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: Zhihe Li, Jing Ying Ma, Irene Kerr, Sarvajit Chakravarty, Sundeep Dugar, George Schreiner, Andrew A Protter
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 291 Issue 4 Pg. H1972-7 (Oct 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16751295 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Indoles
• Vasoconstrictor Agents
• indole-5-carboxamide
• Angiotensin II
• Mitogen-Activated Protein Kinase 14
• Casp3 protein, rat
• Caspase 3
• Caspases
• NG-Nitroarginine Methyl Ester

Topics

• Angiotensin II (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blood Pressure (drug effects, physiology)
• Body Weight (drug effects, physiology)
• Cardiac Output (drug effects, physiology)
• Caspase 3
• Caspases (metabolism)
• Enzyme Inhibitors (pharmacology)
• Heart (drug effects, physiology)
• Indoles (pharmacology)
• Inflammation
• Male
• Mitogen-Activated Protein Kinase 14 (antagonists & inhibitors, metabolism)
• Myocardial Infarction (physiopathology)
• Myocardium (enzymology, pathology)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Organ Size (drug effects, physiology)
• Rats
• Rats, Wistar
• Reperfusion Injury (pathology, physiopathology, prevention & control)
• Stroke Volume (drug effects, physiology)
• Vasoconstrictor Agents (pharmacology)