title: Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury.
abstract: 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 p38alpha MAPK inhibitor. Rats were treated with N(omega)-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 p38alpha 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 p38alpha 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 p38alpha MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38alpha 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.
authors.affiliation: Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
authors.forename: Zhihe
authors.initials: Z
authors.lastname: Li
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: George
authors.initials: G
authors.lastname: Schreiner
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D014662:Vasoconstrictor Agents; C514526:indole-5-carboxamide; D000804:Angiotensin II; D048308:Mitogen-Activated Protein Kinase 14; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019331:NG-Nitroarginine Methyl Ester