Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death
Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death
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DOI：
10.1172/jci200213265
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发表时间：
2002-03-01
影响因子：
15.9
通讯作者：
Husain, M
中科院分区：
文献类型：
--
作者：
Mungrue, IN;Gros, R;Husain, M
诱导型一氧化氮合酶 (iNOS) 表达增加是免疫反应的一个组成部分，并且已在败血性休克、心肌炎、移植排斥、缺血和扩张型心肌病的心肌细胞中得到证实。为了探讨这种表达的后果是适应性的还是致病性的，我们建立了一种转基因小鼠模型，有条件地将人类 iNOS cDNA 的表达靶向心肌。转基因小鼠中 iNOS 的慢性心脏特异性上调导致过氧亚硝酸盐的产生增加。这与轻度炎症细胞浸润、心脏纤维化、肥大和扩张有关。虽然 iNOS 过度表达的小鼠很少出现明显的心力衰竭，但它们因缓慢性心律失常而导致心源性猝死的发生率很高。这种显着的心脏表型通过转基因活性的特异性减弱得以挽救。这些数据表明心肌细胞 NOS 过度表达足以导致心肌病、缓慢性心律失常和心源性猝死。
Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac Fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte NOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.