Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity.
Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity.
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DOI：
10.1016/j.yjmcc.2004.05.006
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发表时间：
2004-08
影响因子：
5
通讯作者：
A. T. Zaman;S. Fujii;D. Goto;T. Furumoto;T. Mishima;Y. Nakai;Jie Dong;S. Imagawa;B. Sobel;A. Kitabatake
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文献类型：
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作者：
A. T. Zaman;S. Fujii;D. Goto;T. Furumoto;T. Mishima;Y. Nakai;Jie Dong;S. Imagawa;B. Sobel;A. Kitabatake
肥胖和胰岛素抵抗会增加冠心病和心肌病的发病风险。我们之前的研究表明，抑制血管紧张素转换酶（ACE）可以防止发生胰岛素抵抗的遗传性肥胖小鼠的冠状动脉微血管周围纤维化。本研究旨在阐明相关机制并确定血管紧张素II (Ang) II衰减的影响。遗传性肥胖的ob/ob小鼠在10至20周内给予ACE抑制剂（替莫april）或Ang II型1 （AT1）受体阻滞剂（奥美沙坦）。测定心肌纤维蛋白溶解的主要生理抑制剂纤溶酶原激活物抑制剂(PAI)-1和原型纤维化分子转化生长因子(TGF)-β1的表达，并测量血管周围冠状动脉纤维化的程度。20周龄的肥胖小鼠血浆中PAI-1和TGF-β1的水平高于瘦小鼠。肥胖小鼠的小动脉和小动脉血管周围冠状动脉纤维化明显，左心室胶原蛋白也增加。免疫组化证实血管周围有1型胶原沉积。免疫组化观察到冠状动脉壁PAI-1和TGF-β明显升高，western blotting证实。当肥胖小鼠在10至20周内接受替莫april或奥美沙坦治疗时，两者的效果相同，并且可以防止血管周围纤维化，血浆PAI-1和TGF-β1，左心室胶原和PAI-1， TGF-β和1型胶原的壁免疫反应性增加。肥胖小鼠左心室c-Jun nh2末端激酶（JNK）活性升高，替莫april和奥美沙坦阻断JNK活性。Ang ii介导的PAI-1和TGF-β1的上调与胶原沉积可能解释了肥胖小鼠血管周围纤维化的机制。ACE的抑制和at1受体的阻断可以防止冠状动脉血管周围纤维化和胶原沉积，甚至在发展为显性糖尿病之前。JNK激活可能是肥胖相关心功能障碍的中介和潜在的治疗靶点。
Obesity and insulin resistance confer increased risk for accelerated coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular fibrosis in genetically obese mice that develop insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of angiotensin II (Ang) II. Genetically obese ob/ob mice were given ACE inhibitor (temocapril) or Ang II type 1 (AT1) receptor blocker (olmesartan) from 10 to 20 weeks. Cardiac expressions of plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and transforming growth factor (TGF)-β1, a prototypic profibrotic molecule, were determined and extent of perivascular coronary fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of PAI-1 and TGF-β1compared with the values in lean counterpart. Perivascular coronary fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular collagen as measured by hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular type 1 collagen. Markedly increased PAI-1 and TGF-β were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with temocapril or olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular fibrosis, plasma PAI-1 and TGF-β1, left ventricular collagen and mural immunoreactivity for PAI-1, TGF-β and collagen type 1. The c-Jun NH2-terminal kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by temocapril and olmesartan. Ang II-mediated upregulation of PAI-1 and TGF-β1with collagen deposition may explain the mechanism of perivascular fibrosis in obese mice. ACE inhibition and blockade of AT1receptor may prevent coronary perivascular fibrosis and collagen deposition even before development of overt diabetes. JNK activation may be a mediator of obesity-related cardiac dysfunction and a potential therapeutic target.