Submitted on April 10, 2008
Revised on October 30, 2008
Accepted on November 3, 2008
Role of Heme Oxygenase-1 in the Cardioprotective Effects of Erythropoietin during Myocardial Ischemia and Reperfusion
Dylan Burger, Fuli Xiang, Lamis Hammoud, Xiangru Lu, and Qingping Feng1*
1 University of Western Ontario
* To whom correspondence should be addressed. E-mail: qfeng{at}uwo.ca.
We recently demonstrated that erythropoietin (EPO) protects cardiomyocytes from apoptosis during myocardial ischemia and reperfusion (I/R). The objective of the present study was to investigate the role of heme oxygenase-1 (HO-1) in the anti-apoptotic effects of EPO. Primary cultures of neonatal mouse cardiomyocytes were subjected to anoxia-reoxygenation (A/R). Pre-treatment with EPO significantly reduced apoptosis in A/R treated cells. This reduction in apoptosis was preceded by an increase in mRNA and protein expression of HO-1. Selective inhibition of HO-1 using chromium mesoporphyrin (CrMP) significantly diminished the ability of EPO to inhibit apoptosis. Co-treatment of EPO with SB202190, an inhibitor of p38 activity, blocked the EPO-mediated HO-1 expression and anti-apoptotic effects, suggesting a p38-dependent mechanism. The in vivo significance of p38 and HO-1 as mediators of EPO's cardioprotection were investigated in mice subjected to myocardial I/R. EPO decreased infarct size, as well as I/R-induced apoptosis in wild-type mice. However, these effects were significantly diminished in HO-1-/- mice. Furthermore, EPO given during ischemia reduced infarct size in mice subjected to I/R and this effect was blocked by CrMP treatment in WT mice. Moreover, inhibition of p38 blocked the cardioprotective effects of EPO. We conclude that upregulation of HO-1 expression via p38 signaling contributes to EPO-mediated cardioprotection during myocardial I/R.
