替米沙坦对家兔动脉粥样硬化的影响和其机制的研究
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摘要
背景和目的:替米沙坦是一种具有部分PPARγ激动作用的新型的血管紧张素Ⅱ受体拮抗剂。替米沙坦是否具有与ARBS抗动脉粥样硬化不完全相同的作用,国内目前没有报道。观察高胆固醇血症时,替米沙坦和氯沙坦对血浆和脂肪细胞IL-6分泌的影响;对动脉壁PPARγ和脂肪组织中PPARγ和CD36的表达的影响,同时探讨其可能机制。
方法:建立兔动脉粥样硬化模型,检测血管壁PPARγ、血脂、IL-6的水平,行脂肪细胞培养。采用逆转录聚合酶链式反应(RT-PCR)来检测PPARγ和CD36mRNA在脂肪细胞的表达情况。
结果:替米沙坦组动脉硬化明显减轻;血脂下降;血管壁PPARγ表达上升;脂肪细胞PPARγ和CD36mRNA表达增加。
结论:替米沙坦较氯沙坦有更强的抗动脉粥样硬化作用;其作用和上调血管壁PPARγ表达,脂肪细胞PPARγ和CD36mRNA表达有关,和降血脂作用有关。有广阔的应用前景。
Atherosclerosis diseases harm human’s healthy seriously. The morbidity and mortality is in the front row of spectrum of disease. Hyperlipoidemia and obesity are important liability factors of sclerosis. Macrophage under subendothelial mediated by CD36 ingests OxLDL and transforms into foam cell. This mechanism play a key role in the process of injury of blood vessels. Regulation of OxLDL in order to inhibition of foam cell formation may become a new target of antiatherosclerosis.
Inflammation reaction participates in nosogenesis of atherosclerosis, and leads to rupture of atheroslcerosis and thrombogenesis. Researchs confirm that high concentration of IL-6 have a intimate relationship with severity of atherosclerosis. IL-6 stimulate liver producting CRP.IL-6 and CRP in circulation system have a intimate relationship with severity and risk of coronary heart disease. Recently we find that,adipocyte can secrete IL-6,and make a great effect on IL-6 level in circulation.Clinical research also find hyperlipoidemia and CHD patients have a high level of IL-6. However ,we still don’t have a clear understand that how adipocyte expresses and secretes IL-6 in pathologic state.and we try to get known whether IL-6 from adipocyte is one of the reason that IL-6 level became higher.Therefore,there is great significance on comprehend the relationship of adipocyte secreting IL-6 and nosogenensis of atherosclerosis disease.
PPARγhave a important regulation function on inflammation and blood fat metabolic process.Research indicated that,PPARγcould induce expression of CD36 on transcriptional level.compose the important signal way of Ox-LDL coming into Monocyte.PPARγcould inhibit lots of inflammation mediators’expression and releasing.
Adipocyte can express PPARγgreatly.Now researchs find that function alteration of adipocyte is the key factor of obesity,adipocyte play an important role in onset process of metabolism syndrome.so we have to recognize the function of adipocyte.So far we consider function alteration of adipocyte have a close relationship with atherosclerosis disease.
ARBS can selectively block up the combination between AngII and AT1. AngII’s biologic activety has been blocked up,as a result ,ARBS can inhibit information and development of atherosclerosis.Telmisartan is a neotype of ARBS,it has similarity with PPARγstimulator Pioglitazone on struction,it is also the stimulator of PPARγ.Pioglitazone’s reports about anti-atherosclerosis are a lot. Whether telmisartan has totally different function from other ARBS on antisclerosis has no report at present.
Objective: To observe hypercholesteremia,Telmisartan and Losartan’s effect on circulation IL-6 level, adipocyte secretion of IL-6, expression of IL-6 in adipocyte and artery wall and CD36,and to discuss the may mechanism.So as to observe the Telmisartan and Losartan’s effect on early atherosclerosis disease and the may mechanism. In order to explain the relationship between adipocyte and atherosclerosis,and the new mechanism of Telmisartan,maybe it will be a new target to deal with atherosclerosis.
Methods: 32 male Japanese Rabbit randomly into normal diet group( group A),high cholesterol diet and Telmisartan group(group B),high cholesterol diet and Losartan group(group C),and hight cholesterol group(group D),each group has 8 rabbits.each group were sacrificed after 16 weeks.Detecting vessel wall PPARγby immunohistochemical method,detecting blood fat expression level by automatic biochemistry analyzer.To cut each group’s aorta specimen staining by SudanIII,in order to detect the percent of atherosclerosis;the distal portion of aorta to the iliac bifurcation was excised,embedded in paraffin ,cut into pieces,stained by HE. Make some lipid tissue under inguinal groove,do the adipocyte culture.Detect PPARγand CD36mRNA expression in adipocyte.
Results :
1. Atherosclerotic plaque area is 72.5±9.8% in high cholesterol group, 39.1±11.7% in telmisartan group and 56.2±13.6% in losartan group. There is significant statistical difference between each two group among telmisartan group(B) , losartan group(C) and the high cholesterol group(D).(B andD P<0.01,B and C P<0.05, C and D P<0.05).
2. Total cholesterol (TC) in group A, B, C and D were 1.36±0.33 mmol/L, 15.74±6.15 mmol/L, 22.72±9.56 mmol/L and 23.51±10.58 mmol/L. There is significant difference between group B and the other three groups.(P <0.01). Low-density lipoprotein (LDL) in group A, B, C and D were respectively 0.72±0.35 mmol/L, 15.32±7.13mmol/L, 20.79±8.83mmol/L and 21.39±10.00mmol/L. There is significant difference between group B and the other three groups.(P <0.01), but no significant difference between group C and group D(P> 0.05). Triglyceride (TG) levels betwwen group B and the other three groups was significant difference (P <0.01); Group C and Group D was no significant difference (P> 0.05).
3. PPARγexpression of the vascular wall in group A, B, C and D respectively is 7.79±1.47%, 10.83±1.35%, 10.65±1.54% and 11.23±1.21%. Group A is a significant difference to each other group(P <0.01). Among Group B, C and D is no significant difference (P> 0.05). TC and LDL levels in Group B are significantly lower than those in group D (P <0.01), but PPARγexpression is no significant difference (P <0.01).
4. IL-6 levels in plasma and fat tissue in high cholesterol group are higher than those in normal diet group (P <0.01), and those in telmisartan group are lower than those of the other three groups (P <0.01). There are not significant difference between Losartan and high cholesterol group(P> 0.05). IL-6 secreted by fat tissue and that in plasma are closely linked in each group(R=0.886, P <0.01).
5.PPARγmRNA expression in adipose tissue in the normal diet group is 85% higher than that in high cholesterol group(P <0. 01) and that in telmisartan group is 51% higher than that in the high cholesterol group. Losartan has no significant effect to PPARγmRNA expression in adipose tissue of rabbits.
6 CD36mRNA expression in the high cholesterol group is higher than that in the control group,meanwhile, that in telmisartan group is 61% higher than in the high cholesterol group. CD36 mRNA expression is not significantly affected by losartan. CD36 mRNA expression in the Losartan group is the lowest of all.
7. PPARγmRNA (r=-0.892. P <0.01) expression in the rabbit adipocytes were significantly negatively correlated to the IL-6 levels.
conclusions :
1. Telmisartan and losartan have anti-atherosclerotic effect and telmisartan is stronger than losartan.
2. Telmisartan can regulate lipid metabolism.
3. Telmisartan can resolve early atherosclerotic lesions significantly, not only with the cholesterol-lowering effect but also with the efect of lower IL-6 levels by cells secreting in the fat tissue and plasma.
4. Telmisartan against atherosclerosis and the PPARγactivation of adipose tissue are related.
6. Hypercholesterolemia-induced inflammatory response can stimulate fat cells secreting IL-6.
7. Telmisartan through decreasing the cholesterol levels in plasma and increaseing the expression of PPARγinhibits the fat cells secreting IL-6 .
方法:建立兔动脉粥样硬化模型,检测血管壁PPARγ、血脂、IL-6的水平,行脂肪细胞培养。采用逆转录聚合酶链式反应(RT-PCR)来检测PPARγ和CD36mRNA在脂肪细胞的表达情况。
结果:替米沙坦组动脉硬化明显减轻;血脂下降;血管壁PPARγ表达上升;脂肪细胞PPARγ和CD36mRNA表达增加。
结论:替米沙坦较氯沙坦有更强的抗动脉粥样硬化作用;其作用和上调血管壁PPARγ表达,脂肪细胞PPARγ和CD36mRNA表达有关,和降血脂作用有关。有广阔的应用前景。
Atherosclerosis diseases harm human’s healthy seriously. The morbidity and mortality is in the front row of spectrum of disease. Hyperlipoidemia and obesity are important liability factors of sclerosis. Macrophage under subendothelial mediated by CD36 ingests OxLDL and transforms into foam cell. This mechanism play a key role in the process of injury of blood vessels. Regulation of OxLDL in order to inhibition of foam cell formation may become a new target of antiatherosclerosis.
Inflammation reaction participates in nosogenesis of atherosclerosis, and leads to rupture of atheroslcerosis and thrombogenesis. Researchs confirm that high concentration of IL-6 have a intimate relationship with severity of atherosclerosis. IL-6 stimulate liver producting CRP.IL-6 and CRP in circulation system have a intimate relationship with severity and risk of coronary heart disease. Recently we find that,adipocyte can secrete IL-6,and make a great effect on IL-6 level in circulation.Clinical research also find hyperlipoidemia and CHD patients have a high level of IL-6. However ,we still don’t have a clear understand that how adipocyte expresses and secretes IL-6 in pathologic state.and we try to get known whether IL-6 from adipocyte is one of the reason that IL-6 level became higher.Therefore,there is great significance on comprehend the relationship of adipocyte secreting IL-6 and nosogenensis of atherosclerosis disease.
PPARγhave a important regulation function on inflammation and blood fat metabolic process.Research indicated that,PPARγcould induce expression of CD36 on transcriptional level.compose the important signal way of Ox-LDL coming into Monocyte.PPARγcould inhibit lots of inflammation mediators’expression and releasing.
Adipocyte can express PPARγgreatly.Now researchs find that function alteration of adipocyte is the key factor of obesity,adipocyte play an important role in onset process of metabolism syndrome.so we have to recognize the function of adipocyte.So far we consider function alteration of adipocyte have a close relationship with atherosclerosis disease.
ARBS can selectively block up the combination between AngII and AT1. AngII’s biologic activety has been blocked up,as a result ,ARBS can inhibit information and development of atherosclerosis.Telmisartan is a neotype of ARBS,it has similarity with PPARγstimulator Pioglitazone on struction,it is also the stimulator of PPARγ.Pioglitazone’s reports about anti-atherosclerosis are a lot. Whether telmisartan has totally different function from other ARBS on antisclerosis has no report at present.
Objective: To observe hypercholesteremia,Telmisartan and Losartan’s effect on circulation IL-6 level, adipocyte secretion of IL-6, expression of IL-6 in adipocyte and artery wall and CD36,and to discuss the may mechanism.So as to observe the Telmisartan and Losartan’s effect on early atherosclerosis disease and the may mechanism. In order to explain the relationship between adipocyte and atherosclerosis,and the new mechanism of Telmisartan,maybe it will be a new target to deal with atherosclerosis.
Methods: 32 male Japanese Rabbit randomly into normal diet group( group A),high cholesterol diet and Telmisartan group(group B),high cholesterol diet and Losartan group(group C),and hight cholesterol group(group D),each group has 8 rabbits.each group were sacrificed after 16 weeks.Detecting vessel wall PPARγby immunohistochemical method,detecting blood fat expression level by automatic biochemistry analyzer.To cut each group’s aorta specimen staining by SudanIII,in order to detect the percent of atherosclerosis;the distal portion of aorta to the iliac bifurcation was excised,embedded in paraffin ,cut into pieces,stained by HE. Make some lipid tissue under inguinal groove,do the adipocyte culture.Detect PPARγand CD36mRNA expression in adipocyte.
Results :
1. Atherosclerotic plaque area is 72.5±9.8% in high cholesterol group, 39.1±11.7% in telmisartan group and 56.2±13.6% in losartan group. There is significant statistical difference between each two group among telmisartan group(B) , losartan group(C) and the high cholesterol group(D).(B andD P<0.01,B and C P<0.05, C and D P<0.05).
2. Total cholesterol (TC) in group A, B, C and D were 1.36±0.33 mmol/L, 15.74±6.15 mmol/L, 22.72±9.56 mmol/L and 23.51±10.58 mmol/L. There is significant difference between group B and the other three groups.(P <0.01). Low-density lipoprotein (LDL) in group A, B, C and D were respectively 0.72±0.35 mmol/L, 15.32±7.13mmol/L, 20.79±8.83mmol/L and 21.39±10.00mmol/L. There is significant difference between group B and the other three groups.(P <0.01), but no significant difference between group C and group D(P> 0.05). Triglyceride (TG) levels betwwen group B and the other three groups was significant difference (P <0.01); Group C and Group D was no significant difference (P> 0.05).
3. PPARγexpression of the vascular wall in group A, B, C and D respectively is 7.79±1.47%, 10.83±1.35%, 10.65±1.54% and 11.23±1.21%. Group A is a significant difference to each other group(P <0.01). Among Group B, C and D is no significant difference (P> 0.05). TC and LDL levels in Group B are significantly lower than those in group D (P <0.01), but PPARγexpression is no significant difference (P <0.01).
4. IL-6 levels in plasma and fat tissue in high cholesterol group are higher than those in normal diet group (P <0.01), and those in telmisartan group are lower than those of the other three groups (P <0.01). There are not significant difference between Losartan and high cholesterol group(P> 0.05). IL-6 secreted by fat tissue and that in plasma are closely linked in each group(R=0.886, P <0.01).
5.PPARγmRNA expression in adipose tissue in the normal diet group is 85% higher than that in high cholesterol group(P <0. 01) and that in telmisartan group is 51% higher than that in the high cholesterol group. Losartan has no significant effect to PPARγmRNA expression in adipose tissue of rabbits.
6 CD36mRNA expression in the high cholesterol group is higher than that in the control group,meanwhile, that in telmisartan group is 61% higher than in the high cholesterol group. CD36 mRNA expression is not significantly affected by losartan. CD36 mRNA expression in the Losartan group is the lowest of all.
7. PPARγmRNA (r=-0.892. P <0.01) expression in the rabbit adipocytes were significantly negatively correlated to the IL-6 levels.
conclusions :
1. Telmisartan and losartan have anti-atherosclerotic effect and telmisartan is stronger than losartan.
2. Telmisartan can regulate lipid metabolism.
3. Telmisartan can resolve early atherosclerotic lesions significantly, not only with the cholesterol-lowering effect but also with the efect of lower IL-6 levels by cells secreting in the fat tissue and plasma.
4. Telmisartan against atherosclerosis and the PPARγactivation of adipose tissue are related.
6. Hypercholesterolemia-induced inflammatory response can stimulate fat cells secreting IL-6.
7. Telmisartan through decreasing the cholesterol levels in plasma and increaseing the expression of PPARγinhibits the fat cells secreting IL-6 .
引文
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