| Angiopoietin-1 protects heart against ischemia/reperfusion injury through VE-cadherin dephosphorylation and myocardiac integrin-β1/ERK/caspase-9 phosphorylation cascade. | |
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MedLine Citation:
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PMID: 21738954 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Early reperfusion after myocardial ischemia that is essential for tissue salvage also causes myocardial and vascular injury. Cardioprotection during reperfusion therapy is an essential aspect of treating myocardial infarction. Angiopoietin-1 is an endothelial-specific angiogenic factor. The potential effects of angiopoietin-1 on cardiomyocytes and vascular cells undergoing reperfusion have not been investigated. We propose a protective mechanism whereby angiopoietin-1 increases the integrity of the endothelial lining and exerts a direct survival effect on cardiomyocytes under myocardial ischemia followed by reperfusion. First, we found that angiopoietin-1 prevents vascular leakage through regulating VE-cadherin phosphorylation. The membrane expression of VE-cadherin was markedly decreased on hypoxia/reoxygenation but was restored by angiopoietin-1 treatment. Interestingly, these effects were mediated by the facilitated binding between SHP2 or PTPμ tyrosine phosphatase and VE-cadherin, leading to de-phosphorylation of VE-cadherin. siRNA against SHP2 or PTPμ abolished the effect of angiopoietin-1 on VE-cadherin de-phosphorylation, and thereby decreased levels of membrane-localized VE-cadherin. Second, we found that angiopoietin-1 prevented cardiomyocyte death, although they lack the angiopoietin-1 receptor Tie2. Angiopoietin-1 increased cardiomyocyte survival through integrin-β1-mediated ERK- phosphorylation, which led to inhibit caspase-9 through phosphorylation at Thr 125 and subsequently reduced active caspase-3. Neutralizing antibody against integrin-β1 blocked these protective effects. In a mouse myocardial ischemia/reperfusion model, angiopoietin-1 enhanced cardiac function; reduction in left ventricular end-systolic dimension (LV-ESD) and left ventricular end-diastolic dimension (LV-EDD) with increase in ejection fraction (EF) and fractional shortening (FS). Our findings suggest the novel cardioprotective mechanisms of angiopoietin-1 which are achieved by reducing both vascular leakage and cardiomyocyte death after ischemia/reperfusion injury. |
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Authors:
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Sae-Won Lee; Joo-Yun Won; Hae-Young Lee; Ho-Jae Lee; Seock-Won Youn; Ji-Young Lee; Chung-Hyun Cho; Hyun-Jai Cho; Seil Oh; In-Ho Chae; Hyo-Soo Kim |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-5 |
Journal Detail:
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Title: Molecular medicine (Cambridge, Mass.) Volume: - ISSN: 1528-3658 ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-7-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9501023 Medline TA: Mol Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Internal Medicine, and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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