Abstract 11776: Overexpressed Phoshodiesterase 3A Regulates Cardiac Function and Protects Hearts from Ischemia/Reperfusion Injury
BACKGROUND: Cyclic adenosine monophosphate (cAMP) plays critical roles in a variety of cardiac myocyte functions, from myocyte contractility to cell survival. Phosphodiesterase 3A (PDE3A) is a major regulator of cAMP in cardiomyocytes. We previously reported that downregulation of PDE3A expression induced myocyte apoptosis by stabilizing inducible cAMP early repressor (ICER). Therefore, we hypothesized that overexpressed PDE3A prevents the cardiac injury by an anti-apoptotic mechanism.
METHODS AND RESULTS: We generated transgenic mice (Tg) with cardiac-specific expression of exogenous PDE3A1. Tg hearts showed a 10-fold increase in PDE3A expression and activity compared to wild-type hearts. Tg mice have reduced cardiac function, characterized by lower heart rate, ejection fraction (52.5 ± 7.8% vs 83.9 ± 4.7%, p<0.01) and expanded left ventricular diameter (4.19 ± 0.19 mm vs 3.10 ± 0.18 mm, p<0.01). However, there was no increase in fibrosis and apoptosis in Tg hearts and the survival rates are also the same between Tg and WT mice. In isolated Tg cardiomyocytes, isoproterenol (ISO)-stimulated sarcomere shortening was impaired, which was completely reversed by PDE3 inhibitor, milrinone, suggesting that PDE3A1 regulates ISO-induced myocardial contractility. Interestingly, ischemia/reperfusion injury-induced myocardial infarct size (4.0 ± 1.8% vs 24.6 ± 3.8%, p<0.01) as well as apoptotic cell number (1.3 ± 1.0% vs 5.6 ± 1.5%, p<0.05) were significantly reduced in Tg mice compared to WT mice. This was associated with increased Bcl-2 and ICER proteins. Moreover, H2O2 stimulated cell death was also significantly attenuated (39.9 ± 5.1% vs 11.1 ± 5.1%, p<0.01) in isolated cardiomyocytes from Tg mice compared to WT mice. We thus conclude that overexpression of PDE3A1 protects ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis.
- © 2011 by American Heart Association, Inc.