Abstract 14584: SIRT1 Activation Mediates Sildenafil-Induced Cardioprotection Against Ischemia/Reperfusion Injury in Mice
Background: It has been well documented that phosphodiesterase-5 inhibitor, sildenafil (SIL) protects against myocardial ischemia/reperfusion (I-R) injury. SIRT1 is part of the class III Sirtuin family of histone deacetylases that deacetylates proteins involved in cellular stress response including those related to I-R injury. Particularly, in response to oxidative stress, SIRT1 and transcription factor FOXO3 form a complex that in turn enhances DNA damage repair and cell cycle arrest. To this context, we hypothesized that SIL-induced cardioprotection may be mediated through activation of SIRT1.
Methods and Results: Adult male ICR mice were treated with SIL (0.7 mg/kg, i.p.), Resveratrol (RSV, 5mg/kg, i.p., a well-known activator of SIRT1 used as the positive control), or saline (0.2 ml, i.p.). The hearts were harvested 24 hours later and homogenized for SIRT1 activity analysis. Both SIL- and RSV-treated mice had increased cardiac SIRT1 activity (P<0.001) as compared to the saline-treated controls 24 hours after the drug treatment. Similarly, in isolated adult mouse ventricular cardiomyocytes, pretreatment with either SIL (1 μM) or RSV (1 μM) for one hour in vitro also upregulated SIRT1 activity (P<0.05). We further examined the causative relationship between SIRT1 activation and SIL-induced late cardioprotection in a mouse model of in vivo regional I-R. As shown in Fig. 1, pretreatment with SIL (or RSV) 24 hours prior to 30 min ischemia and 24 hrs of reperfusion significantly reduced infarct size and the cardioprotective effect was associated with a concomitant significant increase in SIRT1 activity (P<0.05). Moreover, Sirtinol (5 mg/kg, i.p., a SIRT1 inhibitor dissolved in DMSO) completely abolished the infarct-limiting effect of SIL and RSV (P<0.001, Figure 1).
Conclusions: Activation of SIRT1 following SIL treatment plays an essential role in mediating the SIL-induced cardioprotection against I-R injury in mice.
- © 2010 by American Heart Association, Inc.