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Selective inhibition of p38 MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury

Department of Pharmacology, Scios Inc., Fremont, California

Submitted 10 January 2006 ; accepted in final form 26 May 2006

p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38 MAPK inhibitor. Rats were treated with N-nitro-L-arginine methyl ester (L-NAME, 40 mg·kg^–1·day^–1) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg·kg^–1·day^–1) for 3 days. A selective p38 MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38 MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantly reduced macrophage infiltration as judged by reduction of a specific marker, ED-1-positive staining cells (P < 0.05) in the myocardium. Furthermore, cardiomyocyte apoptosis as indicated by caspase-3 immunohistochemical staining was abolished by SD-282, and this effect may contribute to the reduction of myocardial damage evaluated by imaging analysis (P < 0.05 in both cases). Data suggest that p38 MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38 MAPK may be used as a novel cardioprotective strategy in attenuation of inflammatory response and deterioration of cardiac function that occurs in acute cardiovascular disease such as myocardial infarction.

p38 mitogen-activated protein kinase; remodeling

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