期刊
CARDIOVASCULAR RESEARCH
卷 49, 期 4, 页码 798-807出版社
OXFORD UNIV PRESS
DOI: 10.1016/S0008-6363(00)00307-2
关键词
contractile function; free radicals; heart failure; infarction; nitric oxide
资金
- NHLBI NIH HHS [HL63067, HL59791] Funding Source: Medline
Objective: Oxidative stress is implicated in the initiation and progression of congestive heart failure, but the putative reactive species and cellular targets involved remain undefined. We have previously shown that peroxynitrite (ONOO-, an aggressive biological oxidant and nitrating agent) potently inhibits myofibrillar creatine kinase (MM-CK), a critical controller of contractility known to be impaired during heart failure. Here we hypothesized that nitration and inhibition of MM-CK participate in cardiac failure in vivo. Methods: Heart failure was induced in rats by myocardial infarction (left coronary artery ligation) and confirmed by histological analysis at 8 weeks postinfarct (1.3 +/- 1.4 vs. 37.7 +/- 3.2% left ventricular circumference; sham control vs. CHF, n = 10 each). Results: Immunohistochemistry demonstrated significantly increased protein nitration in failing myocardium compared to control (optical density: 0.5 +/- 0.06 vs. 0.93 +/- 0.09, sham vs. CHF, P < 0.05). Significant decreases in MM-CK activity and content were observed in failing hearts (MM-CK k(cat): 6.0 +/- 0.4 vs. 3.0 +/- 0.3 mol/nM M-CK/min, P < 0.05; 6.8 +/- 1.3 vs. 4.7 +/- 1.2% myofibrillar protein, P < 0.05), with no change in myosin ATPase activity. In separate experiments, isolated rat cardiac myofibrils were exposed to ONOO- (2-250 muM) and enzyme studies were conducted. Identical to in vivo studies, selective reductions in MM-CK were observed at ONOO- concentrations as low as 2 muM (IC50=92.5 +/- 6.0 muM); myosin ATPase was unaffected with ONOO- concentrations as high as 250 muM. Concentration dependent nitration of MM-CK occurred and extent of nitration was statistically correlated to extent of CK inhibition (P < 0.001). Immunoprecipitation of MM-CK from failing left ventricle yielded significant evidence of tyrosine nitration. Conclusion: These data demonstrate that cardiac ONOO- formation and perturbation of myofibrillar energetic controllers occur during experimental heart failure; MM-CR may be a critical cellular target in this setting. (C) 2001 Elsevier Science B.V. All rights reserved.
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