Dominant-negative p38α mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus.

The p38 mitogenactivated protein kinase (MAPK) is activated during heart diseases that might be associated with myocardial damage and cardiac remodeling process. Diabetic cardiomyopathy is associated with in creased oxidative stress and inflammation. The purpose of this study was to investigate the role of p38α MAPK after experimental diabetes by using transgenic (TG) mice with cardiacspecific expression of a dominantnegative mutant form of p38α MAPK. The elevation of blood glucose was comparable between the nontransgenic (NTG) and TG mice. The expression of phosphop38 MAPK and phospho MAPKactivated protein kinase 2 levels were significantly suppressed in TG mice heart than in NTG mice after diabetes induction. Left ventricular (LV) dimension in systole was smaller, and the percent fractional shortening was higher in diabetic TG mice compared with diabetic NTG mice. In addition, diabetic TG mice had reduced cardiac myocyte diameter, content of cardiac fibrosis, LV tissue expressions of atrial natriuretic peptide, transforming growth factor β 1, and collagen III compared with diabetic NTG mice. Moreover, LV ex pression of NADPH oxidase subunits, p22^phox, p67^phox, gp9 1^phox, and Nox4, reactive oxygen species and lipid peroxidation levels were significantly increased in diabetic NTG mice, but not in diabetic TO mice. Furthermore, myocardial apoptosis, the number of caspase-3-positive cells, and the downregulation of antiapoptotic protein Bcl-X_L were less in diabetic TG mice compared with diabetic NTO mice. In conclusion, our data establish that p38α MAPK activity is required for cardiac remodeling after diabetes induction and suggest that p38α MAPK may promote cardiomyocyte apoptosis by downregulation of Bcl-X_L. [ABSTRACT FROM AUTHOR]