褪黑素对大鼠血糖、血脂代谢和动脉粥样硬化相关因素影响及机制研究
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摘要
研究背景
褪黑素(melatonin)是一种主要在夜间由松果体合成分泌、受光线明暗及昼夜节律调控的吲哚类激素,研究发现其具有抗自由基和氧化应激、调节机体血脂和血糖代谢等多种心血管相关的生理药理学作用。体内褪黑素水平的下降与动脉粥样硬化性疾病的发生,以及机体的血脂、血糖代谢异常有显著的相关性。但机体血清褪黑素水平的改变与机体脂糖代谢异常是否存在因果关系有待进一步研究。血管内皮炎症在动脉粥样硬化等心血管疾病的发生发展中起着重要的作用。研究发现褪黑素与血管炎症反应和内皮功能之间存在一定的相关性。但褪黑素水平的降低是否可以导致血管炎症的发生,其对血管内皮细胞炎症因子表达的调控及其机制仍有待进一步研究。动脉粥样硬化病变的典型特征是巨噬细胞吞噬大量的脂质,导致泡沫细胞形成。巨噬细胞表面的三磷酸腺苷结合盒转运体A1(ABCA1)、三磷酸腺苷结合盒转运体G1(ABCG1)及其介导的胆固醇外流是细胞胆固醇逆转运的重要始动因素。研究证实,ABCA1介导细胞内胆固醇外流功能障碍能加速动脉粥样硬化的发生和发展,而ABCG1介导的胆固醇外流功能与ABCA1介导的胆固醇外流具有协同作用。褪黑素能否影响ABCA1和ABCG1的表达及其介导的巨噬细胞胆固醇外流功能,目前未见报道。我们通过建立大鼠去松果体致褪黑素缺乏的动物模型,分别对以上三部分进行研究：
第一部分去松果体致褪黑素缺乏大鼠模型的建立及血糖、血脂代谢特点分析
研究目的：
1.建立去松果体致褪黑素缺乏的大鼠动物模型；
2.观察在生理性褪黑素缺乏的环境下大鼠体内血脂、血糖代谢的特点；
研究方法：
1.10周龄雄性Wistar大鼠共36只,随机分为两组。通过松果体摘除手术建立大鼠去松果体致褪黑素缺乏的动物模型(Px组),并以假手术大鼠作为对照组(Con组),检测手术前后大鼠血清夜间褪黑素水平判断褪黑素缺乏模型是否成功；
2.在术前0周,术后4周、8周、16周四个时间点测量褪黑素缺乏大鼠在正常饮食条件下血脂、血糖相关代谢指标的水平,分析其随时间的动态变化特点；
3.测量术后16周大鼠肝脏脂质水平含量,分析其与血脂水平的关系；
研究结果：
1.去松果体组(Px组,N=16)动物夜间褪黑素水平减少至术前的20%,且显著低于假手术对照组(Con组,N=14)(8.19±2.05ng/L和39.98±5.91ng/L,P<0.01),褪黑素缺乏模型制作成功；
2.在术前0周和术后4周、8周、16周各组大鼠血脂血糖水平分别为：
1)血脂代谢指标：两组动物血脂基线水平一致。Px组大鼠血清TG、FFA和VLDL-C水平自术后4周时相比4周Con组大鼠均显著增高,并持续增高至16周(P值均<0.05)。在校正0周基线值后,Px组上述指标的16周相对0周变化值仍较Con组变化值显著增加(P值均<0.05)；
2)糖代谢方面,两组动物血糖和胰岛素水平的基线值水平一致。相比术后16周Con组,术后16周Px组大鼠的血糖水平显著增加(P<0.05),ISI指数的水平显著降低(P<0.05),但INS的的增高无显著意义。在校正了术前0周水平后,术后16周Px组上述阳性指标的变化值相比对照组变化值的差异仍有显著意义(P值均<0.05)；
3.Px组大鼠16周肝脏单位质量的甘油三酯含量相比16周Con组显著增加(P<0.01),但其单位质量的总胆固醇含量两组间比较无显著性差异。
第二部分去松果体致褪黑素缺乏大鼠主动脉内皮炎症因子表达的变化及机制
研究目的：
1.研究褪黑素缺乏环境下大鼠体内血清炎症因子水平的变化,观察其主动脉内皮细胞炎症因子表达的情况,
2.研究褪黑素对体外培养的大鼠主动脉内皮细胞炎症因子表达调控的作用及相关信号通路机制；
研究方法：
1.10周龄雄性Wistar大鼠,建立褪黑素缺乏的大鼠模型组(8只),以假手术组(7只)作为对照(见第一部分)；
2.分别测量褪黑素缺乏大鼠术前0周和术后16周时血清氧化应激和炎症标志物MDA、oxLDL、TNFα、IL-6和CRP的水平,检测大鼠主动脉内皮炎症因子MCP-1、ICAM-1、VCAM-1和MMP-9的表达情况；
3.体外培养大鼠主动脉内皮细胞系,用褪黑素干预oxLDL预刺激的内皮细胞,观察细胞炎症因子蛋白表达的变化,同时检测炎症相关信号通路NF-κB、 P38-MAPK、JNK和ERK磷酸化水平的表达,探讨褪黑素可能的作用机制；
研究结果：
1.两组动物血清炎症因子基线值水平基本一致。在术后16周,Px组N=8)大鼠血清MDA、oxLDL、TNFα、IL-6和CRP水平相比16周Con组(N=7)均显著增加(P值均<0.01)。在校正0周基线值后,Px组上述指标的16周相对0周变化值仍较Con组变化值显著增加(P值均<0.05)；
2.术后16周,Px组大鼠主动脉内皮MCP-1、VCAM-1和MMP-9因子表达水平的IOD值相比16周Con组对应值均显著增加(P值均<0.05)。而Px组大鼠16周ICAM-1表达相比Con组无显著统计学意义；
3.褪黑素剂量依赖性地显著抑制oxLDL诱导大鼠主动脉内皮细胞表面MCP-1、VCAM-1和MMP-9蛋白表达(P值均<0.05)；并剂量依赖性地显著抑制oxLDL诱导RAEC细胞内NF-κB和P38-MAPK通路蛋白磷酸化表达水平(P值均<0.05),但对JNK和ERK1/2蛋白磷酸化表达水平无显著影响。
第三部分去松果体致褪黑素缺乏大鼠腹腔巨噬细胞胆固醇外流的变化及机制
研究目的：
1.研究褪黑素缺乏大鼠腹腔巨噬细胞胆固醇外流功能的变化；
2.研究褪黑素缺乏大鼠腹腔巨噬细胞表面ABCA1和ABCG1的表达情况；
3.探讨褪黑素对巨噬细胞ABCA1表达的相关信号调控机制。
研究方法：
1.10周龄雄性Wistar大鼠,建立褪黑素缺乏的大鼠模型组(共16只),以假手术组(共16只)作为对照(见第一部分)；
2.分别收集培养大鼠术前0周和术后16周的腹腔巨噬细胞,检测褪黑素缺乏大鼠术前0周和术后16周的腹腔巨噬细胞ABCA1、ABCG1和全血清介导的胆固醇外流率,评估不同因素介导外流率的变化；
3.检测术后16周腹腔巨噬细胞ABCA1和ABCG1基因和蛋白表达的变化；
4.体外培养人单核细胞系(THP-1)并诱导分化为巨噬细胞,分别以不同浓度褪黑素干预细胞,观察其对细胞ABCA1表达的影响并探讨其作用的相关信号通路机制。
研究结果：
1.两组动物腹腔巨噬细胞胆固醇外流率基线值基本一致。Px组(N=6)术后16周的全血清诱导(-7.29±5.91%和-3.80±4.79%,P<0.01)以及ABCA1介导的胆固醇外流率相对0周的变化值(-4.21±4.82%和-1.20±2.12%,P<0.01)相比Con组(N=6)对应的变化值均显著下降,但ABCG1介导的胆固醇外流率的变化值在两组间无显著差异。
2.术后16周,Px组(N=6)的腹腔巨噬细胞ABCA1转运体mRNA水平的表达相比16周Con组(N=6)的表达显著下降(P<0.01),但其蛋白表达水平在两组间无显著统计学差异。
3.术后16周,ABCG1转运体mRNA和蛋白水平的表达在两组间均无显著统计学差异。
4.褪黑素剂量依赖性地显著增强THP-1巨噬细胞ABCA1和LXRa的mRNA水平和蛋白水平的表达(P值均<0.05)；PPARy和LXRa拮抗剂均可显著抑制褪黑素对细胞ABCA1蛋白表达的促进作用(P值均<0.001)；褪黑素膜受体MT1/MT2拮抗剂对于褪黑素对细胞ABCA1蛋白表达的调控均无显著影响。
研究结论
1.通过松果体摘除手术成功建立褪黑素缺乏的大鼠动物模型。
2.褪黑素缺乏可显著导致大鼠胰岛素抵抗的发生,影响大鼠血甘油三酯和血糖代谢。
3.褪黑素缺乏促进大鼠体内炎症反应过程,促进并可能通过NF-κB和P38-MAPK通路参与的机制调控大鼠主动脉内皮炎症因子的表达。
4.褪黑素缺乏抑制大鼠腹腔巨噬细胞胆固醇外流及ABCA1基因表达及其介导的胆固醇外流；褪黑素以不依赖于褪黑素膜受体的方式作用于巨噬细胞内的PPARy-LXRa途径,调控细胞ABCA1的表达水平。
Background:
Melatonin (Mel) is an indole-like hormone that synthesized and secreted by pineal gland, with a secretion rhythm controlled by the light-dark cycle (intensity of the light). Researches have found that Mel has a variety of cardiovascular relevant effects, such as the inhibition of oxidants and regulation of blood lipid and glucose metabolism. It has been reported that the decrease of Mel concentration is prominently related with the development of atherosclerotic diseases, and with the increase of the blood lipid and glucose-associated disorders. However, it is unclear whether the alternation of in vivo Mel concentration will lead to such dysmetabolisms. Endothelial inflammation participates in the development of cardiovascular diseases including atherosclerosis (As). Several publications presented a correlation between Mel and vascular inflammation and dysfunction. Nevertheless, mechanism of the effect of Mel on endothelial inflammation remains to be elucidated. Atherosclerotic lesions are typically infiltrated by macrophage-derived foam cells, in which cholesterol esters are overloaded. ATP-binding cassette transporter Al (ABCA1), which expressed on macrophages, plays critical roles in mediating the reverse cholesterol efflux to maintain intracellular cholesterol homeostasis. Studies indicated that the dysfunction of ABCA1mediated cholesterol efflux to apolipoprotein A1was closely associated with As. ATP-binding cassette transporter G1(ABCGl) mediated cholesterol efflux shown to be coordinated to ABCA1in removal of excessive cellular cholesterol, which also plays a role in the development of As. The mechanisms of Mel deficiency on regulating ABCA1and ABCG1expression and their mediated cholesterol efflux function, however, are still unknown. Therefore, we created melatonin-deficiency animal models and performed a study consist of three parts to answer those questions above.
Part I. Creation of Melatonin-Deficiency Rats and the Metabolic Characteristics of their Serum Lipid and Glucose Profiles
Objective:
1. To create melatonin-deficiency animal models in rats.
2. To analyse the metabolic characteristics of their serum lipid and glucose profiles in melatonin-deficiency rats.
Methods:
1. Thirty-six Wistar rats, male,10-week old were included. Melatonin-deficiency (Px) rats were created by pinealectomy. Nocturnal levels of melatonin before and after surgery were measured and compared with those levels in sham-operated (Con) rats to evaluate the success of surgery.
2. Serum lipid and glucose profiles in Px rats were measured at the0week (baseline), and the4th,8th,16th week after surgery respectively, and compared with those profiles in Con rats at each time-point.
3. The contents of total cholesterol and triglyceride in liver tissue were measured at the16th week after surgery respectively, and compared with those in Con rats.
Results:
1. Nocturnal serum level of melatonin in Px group (N=16) was significantly diminished after surgery, compared with that in Con group (N=14)(8.19±2.05ng/L vs.39.98±5.91ng/L, P<0.001, respectively), suggesting a melatonin deficiency state in pinealectomized rats.
2. Comparison of serum lipid and glucose metabolic profiles between Px and Con rats at the0week(baseline), and the4th,8th,16th week after surgery were listed below:
1. Lipid metabolic profile:No significant differences of serum lipid levels at the baseline were observed between the Px (N=16) and Con (N-14) groups. At the4th week after surgical operation, serum TG, VLDL-C and FFA in Px group were all significantly increased compared to those in Con group at4th week(all P<0.05), and continued to be elevated until the16th week (all P<0.05). The changes of serum TG, VLDL-C and FFA levels from baseline at the16th week in Px group were all significantly higher than those in control group (all P<0.05for the between-group comparison).
2. Glucose metabolic profile:No significant differences of serum glucose-relevant parameters at the baseline were observed between the Px (N=8) and Con (N=7) groups. The serum glucose level at the16th week was significantly elevated, with the significant decrease of ISI index in Px group, compared with that in Con group (P<0.05). However, the INS level in Px group had no significant difference from that in Con group. The changes of serum glucose levels, INS and ISI from baseline at the16th week in Px group were all significantly higher than those in Con group (all P<0.05for the between-group comparison).
3. The average content of triglyceride in the liver tissue of the Px group at16th week was significantly higher than that in Con group (P<0.01). However, The average content of total cholesterol in the liver tissue in Px group had no significant difference from that in Con group.
Part II. Changes of Inflammatory Cytokines in Pinealectomized Melatonin-Deficiency Rats and the Underlying Mechanisms
Objective:
1. To investigate the effect of melatonin on in-vivo inflammation and expression of aortic inflammatory cytokines in melatonin-deficiency rats.
2. To study the possible mechanisms of melatonin in regulating the expression of inflammatory cytokines on endothelial cells.
Methods:
1. Wistar rats, male,10-week old were included. Eight melatonin-deficiency (Px) rats were created and compared with seven sham-operated (Con) rats (See Part I).
2. Serum oxidative stress and inflammatory biomarkers MDA, oxLDL, TNF-a, IL-6and CRP in Px rats were measured at the0week and16th week after surgery respectively, and compared with those levels in Con rats. IHC stain of the aorta in each group was performed and quantified to analyse the expression of inflammatory cytokines MCP-1, ICAM-1、VCAM-1and MMP-9in endothelium.
3. Rat aortic endothelial cell lines (RAECs) were pre-incubated with oxLDL and treated by melatonin in vitro. The protein expression of inflammatory cytokines and phosphorylation levels of relevant signal pathways including NFκB, P38-MAPK, ERK and JNK were determined.
Results:
1. Serum levels of MDA, oxLDL, TNF-α, IL-6and CRP in Px group (N=8) at the16th week were all significantly increased, compared with those in Con group (N=7) respectively (all P<0.01). The change from baseline at the16th week for each above-mentioned parameter in Px group was significantly higher than that in Con group (all P<0.05for the between-group comparison).
2. The IOD values of MCP-1, VCAM-1and MMP-9in Px group (N=8) were all significantly elevated compared to those in Con group (N=7)(all P<0.05). However, ICAM-1expression was not significantly changed compared to that in Con group.
3. Melatonin dose-dependently attenuated oxLDL-induced MCP-1, VCAM-1and MMP-9expressions on RAECs (all P<0.05). It also dose-dependently decreased NFκB and P38-MAPK protein phosphorylation levels (all P<0.05), but the phosphorylation levels of ERK1/2and JNK were not affected significantly by melatonin.
Part Ⅲ. Alternations of Cholesterol Efflux of Peritoneal Macrophages in Pinealectomized Melatonin-Deficiency Rats and the Underlying Mechanisms
Objective:
1. To investigate the function of intercellular cholesterol efflux in macrophages from melatonin-deficiency rats.
2. To study the expressions of ABCA1and ABCG1on macrophages from melatonin-deficiency rats.
3. To study the mechanisms of melatonin in regulating the expression of ABCA1on macrophages.
Methods:
1. Wistar rats, male,10-week old were included. Sixteen melatonin-deficiency (Px) rats were created and compared with sixteen sham-operated (Con) rats (See Part Ⅰ).
2. Peritoneal macrophages were collected from Px and Con rats at0week and16th week respectively, and cultured in vitro.
3. Their macrophage cholesterol efflux rates of Px and Con groups at0week and16th week were measured respectively.
4. Their ABCA1, ABCG1mRNA and protein expression levels of the two groups at the16th week were determined respectively.
5. THP-1derived macrophages were cultured and treated by melatonin in vitro. The mechanism of melatonin in regulating ABCA1protein expression was evaluated using different signal pathway/receptor antagonists.
Results:
4. No differences of cholesterol efflux rates of peritoneal macrophages at the baseline were observed between the Px (N=6) and Con (N=6) groups. The differences of serum-induced cholesterol efflux rates (-7.29±5.91%vs.-3.80±4.79%, P<0.01) and ABCA1-induced cholesterol efflux rates (-4.21±4.82%vs.-1.20±2.12%, P<0.01) between0week and16th week in Px group were both significantly lowered, compared to those in Con group respectively. However, those differences of ABCG1-induced cholesterol efflux rates showed no significance between the two groups.
5. The ABCA1mRNA expression level of the peritoneal macrophages was significantly decreased in Px group (N=6) at16th week, compared to that in Con (N=6) group (P<0.001). However, the protein expression level of ABCA1showed no significant differences between the two groups.
6. Neither the mRNA expression level (N=6) nor the protein expression level of ABCG1on peritoneal macrophages showed significant differences between the two groups at the16th week.
7. Melatonin dose-dependently augmented ABCA1and LXRa expressions on the cultured THP-1derived macrophages (all P<0.05). The use of PPARy and LXRa antagonists both significantly attenuated melatonin-induced ABCA1expression. However, the use of melatonin membrane receptor antagonists showed no significant influences on melatonin-induced ABCA1expression on macrophages.
Conclusions:
Melatonin-deficiency rats were successfully created by pinealectomy. Melatonin deficiency initiates blood lipid and glucose-associated disorders, augments in vivo inflammatory state and the expression of aortic inflammatory cytokines in pinealectomized rats. Melatonin regulates these inflammatory cytokines expressions probably via NF-κB and P38-MAPK involved pathways. Melatonin deficiency inhibits the function of cholesterol efflux and ABCAl gene expression of peritoneal macrophage from pinealectomized rats. The PPARy-LXRa pathways were involved in the regulatory effect of melatonin on ABCA1protein expression, with a mechanism independent of melatonin membrane receptors.
褪黑素(melatonin)是一种主要在夜间由松果体合成分泌、受光线明暗及昼夜节律调控的吲哚类激素,研究发现其具有抗自由基和氧化应激、调节机体血脂和血糖代谢等多种心血管相关的生理药理学作用。体内褪黑素水平的下降与动脉粥样硬化性疾病的发生,以及机体的血脂、血糖代谢异常有显著的相关性。但机体血清褪黑素水平的改变与机体脂糖代谢异常是否存在因果关系有待进一步研究。血管内皮炎症在动脉粥样硬化等心血管疾病的发生发展中起着重要的作用。研究发现褪黑素与血管炎症反应和内皮功能之间存在一定的相关性。但褪黑素水平的降低是否可以导致血管炎症的发生,其对血管内皮细胞炎症因子表达的调控及其机制仍有待进一步研究。动脉粥样硬化病变的典型特征是巨噬细胞吞噬大量的脂质,导致泡沫细胞形成。巨噬细胞表面的三磷酸腺苷结合盒转运体A1(ABCA1)、三磷酸腺苷结合盒转运体G1(ABCG1)及其介导的胆固醇外流是细胞胆固醇逆转运的重要始动因素。研究证实,ABCA1介导细胞内胆固醇外流功能障碍能加速动脉粥样硬化的发生和发展,而ABCG1介导的胆固醇外流功能与ABCA1介导的胆固醇外流具有协同作用。褪黑素能否影响ABCA1和ABCG1的表达及其介导的巨噬细胞胆固醇外流功能,目前未见报道。我们通过建立大鼠去松果体致褪黑素缺乏的动物模型,分别对以上三部分进行研究：
第一部分去松果体致褪黑素缺乏大鼠模型的建立及血糖、血脂代谢特点分析
研究目的：
1.建立去松果体致褪黑素缺乏的大鼠动物模型；
2.观察在生理性褪黑素缺乏的环境下大鼠体内血脂、血糖代谢的特点；
研究方法：
1.10周龄雄性Wistar大鼠共36只,随机分为两组。通过松果体摘除手术建立大鼠去松果体致褪黑素缺乏的动物模型(Px组),并以假手术大鼠作为对照组(Con组),检测手术前后大鼠血清夜间褪黑素水平判断褪黑素缺乏模型是否成功；
2.在术前0周,术后4周、8周、16周四个时间点测量褪黑素缺乏大鼠在正常饮食条件下血脂、血糖相关代谢指标的水平,分析其随时间的动态变化特点；
3.测量术后16周大鼠肝脏脂质水平含量,分析其与血脂水平的关系；
研究结果：
1.去松果体组(Px组,N=16)动物夜间褪黑素水平减少至术前的20%,且显著低于假手术对照组(Con组,N=14)(8.19±2.05ng/L和39.98±5.91ng/L,P<0.01),褪黑素缺乏模型制作成功；
2.在术前0周和术后4周、8周、16周各组大鼠血脂血糖水平分别为：
1)血脂代谢指标：两组动物血脂基线水平一致。Px组大鼠血清TG、FFA和VLDL-C水平自术后4周时相比4周Con组大鼠均显著增高,并持续增高至16周(P值均<0.05)。在校正0周基线值后,Px组上述指标的16周相对0周变化值仍较Con组变化值显著增加(P值均<0.05)；
2)糖代谢方面,两组动物血糖和胰岛素水平的基线值水平一致。相比术后16周Con组,术后16周Px组大鼠的血糖水平显著增加(P<0.05),ISI指数的水平显著降低(P<0.05),但INS的的增高无显著意义。在校正了术前0周水平后,术后16周Px组上述阳性指标的变化值相比对照组变化值的差异仍有显著意义(P值均<0.05)；
3.Px组大鼠16周肝脏单位质量的甘油三酯含量相比16周Con组显著增加(P<0.01),但其单位质量的总胆固醇含量两组间比较无显著性差异。
第二部分去松果体致褪黑素缺乏大鼠主动脉内皮炎症因子表达的变化及机制
研究目的：
1.研究褪黑素缺乏环境下大鼠体内血清炎症因子水平的变化,观察其主动脉内皮细胞炎症因子表达的情况,
2.研究褪黑素对体外培养的大鼠主动脉内皮细胞炎症因子表达调控的作用及相关信号通路机制；
研究方法：
1.10周龄雄性Wistar大鼠,建立褪黑素缺乏的大鼠模型组(8只),以假手术组(7只)作为对照(见第一部分)；
2.分别测量褪黑素缺乏大鼠术前0周和术后16周时血清氧化应激和炎症标志物MDA、oxLDL、TNFα、IL-6和CRP的水平,检测大鼠主动脉内皮炎症因子MCP-1、ICAM-1、VCAM-1和MMP-9的表达情况；
3.体外培养大鼠主动脉内皮细胞系,用褪黑素干预oxLDL预刺激的内皮细胞,观察细胞炎症因子蛋白表达的变化,同时检测炎症相关信号通路NF-κB、 P38-MAPK、JNK和ERK磷酸化水平的表达,探讨褪黑素可能的作用机制；
研究结果：
1.两组动物血清炎症因子基线值水平基本一致。在术后16周,Px组N=8)大鼠血清MDA、oxLDL、TNFα、IL-6和CRP水平相比16周Con组(N=7)均显著增加(P值均<0.01)。在校正0周基线值后,Px组上述指标的16周相对0周变化值仍较Con组变化值显著增加(P值均<0.05)；
2.术后16周,Px组大鼠主动脉内皮MCP-1、VCAM-1和MMP-9因子表达水平的IOD值相比16周Con组对应值均显著增加(P值均<0.05)。而Px组大鼠16周ICAM-1表达相比Con组无显著统计学意义；
3.褪黑素剂量依赖性地显著抑制oxLDL诱导大鼠主动脉内皮细胞表面MCP-1、VCAM-1和MMP-9蛋白表达(P值均<0.05)；并剂量依赖性地显著抑制oxLDL诱导RAEC细胞内NF-κB和P38-MAPK通路蛋白磷酸化表达水平(P值均<0.05),但对JNK和ERK1/2蛋白磷酸化表达水平无显著影响。
第三部分去松果体致褪黑素缺乏大鼠腹腔巨噬细胞胆固醇外流的变化及机制
研究目的：
1.研究褪黑素缺乏大鼠腹腔巨噬细胞胆固醇外流功能的变化；
2.研究褪黑素缺乏大鼠腹腔巨噬细胞表面ABCA1和ABCG1的表达情况；
3.探讨褪黑素对巨噬细胞ABCA1表达的相关信号调控机制。
研究方法：
1.10周龄雄性Wistar大鼠,建立褪黑素缺乏的大鼠模型组(共16只),以假手术组(共16只)作为对照(见第一部分)；
2.分别收集培养大鼠术前0周和术后16周的腹腔巨噬细胞,检测褪黑素缺乏大鼠术前0周和术后16周的腹腔巨噬细胞ABCA1、ABCG1和全血清介导的胆固醇外流率,评估不同因素介导外流率的变化；
3.检测术后16周腹腔巨噬细胞ABCA1和ABCG1基因和蛋白表达的变化；
4.体外培养人单核细胞系(THP-1)并诱导分化为巨噬细胞,分别以不同浓度褪黑素干预细胞,观察其对细胞ABCA1表达的影响并探讨其作用的相关信号通路机制。
研究结果：
1.两组动物腹腔巨噬细胞胆固醇外流率基线值基本一致。Px组(N=6)术后16周的全血清诱导(-7.29±5.91%和-3.80±4.79%,P<0.01)以及ABCA1介导的胆固醇外流率相对0周的变化值(-4.21±4.82%和-1.20±2.12%,P<0.01)相比Con组(N=6)对应的变化值均显著下降,但ABCG1介导的胆固醇外流率的变化值在两组间无显著差异。
2.术后16周,Px组(N=6)的腹腔巨噬细胞ABCA1转运体mRNA水平的表达相比16周Con组(N=6)的表达显著下降(P<0.01),但其蛋白表达水平在两组间无显著统计学差异。
3.术后16周,ABCG1转运体mRNA和蛋白水平的表达在两组间均无显著统计学差异。
4.褪黑素剂量依赖性地显著增强THP-1巨噬细胞ABCA1和LXRa的mRNA水平和蛋白水平的表达(P值均<0.05)；PPARy和LXRa拮抗剂均可显著抑制褪黑素对细胞ABCA1蛋白表达的促进作用(P值均<0.001)；褪黑素膜受体MT1/MT2拮抗剂对于褪黑素对细胞ABCA1蛋白表达的调控均无显著影响。
研究结论
1.通过松果体摘除手术成功建立褪黑素缺乏的大鼠动物模型。
2.褪黑素缺乏可显著导致大鼠胰岛素抵抗的发生,影响大鼠血甘油三酯和血糖代谢。
3.褪黑素缺乏促进大鼠体内炎症反应过程,促进并可能通过NF-κB和P38-MAPK通路参与的机制调控大鼠主动脉内皮炎症因子的表达。
4.褪黑素缺乏抑制大鼠腹腔巨噬细胞胆固醇外流及ABCA1基因表达及其介导的胆固醇外流；褪黑素以不依赖于褪黑素膜受体的方式作用于巨噬细胞内的PPARy-LXRa途径,调控细胞ABCA1的表达水平。
Background:
Melatonin (Mel) is an indole-like hormone that synthesized and secreted by pineal gland, with a secretion rhythm controlled by the light-dark cycle (intensity of the light). Researches have found that Mel has a variety of cardiovascular relevant effects, such as the inhibition of oxidants and regulation of blood lipid and glucose metabolism. It has been reported that the decrease of Mel concentration is prominently related with the development of atherosclerotic diseases, and with the increase of the blood lipid and glucose-associated disorders. However, it is unclear whether the alternation of in vivo Mel concentration will lead to such dysmetabolisms. Endothelial inflammation participates in the development of cardiovascular diseases including atherosclerosis (As). Several publications presented a correlation between Mel and vascular inflammation and dysfunction. Nevertheless, mechanism of the effect of Mel on endothelial inflammation remains to be elucidated. Atherosclerotic lesions are typically infiltrated by macrophage-derived foam cells, in which cholesterol esters are overloaded. ATP-binding cassette transporter Al (ABCA1), which expressed on macrophages, plays critical roles in mediating the reverse cholesterol efflux to maintain intracellular cholesterol homeostasis. Studies indicated that the dysfunction of ABCA1mediated cholesterol efflux to apolipoprotein A1was closely associated with As. ATP-binding cassette transporter G1(ABCGl) mediated cholesterol efflux shown to be coordinated to ABCA1in removal of excessive cellular cholesterol, which also plays a role in the development of As. The mechanisms of Mel deficiency on regulating ABCA1and ABCG1expression and their mediated cholesterol efflux function, however, are still unknown. Therefore, we created melatonin-deficiency animal models and performed a study consist of three parts to answer those questions above.
Part I. Creation of Melatonin-Deficiency Rats and the Metabolic Characteristics of their Serum Lipid and Glucose Profiles
Objective:
1. To create melatonin-deficiency animal models in rats.
2. To analyse the metabolic characteristics of their serum lipid and glucose profiles in melatonin-deficiency rats.
Methods:
1. Thirty-six Wistar rats, male,10-week old were included. Melatonin-deficiency (Px) rats were created by pinealectomy. Nocturnal levels of melatonin before and after surgery were measured and compared with those levels in sham-operated (Con) rats to evaluate the success of surgery.
2. Serum lipid and glucose profiles in Px rats were measured at the0week (baseline), and the4th,8th,16th week after surgery respectively, and compared with those profiles in Con rats at each time-point.
3. The contents of total cholesterol and triglyceride in liver tissue were measured at the16th week after surgery respectively, and compared with those in Con rats.
Results:
1. Nocturnal serum level of melatonin in Px group (N=16) was significantly diminished after surgery, compared with that in Con group (N=14)(8.19±2.05ng/L vs.39.98±5.91ng/L, P<0.001, respectively), suggesting a melatonin deficiency state in pinealectomized rats.
2. Comparison of serum lipid and glucose metabolic profiles between Px and Con rats at the0week(baseline), and the4th,8th,16th week after surgery were listed below:
1. Lipid metabolic profile:No significant differences of serum lipid levels at the baseline were observed between the Px (N=16) and Con (N-14) groups. At the4th week after surgical operation, serum TG, VLDL-C and FFA in Px group were all significantly increased compared to those in Con group at4th week(all P<0.05), and continued to be elevated until the16th week (all P<0.05). The changes of serum TG, VLDL-C and FFA levels from baseline at the16th week in Px group were all significantly higher than those in control group (all P<0.05for the between-group comparison).
2. Glucose metabolic profile:No significant differences of serum glucose-relevant parameters at the baseline were observed between the Px (N=8) and Con (N=7) groups. The serum glucose level at the16th week was significantly elevated, with the significant decrease of ISI index in Px group, compared with that in Con group (P<0.05). However, the INS level in Px group had no significant difference from that in Con group. The changes of serum glucose levels, INS and ISI from baseline at the16th week in Px group were all significantly higher than those in Con group (all P<0.05for the between-group comparison).
3. The average content of triglyceride in the liver tissue of the Px group at16th week was significantly higher than that in Con group (P<0.01). However, The average content of total cholesterol in the liver tissue in Px group had no significant difference from that in Con group.
Part II. Changes of Inflammatory Cytokines in Pinealectomized Melatonin-Deficiency Rats and the Underlying Mechanisms
Objective:
1. To investigate the effect of melatonin on in-vivo inflammation and expression of aortic inflammatory cytokines in melatonin-deficiency rats.
2. To study the possible mechanisms of melatonin in regulating the expression of inflammatory cytokines on endothelial cells.
Methods:
1. Wistar rats, male,10-week old were included. Eight melatonin-deficiency (Px) rats were created and compared with seven sham-operated (Con) rats (See Part I).
2. Serum oxidative stress and inflammatory biomarkers MDA, oxLDL, TNF-a, IL-6and CRP in Px rats were measured at the0week and16th week after surgery respectively, and compared with those levels in Con rats. IHC stain of the aorta in each group was performed and quantified to analyse the expression of inflammatory cytokines MCP-1, ICAM-1、VCAM-1and MMP-9in endothelium.
3. Rat aortic endothelial cell lines (RAECs) were pre-incubated with oxLDL and treated by melatonin in vitro. The protein expression of inflammatory cytokines and phosphorylation levels of relevant signal pathways including NFκB, P38-MAPK, ERK and JNK were determined.
Results:
1. Serum levels of MDA, oxLDL, TNF-α, IL-6and CRP in Px group (N=8) at the16th week were all significantly increased, compared with those in Con group (N=7) respectively (all P<0.01). The change from baseline at the16th week for each above-mentioned parameter in Px group was significantly higher than that in Con group (all P<0.05for the between-group comparison).
2. The IOD values of MCP-1, VCAM-1and MMP-9in Px group (N=8) were all significantly elevated compared to those in Con group (N=7)(all P<0.05). However, ICAM-1expression was not significantly changed compared to that in Con group.
3. Melatonin dose-dependently attenuated oxLDL-induced MCP-1, VCAM-1and MMP-9expressions on RAECs (all P<0.05). It also dose-dependently decreased NFκB and P38-MAPK protein phosphorylation levels (all P<0.05), but the phosphorylation levels of ERK1/2and JNK were not affected significantly by melatonin.
Part Ⅲ. Alternations of Cholesterol Efflux of Peritoneal Macrophages in Pinealectomized Melatonin-Deficiency Rats and the Underlying Mechanisms
Objective:
1. To investigate the function of intercellular cholesterol efflux in macrophages from melatonin-deficiency rats.
2. To study the expressions of ABCA1and ABCG1on macrophages from melatonin-deficiency rats.
3. To study the mechanisms of melatonin in regulating the expression of ABCA1on macrophages.
Methods:
1. Wistar rats, male,10-week old were included. Sixteen melatonin-deficiency (Px) rats were created and compared with sixteen sham-operated (Con) rats (See Part Ⅰ).
2. Peritoneal macrophages were collected from Px and Con rats at0week and16th week respectively, and cultured in vitro.
3. Their macrophage cholesterol efflux rates of Px and Con groups at0week and16th week were measured respectively.
4. Their ABCA1, ABCG1mRNA and protein expression levels of the two groups at the16th week were determined respectively.
5. THP-1derived macrophages were cultured and treated by melatonin in vitro. The mechanism of melatonin in regulating ABCA1protein expression was evaluated using different signal pathway/receptor antagonists.
Results:
4. No differences of cholesterol efflux rates of peritoneal macrophages at the baseline were observed between the Px (N=6) and Con (N=6) groups. The differences of serum-induced cholesterol efflux rates (-7.29±5.91%vs.-3.80±4.79%, P<0.01) and ABCA1-induced cholesterol efflux rates (-4.21±4.82%vs.-1.20±2.12%, P<0.01) between0week and16th week in Px group were both significantly lowered, compared to those in Con group respectively. However, those differences of ABCG1-induced cholesterol efflux rates showed no significance between the two groups.
5. The ABCA1mRNA expression level of the peritoneal macrophages was significantly decreased in Px group (N=6) at16th week, compared to that in Con (N=6) group (P<0.001). However, the protein expression level of ABCA1showed no significant differences between the two groups.
6. Neither the mRNA expression level (N=6) nor the protein expression level of ABCG1on peritoneal macrophages showed significant differences between the two groups at the16th week.
7. Melatonin dose-dependently augmented ABCA1and LXRa expressions on the cultured THP-1derived macrophages (all P<0.05). The use of PPARy and LXRa antagonists both significantly attenuated melatonin-induced ABCA1expression. However, the use of melatonin membrane receptor antagonists showed no significant influences on melatonin-induced ABCA1expression on macrophages.
Conclusions:
Melatonin-deficiency rats were successfully created by pinealectomy. Melatonin deficiency initiates blood lipid and glucose-associated disorders, augments in vivo inflammatory state and the expression of aortic inflammatory cytokines in pinealectomized rats. Melatonin regulates these inflammatory cytokines expressions probably via NF-κB and P38-MAPK involved pathways. Melatonin deficiency inhibits the function of cholesterol efflux and ABCAl gene expression of peritoneal macrophage from pinealectomized rats. The PPARy-LXRa pathways were involved in the regulatory effect of melatonin on ABCA1protein expression, with a mechanism independent of melatonin membrane receptors.
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