Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed 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.


OBJECTIVE
We tested the hypothesis that SIL-induced cardioprotection may be mediated through activation of SIRT1.


METHODS
Adult male ICR mice were treated with SIL (0.7 mg/kg, i.p.), Resveratrol (RSV, 5 mg/kg, a putative activator of SIRT1 used as the positive control), or saline (0.2 mL). The hearts were harvested 24 hours later and homogenized for SIRT1 activity analysis.


RESULTS
Both SIL- and RSV-treated mice had increased cardiac SIRT1 activity (P<0.001) as compared to the saline-treated controls 24 hours after drug treatment. In isolated ventricular cardiomyocytes, pretreatment with 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. Pretreatment with SIL (or RSV) 24 hours prior to 30 min ischemia and 24 hours of reperfusion significantly reduced infarct size, which was associated with a significant increase in SIRT1 activity (P<0.05). Moreover, sirtinol (a SIRT1 inhibitor, 5 mg/kg, i.p.) given 30 min before I-R blunted the infarct-limiting effect of SIL and RSV (P<0.001).


CONCLUSIONS
Our study shows that activation of SIRT1 following SIL treatment plays an essential role in mediating the SIL-induced cardioprotection against I-R injury. This newly identified SIRT1-activating property of SIL may have enormous therapeutic implications.
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America ; Touro College of Osteopathic Medicine, New York, New York, United States of America.
Mona
M
Shalwala
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America ; Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
Shu-Guang
SG
Zhu
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Anindita
A
Das
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Fadi N
FN
Salloum
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Lei
L
Xi
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Rakesh C
RC
Kukreja
D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000378:metabolism* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009284:Naphthols / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000517:prevention & control*; D000068677:Sildenafil Citrate; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
D001549:Benzamides; D002316:Cardiotonic Agents; D009284:Naphthols; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C439060:sirtinol; D000068677:Sildenafil Citrate; D056564:Sirtuin 1