Document Detail


Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway.
MedLine Citation:
PMID:  22999860     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-19
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  53     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-04-19     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  858-69     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / genetics
Cardiotonic Agents / pharmacology*
Enzyme Activation / genetics
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors,  metabolism
Gene Knockdown 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*
Grant Support
ID/Acronym/Agency:
HL51045/HL/NHLBI NIH HHS; HL79424/HL/NHLBI NIH HHS; HL93685/HL/NHLBI NIH HHS; R01 HL079424/HL/NHLBI NIH HHS; R01 HL093685/HL/NHLBI NIH HHS; R37 HL051045/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/STAT3 Transcription Factor; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.10.2/Janus Kinase 2; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; W36ZG6FT64/Sirolimus
Comments/Corrections

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