Overexpression of glutaredoxin-2 reduces myocardial cell death by preventing both apoptosis and necrosis.

Abstract

Mitochondrial glutaredoxin-2 (Glrx2) has been recognized as an important redox regulator in mammalian organs including heart. To date no investigations have addressed the potential role of Glrx2 in cardiac disorders. The present study examined if myocardial overexpression of Glrx2 in the heart could rescue the cardiac cells from apoptosis and necrosis induced by ischemia and reperfusion. The human Glrx2 transgene was created by placing a full-length cDNA fragment encoding human mitochondrial Glrx2 downstream to the 5' flanking sequence and promoter of the mouse alpha-myosin heavy chain gene. The isolated hearts from Glrx2 transgenic mice and non-transgenic (wild type) littermates [on c57BL/6xC3H hybrid background] were subjected to 30 min of global ischemia followed by 2 h of reperfusion via working mode. The hearts from Glrx2 transgenic mice displayed significantly improved contractile performance and reduced myocardial infarct size and cardiomyocyte apoptosis. There was a reduction in cytochrome c release and activation of caspase 3 and caspase 9. Glrx2 overexpression also reduced the ischemia/reperfusion-mediated loss of mitochondrial cardiolipin, decreased the activities of reactive oxygen species (ROS) and preserved GSH/GSSG ratio. Glrx2 mediated survival signal appeared to be stemmed from PI-3-kinase-Akt survival signaling pathway and involved the activation of redox sensitive transcription factor NFkappaB and antiapoptotic protein Bcl-2. The results indicated a crucial role of mitochondrial Glrx2 in cardioprotection.

• Authors: Norbert Nagy, Gautam Malik, Arpad Tosaki, Ye-Shih Ho, Nilanjana Maulik, Dipak K Das
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 44 Issue 2 Pg. 252-60 (Feb 2008) ISSN: 1095-8584 [Electronic] England
• PMID: 18076901 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Cardiolipins
• GLRX2 protein, human
• Glutaredoxins
• Cytochromes c
• Caspases

Topics

• Animals
• Apoptosis
• Cardiolipins (metabolism)
• Caspases (metabolism)
• Cell Death
• Cell Survival
• Cytochromes c (metabolism)
• Enzyme Activation
• Female
• Gene Expression
• Glutaredoxins (genetics)
• Humans
• Male
• Mice
• Mice, Transgenic
• Mitochondria, Heart (enzymology, metabolism)
• Myocardial Contraction
• Myocardial Reperfusion Injury
• Myocardium (enzymology, pathology)
• Myocytes, Cardiac (enzymology, metabolism, pathology)
• Necrosis
• Oxidative Stress