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

Rajarajan A. Thandavarayan, Kenichi Watanabe, Meilei Ma, Narasimman Gurusamy, Punniyakoti T. Veeraveedu, Tetsuya Konishi, Shaosong Zhang, Anthony J. Muslin, Makoto Kodama, Yoshifusa Aizawa

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

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 p38α MAPK after experimental diabetes by using transgenic (TG) mice with cardiac-specific expression of a dominant-negative mutant form of p38α 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, p22phox, p67phox, gp91phox, 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-XL were less in diabetic TG mice compared with diabetic NTG 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-XL.

Original languageEnglish (US)
Pages (from-to)H911-H919
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 2009

Keywords

  • Oxidative stress
  • p38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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