IETM在动脉粥样硬化及心脏病发生发展中的作用及机制探讨
发布时间：2018-08-13 09:04
【摘要】：第一部分高糖高脂饮食诱导IETM在代谢综合征相关AS发生发展中的作用及机制探讨 目的：探讨高糖高脂饮食诱发肠源性内毒素血症(IETM)在代谢综合征相关的AS发生、发展中的作用及机制。研究血浆中持续高表达的LPS触发代谢综合征相关的AS发生、发展的作用机制,为防治代谢综合征相关的AS寻求新思路及新途径。 方法：1、64只SD大鼠随机分为对照组(normal group; NC)和模型组(model group; MG),每组各32只；每组再随机分3月、6月、9月、12月4个时段进行观察,每时段8只。对照组喂饲基础饲料,模型组喂饲高糖高脂饲料。 2、放免法及酶联免疫吸附实验测定大鼠外周血内毒素(LPS)、肿瘤坏死因子(TNFα)、C反应蛋白(CRP)、巨噬细胞趋化蛋白-1(MCP-1)及一氧化氮(NO)、内皮素-1(ET-1)、PAI-1的水平。 3、酶联免疫吸附试验测定外周血丙氨酸氨基转移酶(ALT)、游离脂肪酸(FFA)、甘油三酯(TG)、总胆固醇(Tch)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血糖(FPG)、空腹胰岛素(FINS)的水平,并计算胰岛素抵抗指数(HOMA-IR)。 4、摘取主动脉及肝左叶,病理组织学观察主动脉壁粥样斑块的形成及肝脏组织炎症、脂变、纤维化病变。 5、免疫组化法检测CD68阳性的单核／巨噬细胞在动脉壁的浸润情况；检测动脉壁iNOS和NF一κB的表达；检测Tunnel在动脉壁的表达分析细胞凋亡情况。 6、苏月IV(Sudan IV)特殊染色法观察动脉壁及肝细胞的脂质异位沉积。 结果：1、模型组各时段大鼠外周血LPS及炎症相关因子TNF-a、CRP、MCP-1的表达水平明显高于对照组,差异有统计学意义(P0.05)；血管活性因子ET-1、PAI-1的表达水平明显高于对照组,而NO的表达水平低于对照组,差异有显著性(P0.05)。 2、模型组各时段大鼠外周血中ALT、FFA、TG、Tch、LDL的表达水平明显高于对照组,而HDL的水平明显低于对照组,差异有统计学意义(P0.05)；模型组FPG、FINS的表达水平明显高于对照组,胰岛素抵抗指数HOMA-IR的数值显著高于对照组,差异有显著性(P0.05)。 3、主动脉病理组织学：对照组各时段主动脉壁未见明显异常病变；模型组第3月主动脉内皮增生；6月内皮增生进一步加重,内膜明显增厚,内皮下脂质呈条带状沉积；中膜平滑肌细胞增生及弹力纤维紊乱；内膜／中膜比值增大；9月组动脉壁内膜进一步增厚,脂质沉积进一步增多,而中膜开始出现萎缩,内膜／中膜比值进一步增大；粥样斑块形成,其内出现了小灶钙化；12月组内膜/中膜比值保持高水平,差异有统计学意义(P0.05),显示动脉壁钙化明显加重。 4、主动脉单核/巨噬细胞的浸润：对照组动脉壁未见明显单核/巨噬细胞粘附及浸润；模型组第3月主动脉内皮表面粘附个别单核/巨噬细胞,6月组内皮下可见单核/巨噬细胞浸润；9月及12月单核/巨噬细胞在内皮下浸润进一步增多,且主要集中在粥样斑块中,差异有统计学意义(P0.05)。 5、主动脉iNOS的表达：对照组动脉壁内皮细胞及平滑肌细胞iNOS散在少许细胞弱阳性表达。模型组大鼠动脉壁内皮细胞及平滑肌细胞表达iNOS随观察时间的延长阳性表达细胞逐渐增多,强度逐渐增强,各时段间的表达差异有统计学意义(P0.05)。 6、主动脉NF-κB的表达：对照组动脉壁内皮细胞和平滑肌细胞NF-κB的阳性表达呈均匀一致的胞浆弱阳性表达,核无阳性表达；模型组动脉壁内皮细胞和平滑肌细胞出现了核阳性表达,随着观察时间的延长,核阳性表达逐渐增多,胞浆阳性变得不均匀,阳性部位多聚集于核附近,模型组各时段核阳性表达有统计学差异(P0.05)。 7、主动脉Tunel的表达：Tunel检测显示对照组动脉壁内皮细胞和平滑肌细胞仅个别细胞核阳性表达；模型组3月组即可看到动脉壁内皮细胞和平滑肌细胞明显阳性表达；6月组核阳性表达增多；9月组和12月组动脉壁内皮细胞和平滑肌细胞呈弥漫核阳性表达,差异有显著性(P0.05)。 8、肝脏的病理组织学观察：对照组肝细胞未出现明显病变,仅在汇管区见散在个别炎症细胞浸润；模型组从第3个月始大鼠先后发生了脂肪肝、脂肪性肝炎,第6个月出现纤维化,第12个月发展为早期肝硬化。 结论：1、高糖高脂饮食诱导大鼠发生了IETM,血浆中LPS持续高表达。 2、肝脏单核/巨噬细胞被LPS激活,使肝脏发生IR及NAFLD,糖代谢、脂代谢发生紊乱,出现代谢综合征症候群。 3、代谢综合征时,增多的脂质异位沉积到动脉壁,使动脉发生IR； 4、持续慢性炎症、IR及脂质异位沉积损伤了内皮细胞、平滑肌细胞功能,最终导致AS的发生发展。 5、高糖高脂饮食促使IETM发生,血浆高表达的LPS触发了代谢综合征相关的AS的发生及发展。 第二部分高糖高脂饮食诱导IETM在代谢综合征相关的心肌损伤中的作用和机制研究 目的：探讨高糖高脂饮食诱发IETM在代谢综合征相关的心肌损伤发生、发展中的作用和机制,分析血浆中持续高表达的LPS损伤心肌功能的作用机制,为预防代谢综合征相关的心肌损伤提供新思路。 方法：1、动物分组：同第一部分。 2、血清学检测：同第一部分。 3、摘取心肌组织进行病理组织学观察,观察心肌细胞变性、凋亡及纤维化的发生情况。 4、免疫组化法检测CD68阳性的单核／巨噬细胞在心肌中的浸润；检测心肌细胞iNOS和NF-kB的表达；Tunnel检测心肌细胞的凋亡情况。 5、苏丹Ⅳ (Sudan Ⅳ)特殊染色观察心肌中的脂质异位沉积情况。 结果：1、模型组大鼠血清学检测结果：同第一部分。 2、心肌病理组织学观察：对照组大鼠心肌细胞排列整齐、规则,心肌细胞大小、直径正常,未见变性发生,无明显炎症细胞浸润；模型组大鼠3月时段心肌细胞排列尚整齐规则,部分心肌细胞体积增大,心肌纤维间可见散在炎症细胞浸润；6月时段大部分心肌细胞直径增大,炎症细胞浸润明显；9月心肌出现了小灶状坏死,12月组坏死呈多灶状,纤维组织增生,炎症细胞浸润。 3、心肌内脂质异位沉积：心肌内及心肌肌束间于模型组第3月组即可见小点灶状脂质沉积,第6个月脂质沉积增多,第9-12月明显加重,呈斑片状,差异有统计学意义(P0.05)。 4、心肌细胞凋亡：对照组心肌细胞很少发生凋亡；模型组第3月时段散在心肌细胞发生凋亡,6月时段凋亡较明显,9-12月组大部分心肌细胞显示凋亡,差异有显著性(P0.05)。 结论：1、高糖高脂饮食下大鼠发生了IETM及代谢综合征相关的心肌损伤. 2、血浆中LPS持续高表达,激活体内单核／巨噬细胞系统,诱导心肌发生炎症、IR及脂质异位沉积,最终导致心肌细胞凋亡,损伤心肌功能。 3、高糖高脂饮食促使IETM发生,进而诱导了代谢综合征相关的心肌损伤。 第三部分内质网应激在心血管疾病发生发展中的机制研究 目的：探讨内质网应激在代谢相关的AS及心肌损伤发生发展中的机制 方法：1、动物分组：同第一部分 2、血清学检测：同第一部分 3、摘取主动脉及心脏,原位杂交检测CHOP mRNA及Grp78mRNA在动脉壁和心肌中的表达 结果：1、对照组动脉壁内皮细胞、平滑肌细胞及心肌细胞Grp78mRNA为阴性表达或仅少部分弱阳性表达,模型组动脉壁及心肌细胞浆Grp78mRNA阳性表达,且随着观察时间的延长,表达逐渐增强,差异有显著性意义(P0.05)。 2、对照组动脉壁内皮细胞和平滑肌细胞及心肌细胞CHOP mRNA阴性表达,模型组动脉壁及心肌细胞浆CHOP mRNA表达阳性,随鼠龄增大及观察时段延长,CHOP mRNA表达逐渐增强,差异有显著性意义(P0.05)。 结论：1、模型组动脉壁和心肌中CHOP mRNA及Grp78mRNA的表达显著增强,且与病变程度相关。 2、内质网应激在代谢相关的AS及心肌损伤发生发展机制中具有重要作用。
[Abstract]:Part I The role and mechanism of IETM induced by high-sugar and high-fat diet in the development of metabolic syndrome-related AS
Objective: To investigate the role and mechanism of intestinal endotoxemia (IETM) induced by high-glucose and high-fat diet in the occurrence and development of metabolic syndrome-related AS.
Methods: 1,64 SD rats were randomly divided into control group (NC) and model group (MG), 32 rats in each group; each group was randomly divided into 3 months, 6 months, 9 months and 12 months for observation, 8 rats in each period.
2. The levels of LPS, TNF-a, CRP, MCP-1, NO, ET-1 and PAI-1 in peripheral blood of rats were determined by radioimmunoassay and enzyme-linked immunosorbent assay.
3. The levels of alanine aminotransferase (ALT), free fatty acid (FFA), triglyceride (TG), total cholesterol (Tch), high density lipoprotein (HDL), low density lipoprotein (LDL), blood glucose (FPG), fasting insulin (FINS) in peripheral blood were measured by enzyme-linked immunosorbent assay, and the insulin resistance index (HOMA-IR) was calculated.
4. The aorta and the left lobe of the liver were taken out to observe the formation of atherosclerotic plaque in the aorta wall and the inflammation, fatty degeneration and fibrosis of the liver.
5. Immunohistochemistry was used to detect the infiltration of CD68-positive monocytes and macrophages in the arterial wall, the expression of iNOS and NF-kappa B in the arterial wall, and the expression of Tunnel in the arterial wall to analyze the apoptosis.
6, SuYue IV (Sudan IV) special staining method was used to observe the abnormal deposition of lipid in arterial walls and hepatocytes.
Results: 1. The expression levels of LPS and inflammatory related factors TNF-a, CRP, MCP-1 in peripheral blood of model group were significantly higher than those of control group (P 0.05); the expression levels of vascular active factors ET-1 and PAI-1 were significantly higher than those of control group, but the expression level of NO was significantly lower than that of control group (P 0.05).
2. The expression levels of ALT, FFA, TG, Tch and LDL in peripheral blood of model group were significantly higher than those of control group, while the level of HDL was significantly lower than that of control group (P 0.05); the expression levels of FPG and FINS in model group were significantly higher than those of control group, and the insulin resistance index HOMA-IR was significantly higher than that of control group (P 0.05). 05).
3. Histopathology of aorta: There were no obvious abnormal changes in aortic wall in the control group; endothelial hyperplasia in the model group was further aggravated in March; endothelial hyperplasia was further aggravated in June with obvious thickening of endothelium and subendothelial lipid banded deposition; smooth muscle cell proliferation and elastic fiber disorder in the media; the ratio of intima to media increased in September; In group A, the intima of artery wall was further thickened and the lipid deposition was further increased, while the intima-media ratio was further enlarged when the intima-media ratio began to atrophy; the formation of atherosclerotic plaque was accompanied by small calcification; and the intima-media ratio remained high in group B in December (P 0.05).
4. Infiltration of mononuclear/macrophage in aorta: there was no obvious adhesion and infiltration of mononuclear/macrophage in the control group; a few mononuclear/macrophages adhered to the endothelial surface of aorta in the 3rd month of the model group; mononuclear/macrophage infiltration was observed in the subendothelium in the 6th month group; the infiltration of mononuclear/macrophage was further increased in September and December, and the infiltration of mononuclear/macrophage was also increased in the main endothelium. To focus on atheromatous plaque, the difference was statistically significant (P0.05).
5. Expression of iNOS in aorta: The expression of iNOS in endothelial cells and smooth muscle cells of control group was weakly positive. The expression of iNOS in endothelial cells and smooth muscle cells of model group increased gradually with the prolongation of observation time, and the intensity of iNOS increased gradually. The expression of iNOS was statistically significant between different periods (P 0. .05).
6. Expression of NF-kappa B in aorta: In control group, the expression of NF-kappa B in endothelial cells and smooth muscle cells was uniformly weak positive in cytoplasm, but not in nucleus; in model group, the expression of NF-kappa B in endothelial cells and smooth muscle cells was positive in nucleus. With the prolongation of observation time, the expression of NF-kappa B increased gradually and the expression of cytoplasm was positive. The changes were not uniform, and the positive sites were mostly clustered near the nucleus. The positive expression of nucleus in the model group was significantly different (P 0.05).
7. Expression of Tunel in aorta: Tunel assay showed that only a few nuclei were positive in endothelial cells and smooth muscle cells of the control group; obvious positive expression of endothelial cells and smooth muscle cells could be seen in the model group in 3 months; increased expression of nuclear in 6 months; increased expression of endothelial cells and smooth muscle cells in 9 months and 12 months groups. The cells showed positive expression in diffuse nucleus, and the difference was significant (P0.05).
8. Histopathological observation of the liver: There were no obvious pathological changes in the control group, only scattered inflammatory cells infiltration in the portal area; the model group had fatty liver, steatohepatitis, fibrosis in the 6th month and early cirrhosis in the 12th month.
Conclusion: 1. High glucose and high-fat diet induced IETM in rats, and LPS in plasma was highly expressed.
2. Liver monocytes/macrophages are activated by LPS, resulting in IR and NAFLD in the liver, glucose metabolism, lipid metabolism disorders, metabolic syndrome.
3, when metabolic syndrome occurs, more lipid is deposited on the arterial wall, causing IR to occur.
4. Persistent chronic inflammation, IR and lipid ectopic deposition damage the function of endothelial cells and smooth muscle cells, eventually leading to the occurrence and development of AS.
5. High glucose and high fat diet induce IETM, and high expression of LPS in plasma triggers the occurrence and development of metabolic syndrome-related AS.
Part 2 The role and mechanism of IETM induced by high glucose and high fat diet in myocardial injury associated with metabolic syndrome
AIM: To investigate the role and mechanism of IETM induced by high-glucose and high-fat diet in the occurrence and development of myocardial injury associated with metabolic syndrome, and to analyze the mechanism of myocardial injury induced by persistently high-expression of LPS in plasma.
Methods: 1. Animal grouping: same as the first part.
2, serological detection: same as the first part.
3. Myocardial tissue was taken out for histopathological observation to observe the occurrence of myocardial degeneration, apoptosis and fibrosis.
4. Immunohistochemistry was used to detect the infiltration of CD68-positive monocytes and macrophages in myocardium, the expression of iNOS and NF-kB in myocardium, and the apoptosis of myocardium was detected by Tunnel.
5, Sultan IV (Sudan IV) was specially stained to observe the abnormal deposition of lipids in the myocardium.
Results: 1. The serological test results of the model group were same as that of the first part.
2. Myocardial histopathological observation: In the control group, the myocardial cells were arranged regularly, the size and diameter of myocardial cells were normal, no degeneration and no obvious infiltration of inflammatory cells were observed. Most of the myocardial cells were enlarged and infiltrated with inflammatory cells in month 1. Small focal necrosis appeared in September, and multiple focal necrosis appeared in December group.
3. Intramuscular lipid heterotopic deposition: Small focal lipid deposition was observed in the myocardium and between myocardial fascicles in the model group at the 3rd month, increased in the 6th month, and aggravated significantly from the 9th to the 12th month, showing patchy, the difference was statistically significant (P 0.05).
4. Cardiomyocyte apoptosis: In the control group, there was little apoptosis; in the model group, apoptosis occurred in myocardial cells scattered in the 3rd month, and was more obvious in the 6th month. Most of the myocardial cells in the September-December group showed apoptosis, the difference was significant (P 0.05).
CONCLUSION: 1. IETM and metabolic syndrome-related myocardial injury occurred in rats fed with high-glucose and high-fat diet.
2. The high expression of LPS in plasma activates the monocyte/macrophage system in vivo, induces inflammation, IR and heterotopic deposition of lipids in myocardium, eventually leads to cardiomyocyte apoptosis and damages myocardial function.
3, high glucose and high-fat diet promotes IETM and induces metabolic syndrome related myocardial damage.
The third part is the mechanism of endoplasmic reticulum stress in the development of cardiovascular diseases.
Objective: To explore the mechanism of endoplasmic reticulum stress in metabolism related AS and myocardial injury.
Methods: 1. Animal grouping: same as the first part.
2, serological testing: same as the first part.
3. The expression of CHOP mRNA and Grp78 mRNA in arterial wall and myocardium was detected by in situ hybridization.
Results: 1. The expression of Grp78 mRNA in endothelial cells, smooth muscle cells and cardiomyocytes of control group was negative or only a few of them were weakly positive. The expression of Grp78 mRNA in arterial wall and cardiomyocytes of model group was positive, and increased gradually with the observation time, the difference was significant (P 0.05).
2. The expression of CHOP mRNA in endothelial cells and smooth muscle cells and cardiomyocytes was negative in control group. The expression of CHOP mRNA in arterial wall and cardiomyocytes was positive in model group. The expression of CHOP mRNA increased gradually with the age of rats and the prolongation of observation period. The difference was significant (P 0.05).
CONCLUSION: 1. The expression of CHOP mRNA and Grp78 mRNA in the arterial wall and myocardium of the model group was significantly increased, and correlated with the degree of pathological changes.
2. Endoplasmic reticulum stress plays an important role in the pathogenesis of metabolic AS and myocardial injury.
【学位授予单位】：山西医科大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R363
本文编号：2180516
[Abstract]:Part I The role and mechanism of IETM induced by high-sugar and high-fat diet in the development of metabolic syndrome-related AS
Objective: To investigate the role and mechanism of intestinal endotoxemia (IETM) induced by high-glucose and high-fat diet in the occurrence and development of metabolic syndrome-related AS.
Methods: 1,64 SD rats were randomly divided into control group (NC) and model group (MG), 32 rats in each group; each group was randomly divided into 3 months, 6 months, 9 months and 12 months for observation, 8 rats in each period.
2. The levels of LPS, TNF-a, CRP, MCP-1, NO, ET-1 and PAI-1 in peripheral blood of rats were determined by radioimmunoassay and enzyme-linked immunosorbent assay.
3. The levels of alanine aminotransferase (ALT), free fatty acid (FFA), triglyceride (TG), total cholesterol (Tch), high density lipoprotein (HDL), low density lipoprotein (LDL), blood glucose (FPG), fasting insulin (FINS) in peripheral blood were measured by enzyme-linked immunosorbent assay, and the insulin resistance index (HOMA-IR) was calculated.
4. The aorta and the left lobe of the liver were taken out to observe the formation of atherosclerotic plaque in the aorta wall and the inflammation, fatty degeneration and fibrosis of the liver.
5. Immunohistochemistry was used to detect the infiltration of CD68-positive monocytes and macrophages in the arterial wall, the expression of iNOS and NF-kappa B in the arterial wall, and the expression of Tunnel in the arterial wall to analyze the apoptosis.
6, SuYue IV (Sudan IV) special staining method was used to observe the abnormal deposition of lipid in arterial walls and hepatocytes.
Results: 1. The expression levels of LPS and inflammatory related factors TNF-a, CRP, MCP-1 in peripheral blood of model group were significantly higher than those of control group (P 0.05); the expression levels of vascular active factors ET-1 and PAI-1 were significantly higher than those of control group, but the expression level of NO was significantly lower than that of control group (P 0.05).
2. The expression levels of ALT, FFA, TG, Tch and LDL in peripheral blood of model group were significantly higher than those of control group, while the level of HDL was significantly lower than that of control group (P 0.05); the expression levels of FPG and FINS in model group were significantly higher than those of control group, and the insulin resistance index HOMA-IR was significantly higher than that of control group (P 0.05). 05).
3. Histopathology of aorta: There were no obvious abnormal changes in aortic wall in the control group; endothelial hyperplasia in the model group was further aggravated in March; endothelial hyperplasia was further aggravated in June with obvious thickening of endothelium and subendothelial lipid banded deposition; smooth muscle cell proliferation and elastic fiber disorder in the media; the ratio of intima to media increased in September; In group A, the intima of artery wall was further thickened and the lipid deposition was further increased, while the intima-media ratio was further enlarged when the intima-media ratio began to atrophy; the formation of atherosclerotic plaque was accompanied by small calcification; and the intima-media ratio remained high in group B in December (P 0.05).
4. Infiltration of mononuclear/macrophage in aorta: there was no obvious adhesion and infiltration of mononuclear/macrophage in the control group; a few mononuclear/macrophages adhered to the endothelial surface of aorta in the 3rd month of the model group; mononuclear/macrophage infiltration was observed in the subendothelium in the 6th month group; the infiltration of mononuclear/macrophage was further increased in September and December, and the infiltration of mononuclear/macrophage was also increased in the main endothelium. To focus on atheromatous plaque, the difference was statistically significant (P0.05).
5. Expression of iNOS in aorta: The expression of iNOS in endothelial cells and smooth muscle cells of control group was weakly positive. The expression of iNOS in endothelial cells and smooth muscle cells of model group increased gradually with the prolongation of observation time, and the intensity of iNOS increased gradually. The expression of iNOS was statistically significant between different periods (P 0. .05).
6. Expression of NF-kappa B in aorta: In control group, the expression of NF-kappa B in endothelial cells and smooth muscle cells was uniformly weak positive in cytoplasm, but not in nucleus; in model group, the expression of NF-kappa B in endothelial cells and smooth muscle cells was positive in nucleus. With the prolongation of observation time, the expression of NF-kappa B increased gradually and the expression of cytoplasm was positive. The changes were not uniform, and the positive sites were mostly clustered near the nucleus. The positive expression of nucleus in the model group was significantly different (P 0.05).
7. Expression of Tunel in aorta: Tunel assay showed that only a few nuclei were positive in endothelial cells and smooth muscle cells of the control group; obvious positive expression of endothelial cells and smooth muscle cells could be seen in the model group in 3 months; increased expression of nuclear in 6 months; increased expression of endothelial cells and smooth muscle cells in 9 months and 12 months groups. The cells showed positive expression in diffuse nucleus, and the difference was significant (P0.05).
8. Histopathological observation of the liver: There were no obvious pathological changes in the control group, only scattered inflammatory cells infiltration in the portal area; the model group had fatty liver, steatohepatitis, fibrosis in the 6th month and early cirrhosis in the 12th month.
Conclusion: 1. High glucose and high-fat diet induced IETM in rats, and LPS in plasma was highly expressed.
2. Liver monocytes/macrophages are activated by LPS, resulting in IR and NAFLD in the liver, glucose metabolism, lipid metabolism disorders, metabolic syndrome.
3, when metabolic syndrome occurs, more lipid is deposited on the arterial wall, causing IR to occur.
4. Persistent chronic inflammation, IR and lipid ectopic deposition damage the function of endothelial cells and smooth muscle cells, eventually leading to the occurrence and development of AS.
5. High glucose and high fat diet induce IETM, and high expression of LPS in plasma triggers the occurrence and development of metabolic syndrome-related AS.
Part 2 The role and mechanism of IETM induced by high glucose and high fat diet in myocardial injury associated with metabolic syndrome
AIM: To investigate the role and mechanism of IETM induced by high-glucose and high-fat diet in the occurrence and development of myocardial injury associated with metabolic syndrome, and to analyze the mechanism of myocardial injury induced by persistently high-expression of LPS in plasma.
Methods: 1. Animal grouping: same as the first part.
2, serological detection: same as the first part.
3. Myocardial tissue was taken out for histopathological observation to observe the occurrence of myocardial degeneration, apoptosis and fibrosis.
4. Immunohistochemistry was used to detect the infiltration of CD68-positive monocytes and macrophages in myocardium, the expression of iNOS and NF-kB in myocardium, and the apoptosis of myocardium was detected by Tunnel.
5, Sultan IV (Sudan IV) was specially stained to observe the abnormal deposition of lipids in the myocardium.
Results: 1. The serological test results of the model group were same as that of the first part.
2. Myocardial histopathological observation: In the control group, the myocardial cells were arranged regularly, the size and diameter of myocardial cells were normal, no degeneration and no obvious infiltration of inflammatory cells were observed. Most of the myocardial cells were enlarged and infiltrated with inflammatory cells in month 1. Small focal necrosis appeared in September, and multiple focal necrosis appeared in December group.
3. Intramuscular lipid heterotopic deposition: Small focal lipid deposition was observed in the myocardium and between myocardial fascicles in the model group at the 3rd month, increased in the 6th month, and aggravated significantly from the 9th to the 12th month, showing patchy, the difference was statistically significant (P 0.05).
4. Cardiomyocyte apoptosis: In the control group, there was little apoptosis; in the model group, apoptosis occurred in myocardial cells scattered in the 3rd month, and was more obvious in the 6th month. Most of the myocardial cells in the September-December group showed apoptosis, the difference was significant (P 0.05).
CONCLUSION: 1. IETM and metabolic syndrome-related myocardial injury occurred in rats fed with high-glucose and high-fat diet.
2. The high expression of LPS in plasma activates the monocyte/macrophage system in vivo, induces inflammation, IR and heterotopic deposition of lipids in myocardium, eventually leads to cardiomyocyte apoptosis and damages myocardial function.
3, high glucose and high-fat diet promotes IETM and induces metabolic syndrome related myocardial damage.
The third part is the mechanism of endoplasmic reticulum stress in the development of cardiovascular diseases.
Objective: To explore the mechanism of endoplasmic reticulum stress in metabolism related AS and myocardial injury.
Methods: 1. Animal grouping: same as the first part.
2, serological testing: same as the first part.
3. The expression of CHOP mRNA and Grp78 mRNA in arterial wall and myocardium was detected by in situ hybridization.
Results: 1. The expression of Grp78 mRNA in endothelial cells, smooth muscle cells and cardiomyocytes of control group was negative or only a few of them were weakly positive. The expression of Grp78 mRNA in arterial wall and cardiomyocytes of model group was positive, and increased gradually with the observation time, the difference was significant (P 0.05).
2. The expression of CHOP mRNA in endothelial cells and smooth muscle cells and cardiomyocytes was negative in control group. The expression of CHOP mRNA in arterial wall and cardiomyocytes was positive in model group. The expression of CHOP mRNA increased gradually with the age of rats and the prolongation of observation period. The difference was significant (P 0.05).
CONCLUSION: 1. The expression of CHOP mRNA and Grp78 mRNA in the arterial wall and myocardium of the model group was significantly increased, and correlated with the degree of pathological changes.
2. Endoplasmic reticulum stress plays an important role in the pathogenesis of metabolic AS and myocardial injury.
【学位授予单位】：山西医科大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R363
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