Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes.
We examined the cytotoxic effect of iNOS-generated NO in cultured cardiac myocytes treated with IL-1 beta, 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.
Keira
Natsuya
N
Second Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Tatsumi
Tetsuya
T
Matoba
Satoaki
S
Shiraishi
Jun
J
Yamanaka
Satoshi
S
Akashi
Kazuko
K
Kobara
Miyuki
M
Asayama
Jun
J
Fushiki
Shinji
S
Fliss
Henry
H
Nakagawa
Masao
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats
D016207:Cytokines; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat