Abstract 18478: Depletion of Prolyl-4-Hydroxylase Domain 3 Protects Hearts From Injury Induced by Ischemia/Reperfusion and Inhibits Cardiomyocyte Apoptosis
PHD3, a member of a family of Prolyl-4 Hydroxylase Domain (PHD) proteins, has long been considered as a pro-apoptotic protein. Although the pro-apoptotic effect of PHD3 requires its prolyl hydroxylase activity, it is independent of HIF-αs, the common substrates of PHDs. PHD3 is highly expressed in the heart, however, its role in cardiomyocyte apoptosis remains unclear. Whether depletion of PHD3 is cardioprotective need to be determined. To determine whether inhibition or depletion of PHD3 inhibits cardiomyocyte apoptosis and attenuates myocardial injury induced by ischemia-reperfusion, PHD3 knockout mice and their littermate control mice were subjected to left anterior descending (LAD) coronary artery ligation for 40 minutes and then released for reperfusion. By performing Evan’s Blue, triphenyl-tetrazolium chloride and TUNEL staining, we demonstrated that myocardial injury and cardiomyocyte apoptosis were significantly attenuated in PHD3 knockout mice. There were no changes of HIF-1α protein level, the expression of HIF target genes or myocardium capillary density in PHD3 null mice. In vitro, DNA damage response (DDR) and cardiomyocyte apoptosis induced by oxidative stress were significantly inhibited by prolyl hydroxylase inhibitor or depletion of PHD3. Interestingly, DDR activated by hypoxia-reoxygenation (H/R) was also inhibited by inhibition of PHD3. Therefore, we conclude that depletion or inhibition of PHD3 protected hearts from injury induced by ischemia-reperfusion and inhibited cardiomyocyte apoptosis induced by oxidative stress or hypoxia-reperfusion. DDR induced by oxidative stress was dramatically inhibited by depletion or inhibition of PHD3, which may partly contribute to the cardioprotective effect of depletion of PHD3.
- © 2013 by American Heart Association, Inc.