| Rapamycin Protects against Myocardial Ischemia-Reperfusion Injury through JAK2-STAT3 Signaling Pathway. | |
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MedLine Citation:
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PMID: 22999860 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 Langendorf 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 left ventricle 3weeks prior to initiating I/R injury. Infarct size, cardiac function, cardiomyocyte necrosis and apoptosis were assessed. Rapamycin reduced infarct size, improved cardiac function following I/R, limited cardiomyocytes 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 cardioprotecive 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. |
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Authors:
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Anindita Das; Fadi N Salloum; David Durrant; Ramzi Ockaili; Rakesh C Kukreja |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-9-18 |
Journal Detail:
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Title: Journal of molecular and cellular cardiology Volume: - ISSN: 1095-8584 ISO Abbreviation: J. Mol. Cell. Cardiol. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-9-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0262322 Medline TA: J Mol Cell Cardiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012. Published by Elsevier Ltd. |
Affiliation:
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Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia, USA. Electronic address: adas2@vcu.edu. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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