Document Detail

Angiopoietin-1 protects heart against ischemia/reperfusion injury through VE-cadherin dephosphorylation and myocardiac integrin-β1/ERK/caspase-9 phosphorylation cascade.
MedLine Citation:
PMID:  21738954     Owner:  NLM     Status:  MEDLINE    
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 vascular endothelial (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 SH2 domain-containing tyrosine phosphatase (SHP2) or receptor protein tyrosine phosphatase μ (PTPμ) and VE-cadherin, leading to dephosphorylation of VE-cadherin. siRNA against SHP2 or PTPμ abolished the effect of angiopoietin-1 on VE-cadherin dephosphorylation and thereby decreased levels of membrane-localized VE-cadherin. Second, we found that angiopoietin-1 prevented cardiomyocyte death, although cardiomyocytes lack the angiopoietin-1 receptor Tie2. Angiopoietin-1 increased cardiomyocyte survival through integrin-β1-mediated extracellular signal-regulated kinase (ERK) phosphorylation, which inhibited caspase-9 through phosphorylation at Thr¹²⁵ 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 and reduction in left ventricular-end systolic dimension (LV-ESD) and left ventricular-end diastolic dimension (LV-EDD) with an increase in ejection fraction (EF) and fractional shortening (FS). Our findings suggest the novel cardioprotective mechanisms of angiopoietin-1 that are achieved by reducing both vascular leakage and cardiomyocyte death after ischemia/reperfusion injury.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-05
Journal Detail:
Title:  Molecular medicine (Cambridge, Mass.)     Volume:  17     ISSN:  1528-3658     ISO Abbreviation:  Mol. Med.     Publication Date:    2011 Sep-Oct
Date Detail:
Created Date:  2011-10-10     Completed Date:  2012-03-25     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  9501023     Medline TA:  Mol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1095-106     Citation Subset:  IM    
Department of Internal Medicine, and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
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MeSH Terms
Animals, Newborn
Antigens, CD / genetics,  metabolism*
Antigens, CD29 / metabolism*
Blotting, Western
Cadherins / genetics,  metabolism*
Capillary Permeability / drug effects
Caspase 9 / metabolism*
Cell Hypoxia
Cells, Cultured
Extracellular Signal-Regulated MAP Kinases / metabolism*
Heart / drug effects,  physiopathology
Human Umbilical Vein Endothelial Cells / cytology,  drug effects,  metabolism
Mice, Inbred C57BL
Myocardial Reperfusion Injury / metabolism,  physiopathology,  prevention & control*
Myocardium / metabolism,  pathology
Myocytes, Cardiac / cytology,  drug effects,  metabolism
Oxygen / pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics,  metabolism
RNA Interference
Rats, Inbred F344
Recombinant Fusion Proteins / pharmacology*
Grant Support
A062260//PHS HHS
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD29; 0/COMP-Ang1 fusion protein; 0/Cadherins; 0/Recombinant Fusion Proteins; 0/cadherin 5; 7782-44-7/Oxygen; EC Signal-Regulated MAP Kinases; EC Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.4.22.-/Caspase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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