VS 8.8±5.9%,P=0.33)。
9.LPDS诱导的22-OH胆固醇刺激前后胆固醇流出率之差在对照组明显升高(对照组VS 2型糖尿病组,11.0±7.7%VS 6.6±4.7%,P=0.02)。
10.2型糖尿病患者血清PLTP活性较对照组升高,与对照组和全部患者的经由ABCA1的胆固醇流出呈正相关。两组的CETP活性无明显差别。
结论:
1.高表达SR-BI的HepG2细胞,以及在22-OH胆固醇刺激后分别高表达ABCA1和ABCG1的HSF和HUVEC可以用来研究经SR-BI、ABCA1、ABCG1途径胆固醇流出情况。
2.糖尿病患者HDL和LPDS(主要含ApoA1和前βHDL)介导细胞内胆固醇外流能力受损可能对糖尿病细胞内胆固醇沉积有重要意义。
3.糖尿病患者血清对ABCA1介导的细胞内胆固醇外流的促进作用可能与其血PLTP活性升高有关。
前言:
无论在人类试验还是动物实验,越来越多的研究指向雌激素能够减轻心肌肥厚,也有一些试验得到不同的结论。这些不同的结论的原因可能在于使用雌激素的剂量不同。我们既往使用心肌梗死的小鼠研究显示,低剂量的雌激素对心脏有保护作用,而中、高剂量的雌激素可能对心脏有害,可能与肾脏损伤也有一定关系。因此提示雌激素的剂量依赖性作用可能对雌激素替代治疗的结果有重要影响。
研究目的:
1.不同剂量的雌激素替代治疗对卵巢切除后的小鼠心脏的血流动力学、形态学、重量和功能的影响,包括对血压、心率、心肌细胞大小、间质胶原沉积、毛细血管密度、左室重量、容积、功能以及心肌储备的研究。
2.研究雌激素对肾脏功能的影响:包括肾脏重量指数,尿微量白蛋白,肌酐清除率。
3.研究是否雌激素通过不同的信号途径作用于心脏,包括PKC,PI3K,ERK等。
研究方法:
1.通过卵巢切除建立小鼠动物模型,给予不同剂量雌激素替代治疗。
2.喂养8周后,通过器官称重,超声心动图,血流动力学检测等方法评估雌激素对心脏血流动力学、形态学、重量和功能的影响。
3.通过组化染色,评价雌激素对心肌间质胶原和毛细血管密度的影响。
4.通过western blot研究不同剂量雌激素对PI3K,ERK,PKC等通路的影响。
5.将小鼠喂养于代谢笼,通过留取24h尿液测定24h尿微量白蛋白的量以及肌酐清除率评价雌激素对肾脏功能的影响。
结果:
1.雌激素在卵巢切除+低剂量雌激素(ovx+L)组(0.42ug/d)能轻度升高心脏重量指数,但在卵巢切除+中剂量雌激素(ovx+M)组(4.2ug/d)和ovx+H(卵巢切除+高剂量雌激素)组(28.3ug/d)组逐渐降低,在ovx+H组与ovx+L组达到统计学差异(P＜0.05);
2.不同剂量的雌激素替代治疗对卵巢切除术后的小鼠的心肌间质胶原沉积和毛细血管密度没有明显影响,但在ovx+H组的MCSA有降低趋势;
3.各种剂量雌激素对卵巢切除后的小鼠的血压无明显影响,但在ovx+H组心率明显降低(P＜0.05 VS sham,ovx+placebo,P＜0.01 VS ovx+VL,ovx+L);
4.中、高剂量雌激素使卵巢切除术后的小鼠心脏射血功能轻度下降(ovx+placebo、ovx+M和ovx+H组的EF分别为80.89±0.46,77.48±1.09,78.87±0.63,P＜0.05)随雌激素剂量增加,左心室收缩和舒张期内径有增加趋势;
5.不同剂量的雌激素对卵巢切除术后的小鼠的心肌收缩和舒张储备功能均没有明显影响;
6.随雌激素替代治疗的剂量的增加,肾脏重量指数逐渐升高,24小时尿白蛋白逐渐增高,在ovx+L,ovx+M和ovx+H组相对ovx均达到统计差异(P＜0.05VS sham,P＜0.01 VS ovx+placebo,P＜0.05 VS sham+VL);肌酐清除率随雌激素剂量升高有降低趋势(P=0.056);
7.在与心肌肥厚有关的信号通路研究中,中、高剂量雌激素明显激活PKC和PI3K通路,而ERK和P70S6K受抑制;在ovx+VL或ovx+L组相反。
结论:
1.低剂量雌激素可能通过ERK和P70S6K、高剂量雌激素可能通过PKC和PI3K的信号转导通路而作用于心肌的结构和生长;低剂量和高剂量的雌激素替代治疗可能通过不同的信号转导通路影响心肌结构和生长。
2.本实验使用的雌激素剂量对卵巢切除术后小鼠心肌的胶原沉积、毛细血管密度没有影响,但心肌细胞横截面积有降低趋势。
3.高剂量雌激素替代治疗组小鼠对心脏的结构和功能有一定的影响,使得心室内径扩大,心脏重量降低,收缩功能轻度下降,表明高剂量的雌激素替代治疗可能对基线时的小鼠均有一定的毒性作用。
4.随雌激素替代治疗剂量的升高,小鼠的肾脏的损害加重,包括尿白蛋白升高,肾脏增大,肌酐清除率降低。
Background:
Type 2 diabetes patients tend to have lipid disorder.It is well accepted that reverse cholesterol transport(RCT) is abnormal in type 2 diabetes.This study will focus on change of cholesterol efflux among this group of patients,which is regarded as the initial important step of reverse cholesterol transport.
Previous research shows that,efflux of cholesterol from cultured fibroblast to high-glucose plasma decreased compared to controls[1],and the ability of efflux from Fu5AH to plasma of diabetes was also injuried[2].However,it was recently reported that the ability of plasma of type 1 diabetes to induce cholesterol efflux from Fu5AH and HSF overexpressed ABCA1 was enhanced[3].Actually,the plasma of diabetes contains a lot of components,and some of these components would influence the cholesterol efflux,such as the levels of insulin[4],glucose,cytokine[5],glucosylated lipoprotein[7],et al.,so the efflux of cholesterol not only depends on HDL,but other factors.It is not clear whether the disorder of non-lipoprotein or the "quality" or "quantity" of HDL plays an important role in the cholesterol efflux.
Among the studies of efflux of cholesterol,ABCA1,SR-BI are the most often studied membrane proteins[8].Recently,ABCG1 was reported to be an important half-tranportor in cholesterol efflux.Besides that,cholesterol can also efflux via ABCG4,ABCG8 and diffusion.Some cells,for example HepG2,HSF,can express membrane proteins exclusively,so that they can be used to study the function of some membrane protein.
It was proved[7]that the efflux of cholesterol in vitro could predict the atherosclerosis levels in diabetes and non-diabetes.We are going to find out the characteristics of the cholesterol efflux in peripheral cells of type 2 diabetes through the study in vitro.
Objectives:
1.To determine the expression ofSR-BI,ABCA1,and ABCG1 in HepG2,HSF,and HUVEC cells.
2.In order to find out of effects of plasma and HDL of type 2 diabetes on cholesterol efflux from peripheral cells,we investigate the different effect of HDL,LPDS and serum of type 2 diabetes patients on the cholesterol efflux via ABCA1 and SR-BI exclusively
Methods:
1.Isolate and culture the HSF and HUVEC cells with tissue adherence and collagenase perfusion.
2.Test the expression of SR-BI,ABCA1,ABCG1 in HepG2,HSF,HUVEC with RT-PCR and Western Blot.
3.Isolate HDL and LPDS from plasma with ultracentrifugation.
4.Compare the ability of cholesterol efflux between type 2 diabetes and non-diabetes patients with H3 isotope labeled HDL.
5.Determine the cholesterol efflux via ABCA1 with the difference between basic and post-stimulated with 22-OH cholesterol in HSF to determine the the cholesterol efflux via SR-BI with HepG2.
6.Test the activity of PLTP and CETP with fluorescent self-quenched method.
7.Determine the relationship between the ability of cholesterol efflux and basic data, activity of PLTP,CETP of patients.
8.Data analysis by SPSS 13.0.
Results:
1.HSF could be isolated,cultured with tissue adhesive method.
2.HUVEC could be isolated,cultured successfully with collagenase perfusion method.
3.RT-PCR and Western Blot proved that HepG2 could highly express SR-BI,and the ABCA1 and ABCG1 could be highly expressed in HSF and HUVEC respectively after stimulated with 22-OH cholesterol.
4.HDL and LPDS could be isolated successfully from plasma with ultracentrifugation method.
5.The HDL of type 2 diabetes patients has a reduced ability to induce cholesterol efflux from HepG2 cells than non-diabetes(P=0.0015).
6.There was no significant difference in the ability of serum to induce cholesterol efflux from HepG2 between the diabetes and control group(P=0.19).
7.The difference of the ability of HDL to induce cholesterol efflux from HSF between basic and post-stimulated with 22-OH cholesterol had no difference in both groups.
8.The difference of the ability of serum to induce cholesterol efflux from HSF between basic and post-stimulated with 22-OH cholesterol had no significant difference in both groups.(control VS type 2 diabetes,5.7±4.4%VS 8.8±5.9%,P=0.33).
9.The difference of the ability of LPDS to induce cholesterol efflux from HSF between basic and post-stimulated with 22-OH cholesterol was higher in controls (control VS type 2 diabetes,11.0±7.7%VS 6.6±4.7%,P=0.02).
10.The activity of PLTP in type 2 diabetes is significantly higher than in controls, and positively related with the ability of cholesterol efflux via ABCA1 in controls and in all patients.The difference of the activity of CETP in both groups was not observed.
Conclusions:
1.HepG2 strongly expresses SR-BI,while HSF and HUVEC highly express ABCA1 and ABCG1 exclusively after stimulating by 22-OH cholesterol.These cell strains can be used to study cholesterol efflux via SR-BI、ABCA1、ABCG1.
2.HDL and LPDS(contains apoA1 and pre-βHDL)of type 2 diabetes patients is deficient in the ability to induce cholesterol efflux from HepG2,which may contribute to cholesterol deposit in peripheral cells of diabetes patients.
3.The activity of PLTP is higher in type 2 diabetes compared with controls,which may contribute to the enhanced ability of cholesterol efflux of serum via ABCA1 in type 2 diabetes.
Background:
Observational studies as well as animal experiments have indicated that estrogen attenuates cardiac hypertrophy,indicating a cardioprotective role for estrogen. However,conflicting results have been reported.The controversies regarding the effect of estrogen on the heart could be related in part to the dose used.Our previous study using a mouse model of myocardial infarction showed that low dose of estrogen is cardioprotective,whereas at moderate and higher dose,it become detrimental to the heart and is associated with renal damage.This indicates that the dose-dependent effect of estrogen may play an important role in the outcomes of estrogen replacement therapy.
Objectives:
1.To determine the dose effect of estrogen replacement on cardiac hemodynamics, morphology,mass and cardiac function in ovariectomized mice.This includes measurement of blood pressure and heart rate,myocyte size,interstitial collage deposition,capillary density,left ventricular mass,dimensions and function,as well as cardiac reserves.
2.To determine the effect of estrogen on renal function,including kidney mass, albuminuria and creatinine clearance;
3.To study whether the dose dependent effects of estrogen are due to activation of different signaling pathways,including PKC,PI3K,ERK.
Methods:
1.Mice were subject ovariectomy(ovx) or sham ovx.Estrogen replacement was initiated after ovx at dose of 0.025(very low),0.24(low),4.2(moderate) and 28.3 μg/day(high) via subcutaneous implantation of estrogen-containing pellets.
2.Using echocardiography and intra-cardiac catheterization,we evaluated the dose effects of estrogen on left ventricular(LV) mass,dimensions and function,as well as LV functional response to isoproterenol,a measure of functional preservation;
3.Immunohistochemistry was used to study the dose effects of estrogen on myocardial interstitial collagen deposition and myocyte cross-sectional area capillary density;
4.Western blot was used to determine the dose effect of estrogen on protein expression of PI3K,ERK,PKC.
5.Metabolism cage was used to study the dose effect of estrogen on 24 hr albuminuria and creatinine clearance.
Results:
1.Low dose estrogen at(ovx+L) slightly increased heart weight,whereas at higher doses(4.2ug/d and 28.3μg/d),estrogen decreased heart weight(p＜0.05 ovx+H vs ovx+L);
2.No dose-effect was observed in collagen deposition and capillary density in the heart,but the MCSA in ovx+H tends to deline.
3.Estrogen had no effect on blood pressure in all groups;however,heart rate was gradually decreased with increased dosage(p＜0.05 ovx+H vs sham,ovx,ovx+VL and ovx+L);
4.LVEF was decreased in the ovx+M,ovx+H compared to ovx+placebo(LVEF in ovx+placebo,ovx+M,ovx+H is 80.89±0.46,77.48±1.09,78.87±0.63,P＜0.05); however,with increased dose of estrogen,estrogen tended to increase LVDs, LVDd(P＜0.05).
5.Functional preservation was not changed by the different doses of estrogen;
6.With increasing doses of estrogen,kidney mass and 24 hr albumin excretion increased significantly(P＜0.05 VS sham,P＜0.01 VS ovx+placebo,P＜0.05 VS sham+VL),whereas creatinine clearance tended to decline(P=0.056).
7.Moderate and high doses of estrogen activated PCK and PI3K,whereas ERK and P70S6K tended to decline with increasing dose of estrogen.
Conclusions:
1.Low dose of estrogen may effect the structure and function of heart via ERK signaling pathway,while high dose of estrogen does via PKC and PI3K;then, Low and high doses of estrogen may influence the growth of myocytes through different signaling pathway.
2.There is no significant effect on the collagen deposit and capillary density with the doses of estrogen which is used in this experiment,but the MCSA in ovx+H tends to deline.
3.But high dose of estrogen may influence the structure and function to a certain extent:it resulted in the ventricular chamber enlargement,heart mass/body weight decline,and left ventricular ejection fraction fall a little;it also increase the mortality in the post-MI mice,decrease the left ventricular ejection fraction.It indicated that high dose of estrogen might impair the heart function both in basic and post-MI mice.
4.Estrogen had a detrimental effect on renal function,including increasing albuminuria and enlarges kidney mass,which may result from the vascular endothelium injuries due to the change in blood lipid.
2型糖尿病患者常有血脂异常。已证实2型糖尿病患者的胆固醇逆转运途径存在异常,而细胞内胆固醇外流是胆固醇逆转运途径的重要的初始步骤,本研究主要针对胆固醇外流这一步骤进行探讨。
以往的研究证实,2型糖尿病患者细胞内的胆固醇外流的能力可能是降低的。如:从培养的纤维母细胞到含高糖的血浆的胆固醇转运是降低的[1],胆固醇从Fu5Ah细胞流出到糖尿病血浆的能力也是受损的[2]。但近期也有研究显示,1型糖尿病血浆诱导Fu5AH细胞和高表达ABCA1的HSF细胞的胆固醇外流的能力反而是升高的[3]。糖尿病患者血浆成分变化较为复杂,许多因素可以影响胆固醇外流。如血浆中胰岛素含量[4],血糖水平,细胞因子水平[5],脂蛋白糖化情况[7]等,胆固醇外流率并不能完全取决于HDL。因此,糖尿病患者血浆中非脂质成分的异常,还是HDL质或量的异常在影响细胞内胆固醇流出方面起主要作用,至今仍不明确。
在胆固醇逆转运的第一步一胆固醇从外周细胞流出中,ABCA1,SR-BI是迄今为止研究最多的促进胆固醇流出的细胞表面蛋白[8]。近期发现的ABCG1也是在胆固醇流出和流入途径中均起到重要作用的半转运体。除了通过ABCA1,ABCG1,SR-BI途径外,细胞内的胆固醇还可以通过ABCG4、ABCG5、自由扩散等多种方式流出。多个文献显示,有些细胞可以表达相对单一的介导胆固醇转运的细胞表面蛋白,因而可以利用这些细胞相对专一地研究某个细胞表面蛋白对胆固醇外流的作用。
文献显示[7],体外的细胞胆固醇流出实验能够预测糖尿病和非糖尿病患者动脉粥样硬化的病变程度。因此,通过对细胞内胆固醇外流的体外实验研究,我们希望能够间接了解2型糖尿病患者体内外周细胞胆固醇外流的情况。
研究目的:
1.了解HepG2、HSF、HUVEC细胞SR-BI、ABCA1、ABCG1表达的情况。
2.通过对2型糖尿病患者的HDL、无脂血浆及全血血清对经由ABCA1,SR-BI胆固醇流出途径的研究,并与非2型糖尿病组比较,了解2型糖尿病患者血清及其HDL影响细胞内胆固醇外流的特点。
方法:
1.原代分离和培养HSF和HUVEC细胞。
2.RT-PCR和Western Blot方法鉴定三种HepG2、HSF、HUVEC细胞上ABCA1、SR-BI、ABCG1含量。
3.使用超速离心方法分离非2型糖尿病组(对照组)和2型糖尿病组患者血浆中HDL和LPDS,并用苏丹黑染色鉴定。
4.给实验细胞负载H~3标记的胆固醇,分别用非2型糖尿病组和2型糖尿病组的血清、LPDS、HDL诱导HepG2和HSF细胞内胆固醇外流,测定胆固醇流出率。
5.将22-OH胆固醇刺激前后的HSF的胆固醇流出率之差作为经由ABCA1途径的胆固醇流出率。HepG2的胆固醇流出率作为经由SR-BI途径的胆固醇流出率。
6.用荧光标记的方法测定两组PLTP和CETP的活性。
7.将胆固醇流出率与患者的基础资料、PLTP、CETP活性等进行相关性分析。
8.统计分析:采用SPSS 13.0软件进行统计分析。
结果:
1.使用组织贴块培养法可成功分离培养HSF细胞。
2.使用胶原酶灌注分离法可快速成功分离培养HUVEC细胞,培养过程须添加生长因子复合物。
3.用RT-PCR和Western Blot方法证实,HepG2细胞可高表达SR-BI,而HSF和HUVEC细胞在22-OH胆固醇刺激后可分别高表达ABCA1和ABCG1。
4.超速离心分离法可较好的分离出纯度较高的HDL和LPDS。
5.2型糖尿病组的HDL诱导HepG2细胞胆固醇外流能力较对照组明显减弱(P=0.0015)。
6.2型糖尿病组的血清诱导HepG2细胞胆固醇外流的能力较对照组无明显差异(P=0.19)。
7.2型糖尿病与对照组相比的HDL诱导22-OH胆固醇刺激ABCA1高表达前后的胆固醇流出率差值,在两组之间没有明显差异。
8.全血血清诱导的22-OH胆固醇刺激前后的胆固醇流出率差值在2型糖尿病组较对照组差异无显著性(对照组VS 2型糖尿病组,5.7±4.4%VS 8.8±5.9%,P=0.33)。
9.LPDS诱导的22-OH胆固醇刺激前后胆固醇流出率之差在对照组明显升高(对照组VS 2型糖尿病组,11.0±7.7%VS 6.6±4.7%,P=0.02)。
10.2型糖尿病患者血清PLTP活性较对照组升高,与对照组和全部患者的经由ABCA1的胆固醇流出呈正相关。两组的CETP活性无明显差别。
结论:
1.高表达SR-BI的HepG2细胞,以及在22-OH胆固醇刺激后分别高表达ABCA1和ABCG1的HSF和HUVEC可以用来研究经SR-BI、ABCA1、ABCG1途径胆固醇流出情况。
2.糖尿病患者HDL和LPDS(主要含ApoA1和前βHDL)介导细胞内胆固醇外流能力受损可能对糖尿病细胞内胆固醇沉积有重要意义。
3.糖尿病患者血清对ABCA1介导的细胞内胆固醇外流的促进作用可能与其血PLTP活性升高有关。
前言:
无论在人类试验还是动物实验,越来越多的研究指向雌激素能够减轻心肌肥厚,也有一些试验得到不同的结论。这些不同的结论的原因可能在于使用雌激素的剂量不同。我们既往使用心肌梗死的小鼠研究显示,低剂量的雌激素对心脏有保护作用,而中、高剂量的雌激素可能对心脏有害,可能与肾脏损伤也有一定关系。因此提示雌激素的剂量依赖性作用可能对雌激素替代治疗的结果有重要影响。
研究目的:
1.不同剂量的雌激素替代治疗对卵巢切除后的小鼠心脏的血流动力学、形态学、重量和功能的影响,包括对血压、心率、心肌细胞大小、间质胶原沉积、毛细血管密度、左室重量、容积、功能以及心肌储备的研究。
2.研究雌激素对肾脏功能的影响:包括肾脏重量指数,尿微量白蛋白,肌酐清除率。
3.研究是否雌激素通过不同的信号途径作用于心脏,包括PKC,PI3K,ERK等。
研究方法:
1.通过卵巢切除建立小鼠动物模型,给予不同剂量雌激素替代治疗。
2.喂养8周后,通过器官称重,超声心动图,血流动力学检测等方法评估雌激素对心脏血流动力学、形态学、重量和功能的影响。
3.通过组化染色,评价雌激素对心肌间质胶原和毛细血管密度的影响。
4.通过western blot研究不同剂量雌激素对PI3K,ERK,PKC等通路的影响。
5.将小鼠喂养于代谢笼,通过留取24h尿液测定24h尿微量白蛋白的量以及肌酐清除率评价雌激素对肾脏功能的影响。
结果:
1.雌激素在卵巢切除+低剂量雌激素(ovx+L)组(0.42ug/d)能轻度升高心脏重量指数,但在卵巢切除+中剂量雌激素(ovx+M)组(4.2ug/d)和ovx+H(卵巢切除+高剂量雌激素)组(28.3ug/d)组逐渐降低,在ovx+H组与ovx+L组达到统计学差异(P＜0.05);
2.不同剂量的雌激素替代治疗对卵巢切除术后的小鼠的心肌间质胶原沉积和毛细血管密度没有明显影响,但在ovx+H组的MCSA有降低趋势;
3.各种剂量雌激素对卵巢切除后的小鼠的血压无明显影响,但在ovx+H组心率明显降低(P＜0.05 VS sham,ovx+placebo,P＜0.01 VS ovx+VL,ovx+L);
4.中、高剂量雌激素使卵巢切除术后的小鼠心脏射血功能轻度下降(ovx+placebo、ovx+M和ovx+H组的EF分别为80.89±0.46,77.48±1.09,78.87±0.63,P＜0.05)随雌激素剂量增加,左心室收缩和舒张期内径有增加趋势;
5.不同剂量的雌激素对卵巢切除术后的小鼠的心肌收缩和舒张储备功能均没有明显影响;
6.随雌激素替代治疗的剂量的增加,肾脏重量指数逐渐升高,24小时尿白蛋白逐渐增高,在ovx+L,ovx+M和ovx+H组相对ovx均达到统计差异(P＜0.05VS sham,P＜0.01 VS ovx+placebo,P＜0.05 VS sham+VL);肌酐清除率随雌激素剂量升高有降低趋势(P=0.056);
7.在与心肌肥厚有关的信号通路研究中,中、高剂量雌激素明显激活PKC和PI3K通路,而ERK和P70S6K受抑制;在ovx+VL或ovx+L组相反。
结论:
1.低剂量雌激素可能通过ERK和P70S6K、高剂量雌激素可能通过PKC和PI3K的信号转导通路而作用于心肌的结构和生长;低剂量和高剂量的雌激素替代治疗可能通过不同的信号转导通路影响心肌结构和生长。
2.本实验使用的雌激素剂量对卵巢切除术后小鼠心肌的胶原沉积、毛细血管密度没有影响,但心肌细胞横截面积有降低趋势。
3.高剂量雌激素替代治疗组小鼠对心脏的结构和功能有一定的影响,使得心室内径扩大,心脏重量降低,收缩功能轻度下降,表明高剂量的雌激素替代治疗可能对基线时的小鼠均有一定的毒性作用。
4.随雌激素替代治疗剂量的升高,小鼠的肾脏的损害加重,包括尿白蛋白升高,肾脏增大,肌酐清除率降低。
Background:
Type 2 diabetes patients tend to have lipid disorder.It is well accepted that reverse cholesterol transport(RCT) is abnormal in type 2 diabetes.This study will focus on change of cholesterol efflux among this group of patients,which is regarded as the initial important step of reverse cholesterol transport.
Previous research shows that,efflux of cholesterol from cultured fibroblast to high-glucose plasma decreased compared to controls[1],and the ability of efflux from Fu5AH to plasma of diabetes was also injuried[2].However,it was recently reported that the ability of plasma of type 1 diabetes to induce cholesterol efflux from Fu5AH and HSF overexpressed ABCA1 was enhanced[3].Actually,the plasma of diabetes contains a lot of components,and some of these components would influence the cholesterol efflux,such as the levels of insulin[4],glucose,cytokine[5],glucosylated lipoprotein[7],et al.,so the efflux of cholesterol not only depends on HDL,but other factors.It is not clear whether the disorder of non-lipoprotein or the "quality" or "quantity" of HDL plays an important role in the cholesterol efflux.
Among the studies of efflux of cholesterol,ABCA1,SR-BI are the most often studied membrane proteins[8].Recently,ABCG1 was reported to be an important half-tranportor in cholesterol efflux.Besides that,cholesterol can also efflux via ABCG4,ABCG8 and diffusion.Some cells,for example HepG2,HSF,can express membrane proteins exclusively,so that they can be used to study the function of some membrane protein.
It was proved[7]that the efflux of cholesterol in vitro could predict the atherosclerosis levels in diabetes and non-diabetes.We are going to find out the characteristics of the cholesterol efflux in peripheral cells of type 2 diabetes through the study in vitro.
Objectives:
1.To determine the expression ofSR-BI,ABCA1,and ABCG1 in HepG2,HSF,and HUVEC cells.
2.In order to find out of effects of plasma and HDL of type 2 diabetes on cholesterol efflux from peripheral cells,we investigate the different effect of HDL,LPDS and serum of type 2 diabetes patients on the cholesterol efflux via ABCA1 and SR-BI exclusively
Methods:
1.Isolate and culture the HSF and HUVEC cells with tissue adherence and collagenase perfusion.
2.Test the expression of SR-BI,ABCA1,ABCG1 in HepG2,HSF,HUVEC with RT-PCR and Western Blot.
3.Isolate HDL and LPDS from plasma with ultracentrifugation.
4.Compare the ability of cholesterol efflux between type 2 diabetes and non-diabetes patients with H3 isotope labeled HDL.
5.Determine the cholesterol efflux via ABCA1 with the difference between basic and post-stimulated with 22-OH cholesterol in HSF to determine the the cholesterol efflux via SR-BI with HepG2.
6.Test the activity of PLTP and CETP with fluorescent self-quenched method.
7.Determine the relationship between the ability of cholesterol efflux and basic data, activity of PLTP,CETP of patients.
8.Data analysis by SPSS 13.0.
Results:
1.HSF could be isolated,cultured with tissue adhesive method.
2.HUVEC could be isolated,cultured successfully with collagenase perfusion method.
3.RT-PCR and Western Blot proved that HepG2 could highly express SR-BI,and the ABCA1 and ABCG1 could be highly expressed in HSF and HUVEC respectively after stimulated with 22-OH cholesterol.
4.HDL and LPDS could be isolated successfully from plasma with ultracentrifugation method.
5.The HDL of type 2 diabetes patients has a reduced ability to induce cholesterol efflux from HepG2 cells than non-diabetes(P=0.0015).
6.There was no significant difference in the ability of serum to induce cholesterol efflux from HepG2 between the diabetes and control group(P=0.19).
7.The difference of the ability of HDL to induce cholesterol efflux from HSF between basic and post-stimulated with 22-OH cholesterol had no difference in both groups.
8.The difference of the ability of serum to induce cholesterol efflux from HSF between basic and post-stimulated with 22-OH cholesterol had no significant difference in both groups.(control VS type 2 diabetes,5.7±4.4%VS 8.8±5.9%,P=0.33).
9.The difference of the ability of LPDS to induce cholesterol efflux from HSF between basic and post-stimulated with 22-OH cholesterol was higher in controls (control VS type 2 diabetes,11.0±7.7%VS 6.6±4.7%,P=0.02).
10.The activity of PLTP in type 2 diabetes is significantly higher than in controls, and positively related with the ability of cholesterol efflux via ABCA1 in controls and in all patients.The difference of the activity of CETP in both groups was not observed.
Conclusions:
1.HepG2 strongly expresses SR-BI,while HSF and HUVEC highly express ABCA1 and ABCG1 exclusively after stimulating by 22-OH cholesterol.These cell strains can be used to study cholesterol efflux via SR-BI、ABCA1、ABCG1.
2.HDL and LPDS(contains apoA1 and pre-βHDL)of type 2 diabetes patients is deficient in the ability to induce cholesterol efflux from HepG2,which may contribute to cholesterol deposit in peripheral cells of diabetes patients.
3.The activity of PLTP is higher in type 2 diabetes compared with controls,which may contribute to the enhanced ability of cholesterol efflux of serum via ABCA1 in type 2 diabetes.
Background:
Observational studies as well as animal experiments have indicated that estrogen attenuates cardiac hypertrophy,indicating a cardioprotective role for estrogen. However,conflicting results have been reported.The controversies regarding the effect of estrogen on the heart could be related in part to the dose used.Our previous study using a mouse model of myocardial infarction showed that low dose of estrogen is cardioprotective,whereas at moderate and higher dose,it become detrimental to the heart and is associated with renal damage.This indicates that the dose-dependent effect of estrogen may play an important role in the outcomes of estrogen replacement therapy.
Objectives:
1.To determine the dose effect of estrogen replacement on cardiac hemodynamics, morphology,mass and cardiac function in ovariectomized mice.This includes measurement of blood pressure and heart rate,myocyte size,interstitial collage deposition,capillary density,left ventricular mass,dimensions and function,as well as cardiac reserves.
2.To determine the effect of estrogen on renal function,including kidney mass, albuminuria and creatinine clearance;
3.To study whether the dose dependent effects of estrogen are due to activation of different signaling pathways,including PKC,PI3K,ERK.
Methods:
1.Mice were subject ovariectomy(ovx) or sham ovx.Estrogen replacement was initiated after ovx at dose of 0.025(very low),0.24(low),4.2(moderate) and 28.3 μg/day(high) via subcutaneous implantation of estrogen-containing pellets.
2.Using echocardiography and intra-cardiac catheterization,we evaluated the dose effects of estrogen on left ventricular(LV) mass,dimensions and function,as well as LV functional response to isoproterenol,a measure of functional preservation;
3.Immunohistochemistry was used to study the dose effects of estrogen on myocardial interstitial collagen deposition and myocyte cross-sectional area capillary density;
4.Western blot was used to determine the dose effect of estrogen on protein expression of PI3K,ERK,PKC.
5.Metabolism cage was used to study the dose effect of estrogen on 24 hr albuminuria and creatinine clearance.
Results:
1.Low dose estrogen at(ovx+L) slightly increased heart weight,whereas at higher doses(4.2ug/d and 28.3μg/d),estrogen decreased heart weight(p＜0.05 ovx+H vs ovx+L);
2.No dose-effect was observed in collagen deposition and capillary density in the heart,but the MCSA in ovx+H tends to deline.
3.Estrogen had no effect on blood pressure in all groups;however,heart rate was gradually decreased with increased dosage(p＜0.05 ovx+H vs sham,ovx,ovx+VL and ovx+L);
4.LVEF was decreased in the ovx+M,ovx+H compared to ovx+placebo(LVEF in ovx+placebo,ovx+M,ovx+H is 80.89±0.46,77.48±1.09,78.87±0.63,P＜0.05); however,with increased dose of estrogen,estrogen tended to increase LVDs, LVDd(P＜0.05).
5.Functional preservation was not changed by the different doses of estrogen;
6.With increasing doses of estrogen,kidney mass and 24 hr albumin excretion increased significantly(P＜0.05 VS sham,P＜0.01 VS ovx+placebo,P＜0.05 VS sham+VL),whereas creatinine clearance tended to decline(P=0.056).
7.Moderate and high doses of estrogen activated PCK and PI3K,whereas ERK and P70S6K tended to decline with increasing dose of estrogen.
Conclusions:
1.Low dose of estrogen may effect the structure and function of heart via ERK signaling pathway,while high dose of estrogen does via PKC and PI3K;then, Low and high doses of estrogen may influence the growth of myocytes through different signaling pathway.
2.There is no significant effect on the collagen deposit and capillary density with the doses of estrogen which is used in this experiment,but the MCSA in ovx+H tends to deline.
3.But high dose of estrogen may influence the structure and function to a certain extent:it resulted in the ventricular chamber enlargement,heart mass/body weight decline,and left ventricular ejection fraction fall a little;it also increase the mortality in the post-MI mice,decrease the left ventricular ejection fraction.It indicated that high dose of estrogen might impair the heart function both in basic and post-MI mice.
4.Estrogen had a detrimental effect on renal function,including increasing albuminuria and enlarges kidney mass,which may result from the vascular endothelium injuries due to the change in blood lipid.
引文
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