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

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 p38alpha MAPK after experimental diabetes by using transgenic (TG) mice with cardiac-specific expression of a dominant-negative mutant form of p38alpha 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 beta1, 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 p38alpha MAPK activity is required for cardiac remodeling after diabetes induction and suggest that p38alpha MAPK may promote cardiomyocyte apoptosis by downregulation of Bcl-X(L).

Ginsenoside Rg1 ameliorates oxidative stress and myocardial apoptosis in streptozotocin-induced diabetic rats

“…Throughout the process of apoptosis, proteins of the caspase and Bcl-2 families have crucial roles. Apoptosis is an important mechanism of myocardial cell damage in diabetic disease, and proteins of the caspase and Bcl-2 families are also involved (Li et al, 2008;Chen et al, 2009;Liu et al, 2009;Thandavarayan et al, 2009). CASP3 is a member of the caspase family and has been recognized as an important initiator and promoter of apoptosis.…”

“…Estrogen was found to exert a protective effect in cardiomyocytes related to induction of the Bcl-xL gene (Morrissy et al, 2010). Many signaling pathways, such as p38 and MitogenActivated Protein Kinase (MAPK), may prevent apoptosis of cardiomyocytes in an STZ-induced model of DM via up-regulation of Bcl-xL protein expression (Thandavarayan et al, 2009). Our study showed that treatment with ginsenoside Rg1 could restore myocardial protein levels of Bcl-xL in a dose-dependent manner, suggesting that regulation of Bcl-2 family proteins may be involved in the antiapoptotic effect of Rg1 in diabetic myocardium.…”

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

“…The activation of p38-MAPK pathway also impairs insulin action into the myocardium increasing free radical-mediated infarction [78]. Diabetic mice with abbrogated gene expression of the p38-MAPK had decreased levels of free radical production as well as lower degree of myocardial damage and apoptosis compared with normal gene expression mice [79]. Cardiomyocytes were protected against oxidative stress-induced hyperglycemic toxicity through inhibition of the p38-MAPK signaling pathway [80].…”

Schisandrin B Prevents Doxorubicin Induced Cardiac Dysfunction by Modulation of DNA Damage, Oxidative Stress and Inflammation Through Inhibition of MAPK/p53 Signaling

“…The formation of hydroxyl radical (ÁOH) was detected with 5,5 0 -dimethyl-1-pyrroline-1-oxide (DMPO) as a spin trap [3,21]. The hearts were homogenized in cold PBS (100 mg hearts/ml), incubated with 200 μmol/L Dox (group V and Sch B treated) or without Dox (group N) for 10 minutes, and then added to 0.05 ml of 9.0 mol/L DMPO.…”