Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway.

Abstract

Rapamycin (Sirolimus®) is used to prevent rejection of transplanted organs and coronary restenosis. We reported that rapamycin induced cardioprotection against ischemia-reperfusion (I/R) injury through opening of mitochondrial K(ATP) channels. However, signaling mechanisms in rapamycin-induced cardioprotection are currently unknown. Considering that STAT3 is protective in the heart, we investigated the potential role of this transcription factor in rapamycin-induced protection against (I/R) injury. Adult male ICR mice were treated with rapamycin (0.25mg/kg, i.p.) or vehicle (DMSO) with/without inhibitor of JAK2 (AG-490) or STAT3 (stattic). One hour later, the hearts were subjected to I/R either in Langendorff mode or in situ ligation of left coronary artery. Additionally, primary murine cardiomyocytes were subjected to simulated ischemia-reoxygenation (SI/RO) injury in vitro. For in situ targeted knockdown of STAT3, lentiviral vector containing short hairpin RNA was injected into the left ventricle 3 weeks prior to initiating I/R injury. Infarct size, cardiac function, and cardiomyocyte necrosis and apoptosis were assessed. Rapamycin reduced infarct size, improved cardiac function following I/R, and limited cardiomyocyte necrosis as well as apoptosis following SI/RO which were blocked by AG-490 and stattic. In situ knock-down of STAT3 attenuated rapamycin-induced protection against I/R injury. Rapamycin triggered unique cardioprotective signaling including phosphorylation of ERK, STAT3, eNOS and glycogen synthase kinase-3ß in concert with increased prosurvival Bcl-2 to Bax ratio. Our data suggest that JAK2-STAT3 signaling plays an essential role in rapamycin-induced cardioprotection. We propose that rapamycin is a novel and clinically relevant pharmacological strategy to target STAT3 activation for treatment of myocardial infarction.

• Authors: Anindita Das, Fadi N Salloum, David Durrant, Ramzi Ockaili, Rakesh C Kukreja
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 53 Issue 6 Pg. 858-69 (Dec 2012) ISSN: 1095-8584 [Electronic] England
• PMID: 22999860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Cardiotonic Agents
• STAT3 Transcription Factor
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Janus Kinase 2
• Extracellular Signal-Regulated MAP Kinases
• Sirolimus

Topics

• Animals
• Apoptosis (genetics)
• Cardiotonic Agents (pharmacology)
• Enzyme Activation (genetics)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Gene Knockdown Techniques
• In Vitro Techniques
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Myocardial Reperfusion Injury (genetics, metabolism)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Nitric Oxide Synthase Type II (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)