Inhibition of p38 MAP kinase improves survival of cardiac myocytes with hypoxia and burn serum challenge.

This study was aimed to investigate the effects of SB203580, the specific p38 mitogen-activated protein (MAP) kinase inhibitor, on cardiac myocyte survival and secretion of cytokines in an in vitro model of hypoxia and burn serum challenge. Results demonstrated that hypoxia and burn serum induced a persistent activation of p38 MAP kinase in primary cultured neonatal rat cardiomyocytes during the 12h period of stimulation, concomitant with a time-dependent increased expression of tumor necrosis factor (TNF)-alpha and inducible nitric oxide (iNOS), a progressively developed oxidative stress reflected by malondialdehyde (MDA) production, and myocytes injury evidenced by the increased levels of released lactate dehydrogenase (LDH) and the decreased myocyte viability. Furthermore, hypoxia and burn serum resulted in a significant increase in myocyte apoptosis, which may account for the impairment of myocyte viability as observed. SB203580 abolished p38 MAP kinase activation, blunted the upregulation of TNF-alpha, iNOS and the subsequent nitric oxide (NO) production, reduced oxidative stress, and alleviated hypoxia and burn serum-induced myocytes injury or apoptosis. These results demonstrated for the first time that inhibition of p38 MAP kinase improves survival of cardiac myocytes with hypoxia and burn serum challenge possibly via reducing the production of cytokines, such as TNF-alpha and NO, and the subsequent oxidative stress, providing strong evidence that the excessive inflammatory cytokines produced by cardiomyocytes themselves may be sufficient to cause myocardial injury after burn.