Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes

N. KEIRA, T. TATSUMI, S. MATOBA, J. SHIRAISHI, S. YAMANAKA, K. AKASHI, M. KOBARA, J. ASAYAMA, S. FUSHIKI, H. FLISS AND M. NAKAGAWA. Lethal Effect of Cytokine-induced Nitric Oxide and Peroxynitrite on Cultured Rat Cardiac Myocytes. Journal of Molecular and Cellular Cardiology (2002) 34, 583-596. We examined the cytotoxic effect of iNOS-generated NO in cultured cardiac myocytes treated with IL-1beta, IFN-gamma and LPS. Treatment of the myocytes with cytokines for 48 h resulted in a marked NO production, a significant decline in cellular ATP content, and a significant increase in myocyte death with morphological characteristics of necrosis. Moreover, immunohistochemical examination showed that the cytokines caused nitrotyrosine formation in the injured myocytes. Uric acid and L-cysteine which have the ability to quench peroxynitrite significantly attenuated these cytokine-induced effects, although they did not alter NO production or the decline in cellular ATP. These data suggest that NO production induced by cytokines can not only cause deleterious effects in the myocardial energy balance but also induce myocytes necrosis, through the formation of peroxynitrite. (C) 2002 Elsevier Science Ltd. All rights reserved.