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    
Abstract/OtherAbstract:
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.
Authors:
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    
Affiliation:
Department of Internal Medicine, and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
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MeSH Terms
Descriptor/Qualifier:
Animals
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
Humans
Male
Mice
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
Rats, Inbred F344
Recombinant Fusion Proteins / pharmacology*
Grant Support
ID/Acronym/Agency:
A062260//PHS HHS
Chemical
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 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.4.22.-/Caspase 9
Comments/Corrections

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


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