N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster
N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster
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DOI：
10.1089/ars.2008.2069
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发表时间：
2008-12-01
影响因子：
6.6
通讯作者：
Iwasaka, Toshiji
中科院分区：
文献类型：
--
作者：
Matsuhisa, Seiji;Otani, Hajime;Iwasaka, Toshiji
通过激活血管紧张素Ⅱ1型受体(AT1R)介导的氧化应激在心力衰竭的进展中起着至关重要的作用。我们研究了N-乙酰半胱氨酸(NAC)和AT1R阻滞剂对BIO14.6心肌病金黄地鼠氧化应激和左心室重构的影响。心肌病仓鼠给予NAC或AT1R阻滞剂氯沙坦治疗20周。尽管NAC和氯沙坦抑制心肌病仓鼠心脏的氧化应激和iNOS的上调，但只有氯沙坦能抑制心肌病仓鼠的左室腔扩张、心肌纤维化和左心功能不全。与NAC共同处理可阻断氯沙坦对与抑制磷脂酰肌醇3-激酶(PI3K)/Akt和eNOS激活相关的左室重构的保护作用。诱导型一氧化氮合酶抑制剂1400W或非选择性一氧化氮合酶抑制剂N omega-硝基-L-精氨酸甲酯(L-NAME)可加重心肌病金黄地鼠左室重构。然而，L的名字，而不是1400W，取消了氯沙坦介导的抑制左室重构。这些结果表明，氧化还原敏感的iNOS上调在防止BIO14.6心肌病仓鼠左室重构中起着至关重要的作用。氯沙坦通过将心肌保护机制从iNOS依赖转换为eNOS依赖来抑制左室重构，而NAC通过抑制氧化还原敏感的PI3K/Akt和eNOS的激活来取消氯沙坦的保护作用。
Oxidative stress mediated by activation of angiotensin II type-1 receptor (AT1R) plays a crucial role in the progression of heart failure. We investigated the effect of N-acetylcysteine (NAC) and an AT1R blocker on oxidative stress and left ventricular (LV) remodeling in BIO14.6 cardiomyopathy hamsters. The cardiomyopathy hamsters were treated with NAC or the AT1R blocker losartan for 20 weeks. Although NAC and losartan inhibited oxidative stress and upregulation of iNOS in the cardiomyopathy hamster heart, only losartan inhibited LV chamber dilation, myocardial fibrosis, and LV dysfunction in the cardiomyopathy hamster. Co-treatment with NAC abolished the protective effect of losartan against LV remodeling associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt and eNOS activation. An iNOS inhibitor 1400W or a nonselective NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) exacerbated LV remodeling in the cardiomyopathy hamster. However, L-NAME but not 1400W abrogated losartan-mediated inhibition of LV remodeling. These results suggest that redox-sensitive upregulation of iNOS plays a crucial role in preventing LV remodeling in the BIO14.6 cardiomyopathy hamster. Losartan inhibits LV remodeling by switching the cardioprotective mechanism from iNOS-to eNOS-dependence, but NAC abolishes the protective effect of losartan by inhibiting redox-sensitive activation of PI3K/Akt and eNOS in the cardiomyopathy hamster.