Candesartan cilexetil protects from cardiac myosin induced cardiotoxicity via reduction of endoplasmic reticulum stress and apoptosis in rats: Involvement of ACE2-Ang (1-7)-mas axis
Candesartan cilexetil protects from cardiac myosin induced cardiotoxicity via reduction of endoplasmic reticulum stress and apoptosis in rats: Involvement of ACE2-Ang (1-7)-mas axis
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DOI：
10.1016/j.tox.2011.11.008
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发表时间：
2012-01-27
期刊：
影响因子：
4.5
通讯作者：
Watanabe, Kenichi
中科院分区：
文献类型：
--
作者：
Arumugam, Somasundaram;Thandavarayan, Rajarajan A.;Watanabe, Kenichi
坎地沙坦酯是一种血管紧张素（Ang）II受体1阻滞剂，据报道可抑制各种心血管并发症中的心肌损伤，但其有效预防扩张型心肌病（DCM）进展的方式尚不清楚。新出现的证据表明，使用All受体阻滞剂观察到的益处至少部分可归因于在这些药物给药期间观察到的Ang（1-7）水平升高。RAS的新组分ACE 2和Ang（1-7）受体mas的鉴定为考虑RAS的血管舒张臂的存在提供了基本要素，所述血管舒张臂由ACE 2-Ang（1-7）-mas轴表示。本研究采用注射猪心肌肌球蛋白的方法制备扩张型心肌病大鼠模型。免疫后28天，大鼠腹腔内给予坎地沙坦酯1或10 mg/kg/天，持续4周。采用免疫印迹法和组织病理学染色技术检测心肌Ang受体的表达和钙稳态、内质网（ER）应激和细胞凋亡的标志物。坎地沙坦以剂量依赖性方式改善DCM大鼠心肌中的功能标志物，并上调心肌中的Ang（1-7）、ACE 2和肥大细胞。坎地沙坦组大鼠的各种内质网应激和凋亡标志物均减弱，凋亡细胞数量显著低于溶剂组。这些结果表明坎地沙坦治疗通过激活RAS的反调节臂以及可能通过调节ER应激和随后的心脏细胞凋亡来预防DCM的进展。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Candesartan cilexetil, an angiotensin (Ang) II receptor 1 blocker was reported to suppress the myocardial damage in various cardiovascular complications but the mode by which it is effective in preventing the progression of dilated cardiomyopathy (DCM) is unknown. Emerging evidences suggest that, at least, part of the benefits observed with the use of All receptor blockers could be attributed to the increased Ang (1-7) levels observed during administration of these agents. Identification of the novel components of the RAS, ACE2 and Ang (1-7) receptor mas, provided essential elements for considering the existence of a vasodilator arm of the RAS, represented by the ACE2-Ang (1-7)-mas axis. In this study, rat model of DCM was prepared by injection with porcine cardiac myosin. Twenty-eight days after immunization, candesartan cilexetil was administered intraperitoneally at 1 or 10 mg/kg/day to rats for four weeks. Myocardial expression of Ang receptors and markers of calcium homeostasis, endoplasmic reticulum (ER) stress and apoptosis were measured by Western blotting and histopathological staining techniques. Candesartan improved the functional markers in a dose-dependent manner and also upregulated Ang (1-7), ACE2 and mast in the myocardium of DCM rats. Various ER stress and apoptosis markers were attenuated and the number apoptotic cells were significantly lower in the candesartan treated rats compared with those of the vehicle group. These findings suggest that candesartan treatment prevented the progression of DCM by activation of the counter regulatory arm of the RAS and possibly through modulation of ER stress and subsequently, cardiac apoptosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.