發(fā)布時(shí)間：2018-08-13 09:04

【摘要】：第一部分高糖高脂飲食誘導(dǎo)IETM在代謝綜合征相關(guān)AS發(fā)生發(fā)展中的作用及機(jī)制探討 目的：探討高糖高脂飲食誘發(fā)腸源性?xún)?nèi)毒素血癥(IETM)在代謝綜合征相關(guān)的AS發(fā)生、發(fā)展中的作用及機(jī)制。研究血漿中持續(xù)高表達(dá)的LPS觸發(fā)代謝綜合征相關(guān)的AS發(fā)生、發(fā)展的作用機(jī)制,為防治代謝綜合征相關(guān)的AS尋求新思路及新途徑。 方法：1、64只SD大鼠隨機(jī)分為對(duì)照組(normal group; NC)和模型組(model group; MG),每組各32只；每組再隨機(jī)分3月、6月、9月、12月4個(gè)時(shí)段進(jìn)行觀察,每時(shí)段8只。對(duì)照組喂飼基礎(chǔ)飼料,模型組喂飼高糖高脂飼料。 2、放免法及酶聯(lián)免疫吸附實(shí)驗(yàn)測(cè)定大鼠外周血內(nèi)毒素(LPS)、腫瘤壞死因子(TNFα)、C反應(yīng)蛋白(CRP)、巨噬細(xì)胞趨化蛋白-1(MCP-1)及一氧化氮(NO)、內(nèi)皮素-1(ET-1)、PAI-1的水平。 3、酶聯(lián)免疫吸附試驗(yàn)測(cè)定外周血丙氨酸氨基轉(zhuǎn)移酶(ALT)、游離脂肪酸(FFA)、甘油三酯(TG)、總膽固醇(Tch)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血糖(FPG)、空腹胰島素(FINS)的水平,并計(jì)算胰島素抵抗指數(shù)(HOMA-IR)。 4、摘取主動(dòng)脈及肝左葉,病理組織學(xué)觀察主動(dòng)脈壁粥樣斑塊的形成及肝臟組織炎癥、脂變、纖維化病變。 5、免疫組化法檢測(cè)CD68陽(yáng)性的單核／巨噬細(xì)胞在動(dòng)脈壁的浸潤(rùn)情況；檢測(cè)動(dòng)脈壁iNOS和NF一κB的表達(dá)；檢測(cè)Tunnel在動(dòng)脈壁的表達(dá)分析細(xì)胞凋亡情況。 6、蘇月IV(Sudan IV)特殊染色法觀察動(dòng)脈壁及肝細(xì)胞的脂質(zhì)異位沉積。 結(jié)果：1、模型組各時(shí)段大鼠外周血LPS及炎癥相關(guān)因子TNF-a、CRP、MCP-1的表達(dá)水平明顯高于對(duì)照組,差異有統(tǒng)計(jì)學(xué)意義(P0.05)；血管活性因子ET-1、PAI-1的表達(dá)水平明顯高于對(duì)照組,而NO的表達(dá)水平低于對(duì)照組,差異有顯著性(P0.05)。 2、模型組各時(shí)段大鼠外周血中ALT、FFA、TG、Tch、LDL的表達(dá)水平明顯高于對(duì)照組,而HDL的水平明顯低于對(duì)照組,差異有統(tǒng)計(jì)學(xué)意義(P0.05)；模型組FPG、FINS的表達(dá)水平明顯高于對(duì)照組,胰島素抵抗指數(shù)HOMA-IR的數(shù)值顯著高于對(duì)照組,差異有顯著性(P0.05)。 3、主動(dòng)脈病理組織學(xué)：對(duì)照組各時(shí)段主動(dòng)脈壁未見(jiàn)明顯異常病變；模型組第3月主動(dòng)脈內(nèi)皮增生；6月內(nèi)皮增生進(jìn)一步加重,內(nèi)膜明顯增厚,內(nèi)皮下脂質(zhì)呈條帶狀沉積；中膜平滑肌細(xì)胞增生及彈力纖維紊亂；內(nèi)膜／中膜比值增大；9月組動(dòng)脈壁內(nèi)膜進(jìn)一步增厚,脂質(zhì)沉積進(jìn)一步增多,而中膜開(kāi)始出現(xiàn)萎縮,內(nèi)膜／中膜比值進(jìn)一步增大；粥樣斑塊形成,其內(nèi)出現(xiàn)了小灶鈣化；12月組內(nèi)膜/中膜比值保持高水平,差異有統(tǒng)計(jì)學(xué)意義(P0.05),顯示動(dòng)脈壁鈣化明顯加重。 4、主動(dòng)脈單核/巨噬細(xì)胞的浸潤(rùn)：對(duì)照組動(dòng)脈壁未見(jiàn)明顯單核/巨噬細(xì)胞粘附及浸潤(rùn)；模型組第3月主動(dòng)脈內(nèi)皮表面粘附個(gè)別單核/巨噬細(xì)胞,6月組內(nèi)皮下可見(jiàn)單核/巨噬細(xì)胞浸潤(rùn)；9月及12月單核/巨噬細(xì)胞在內(nèi)皮下浸潤(rùn)進(jìn)一步增多,且主要集中在粥樣斑塊中,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。 5、主動(dòng)脈iNOS的表達(dá)：對(duì)照組動(dòng)脈壁內(nèi)皮細(xì)胞及平滑肌細(xì)胞iNOS散在少許細(xì)胞弱陽(yáng)性表達(dá)。模型組大鼠動(dòng)脈壁內(nèi)皮細(xì)胞及平滑肌細(xì)胞表達(dá)iNOS隨觀察時(shí)間的延長(zhǎng)陽(yáng)性表達(dá)細(xì)胞逐漸增多,強(qiáng)度逐漸增強(qiáng),各時(shí)段間的表達(dá)差異有統(tǒng)計(jì)學(xué)意義(P0.05)。 6、主動(dòng)脈NF-κB的表達(dá)：對(duì)照組動(dòng)脈壁內(nèi)皮細(xì)胞和平滑肌細(xì)胞NF-κB的陽(yáng)性表達(dá)呈均勻一致的胞漿弱陽(yáng)性表達(dá),核無(wú)陽(yáng)性表達(dá)；模型組動(dòng)脈壁內(nèi)皮細(xì)胞和平滑肌細(xì)胞出現(xiàn)了核陽(yáng)性表達(dá),隨著觀察時(shí)間的延長(zhǎng),核陽(yáng)性表達(dá)逐漸增多,胞漿陽(yáng)性變得不均勻,陽(yáng)性部位多聚集于核附近,模型組各時(shí)段核陽(yáng)性表達(dá)有統(tǒng)計(jì)學(xué)差異(P0.05)。 7、主動(dòng)脈Tunel的表達(dá)：Tunel檢測(cè)顯示對(duì)照組動(dòng)脈壁內(nèi)皮細(xì)胞和平滑肌細(xì)胞僅個(gè)別細(xì)胞核陽(yáng)性表達(dá)；模型組3月組即可看到動(dòng)脈壁內(nèi)皮細(xì)胞和平滑肌細(xì)胞明顯陽(yáng)性表達(dá)；6月組核陽(yáng)性表達(dá)增多；9月組和12月組動(dòng)脈壁內(nèi)皮細(xì)胞和平滑肌細(xì)胞呈彌漫核陽(yáng)性表達(dá),差異有顯著性(P0.05)。 8、肝臟的病理組織學(xué)觀察：對(duì)照組肝細(xì)胞未出現(xiàn)明顯病變,僅在匯管區(qū)見(jiàn)散在個(gè)別炎癥細(xì)胞浸潤(rùn)；模型組從第3個(gè)月始大鼠先后發(fā)生了脂肪肝、脂肪性肝炎,第6個(gè)月出現(xiàn)纖維化,第12個(gè)月發(fā)展為早期肝硬化。 結(jié)論：1、高糖高脂飲食誘導(dǎo)大鼠發(fā)生了IETM,血漿中LPS持續(xù)高表達(dá)。 2、肝臟單核/巨噬細(xì)胞被LPS激活,使肝臟發(fā)生IR及NAFLD,糖代謝、脂代謝發(fā)生紊亂,出現(xiàn)代謝綜合征癥候群。 3、代謝綜合征時(shí),增多的脂質(zhì)異位沉積到動(dòng)脈壁,使動(dòng)脈發(fā)生IR； 4、持續(xù)慢性炎癥、IR及脂質(zhì)異位沉積損傷了內(nèi)皮細(xì)胞、平滑肌細(xì)胞功能,最終導(dǎo)致AS的發(fā)生發(fā)展。 5、高糖高脂飲食促使IETM發(fā)生,血漿高表達(dá)的LPS觸發(fā)了代謝綜合征相關(guān)的AS的發(fā)生及發(fā)展。 第二部分高糖高脂飲食誘導(dǎo)IETM在代謝綜合征相關(guān)的心肌損傷中的作用和機(jī)制研究 目的：探討高糖高脂飲食誘發(fā)IETM在代謝綜合征相關(guān)的心肌損傷發(fā)生、發(fā)展中的作用和機(jī)制,分析血漿中持續(xù)高表達(dá)的LPS損傷心肌功能的作用機(jī)制,為預(yù)防代謝綜合征相關(guān)的心肌損傷提供新思路。 方法：1、動(dòng)物分組：同第一部分。 2、血清學(xué)檢測(cè)：同第一部分。 3、摘取心肌組織進(jìn)行病理組織學(xué)觀察,觀察心肌細(xì)胞變性、凋亡及纖維化的發(fā)生情況。 4、免疫組化法檢測(cè)CD68陽(yáng)性的單核／巨噬細(xì)胞在心肌中的浸潤(rùn)；檢測(cè)心肌細(xì)胞iNOS和NF-kB的表達(dá)；Tunnel檢測(cè)心肌細(xì)胞的凋亡情況。 5、蘇丹Ⅳ (Sudan Ⅳ)特殊染色觀察心肌中的脂質(zhì)異位沉積情況。 結(jié)果：1、模型組大鼠血清學(xué)檢測(cè)結(jié)果：同第一部分。 2、心肌病理組織學(xué)觀察：對(duì)照組大鼠心肌細(xì)胞排列整齊、規(guī)則,心肌細(xì)胞大小、直徑正常,未見(jiàn)變性發(fā)生,無(wú)明顯炎癥細(xì)胞浸潤(rùn)；模型組大鼠3月時(shí)段心肌細(xì)胞排列尚整齊規(guī)則,部分心肌細(xì)胞體積增大,心肌纖維間可見(jiàn)散在炎癥細(xì)胞浸潤(rùn)；6月時(shí)段大部分心肌細(xì)胞直徑增大,炎癥細(xì)胞浸潤(rùn)明顯；9月心肌出現(xiàn)了小灶狀壞死,12月組壞死呈多灶狀,纖維組織增生,炎癥細(xì)胞浸潤(rùn)。 3、心肌內(nèi)脂質(zhì)異位沉積：心肌內(nèi)及心肌肌束間于模型組第3月組即可見(jiàn)小點(diǎn)灶狀脂質(zhì)沉積,第6個(gè)月脂質(zhì)沉積增多,第9-12月明顯加重,呈斑片狀,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。 4、心肌細(xì)胞凋亡：對(duì)照組心肌細(xì)胞很少發(fā)生凋亡；模型組第3月時(shí)段散在心肌細(xì)胞發(fā)生凋亡,6月時(shí)段凋亡較明顯,9-12月組大部分心肌細(xì)胞顯示凋亡,差異有顯著性(P0.05)。 結(jié)論：1、高糖高脂飲食下大鼠發(fā)生了IETM及代謝綜合征相關(guān)的心肌損傷. 2、血漿中LPS持續(xù)高表達(dá),激活體內(nèi)單核／巨噬細(xì)胞系統(tǒng),誘導(dǎo)心肌發(fā)生炎癥、IR及脂質(zhì)異位沉積,最終導(dǎo)致心肌細(xì)胞凋亡,損傷心肌功能。 3、高糖高脂飲食促使IETM發(fā)生,進(jìn)而誘導(dǎo)了代謝綜合征相關(guān)的心肌損傷。 第三部分內(nèi)質(zhì)網(wǎng)應(yīng)激在心血管疾病發(fā)生發(fā)展中的機(jī)制研究 目的：探討內(nèi)質(zhì)網(wǎng)應(yīng)激在代謝相關(guān)的AS及心肌損傷發(fā)生發(fā)展中的機(jī)制 方法：1、動(dòng)物分組：同第一部分 2、血清學(xué)檢測(cè)：同第一部分 3、摘取主動(dòng)脈及心臟,原位雜交檢測(cè)CHOP mRNA及Grp78mRNA在動(dòng)脈壁和心肌中的表達(dá) 結(jié)果：1、對(duì)照組動(dòng)脈壁內(nèi)皮細(xì)胞、平滑肌細(xì)胞及心肌細(xì)胞Grp78mRNA為陰性表達(dá)或僅少部分弱陽(yáng)性表達(dá),模型組動(dòng)脈壁及心肌細(xì)胞漿Grp78mRNA陽(yáng)性表達(dá),且隨著觀察時(shí)間的延長(zhǎng),表達(dá)逐漸增強(qiáng),差異有顯著性意義(P0.05)。 2、對(duì)照組動(dòng)脈壁內(nèi)皮細(xì)胞和平滑肌細(xì)胞及心肌細(xì)胞CHOP mRNA陰性表達(dá),模型組動(dòng)脈壁及心肌細(xì)胞漿CHOP mRNA表達(dá)陽(yáng)性,隨鼠齡增大及觀察時(shí)段延長(zhǎng),CHOP mRNA表達(dá)逐漸增強(qiáng),差異有顯著性意義(P0.05)。 結(jié)論：1、模型組動(dòng)脈壁和心肌中CHOP mRNA及Grp78mRNA的表達(dá)顯著增強(qiáng),且與病變程度相關(guān)。 2、內(nèi)質(zhì)網(wǎng)應(yīng)激在代謝相關(guān)的AS及心肌損傷發(fā)生發(fā)展機(jī)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.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R363

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