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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H911    most recent 00124.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Thandavarayan, R. A. Articles by Aizawa, Y. PubMed PubMed Citation Articles by Thandavarayan, R. A. Articles by Aizawa, Y.

TRANSLATIONAL PHYSIOLOGY

Dominant-negative p38 mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus

¹Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan; ²Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; ³Department of Functional and Analytical Food Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan; ⁴Lightlab Imaging, Westford, Massachusetts; ⁵Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and ⁶First Department of Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Submitted 6 February 2009 ; accepted in final form 14 July 2009

The p38 mitogen-activated protein kinase (MAPK) is activated during heart diseases that might be associated with myocardial damage and cardiac remodeling process. Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. The purpose of this study was to investigate the role of p38 MAPK after experimental diabetes by using transgenic (TG) mice with cardiac-specific expression of a dominant-negative mutant form of p38 MAPK. The elevation of blood glucose was comparable between the nontransgenic (NTG) and TG mice. The expression of phospho-p38 MAPK and phospho-MAPK-activated 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 β1, and collagen III compared with diabetic NTG mice. Moreover, LV expression of NADPH oxidase subunits, p22^phox, p67^phox, gp91^phox, and Nox4, reactive oxygen species and lipid peroxidation levels were significantly increased in diabetic NTG mice, but not in diabetic TG 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 NTG mice. In conclusion, our data establish that p38 MAPK activity is required for cardiac remodeling after diabetes induction and suggest that p38 MAPK may promote cardiomyocyte apoptosis by downregulation of Bcl-X_L.

p38 mitogen-activated protein kinase; oxidative stress