Document Detail


Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway.
MedLine Citation:
PMID:  18689794     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: We investigated the role of the Akt-glycogen synthase kinase (GSK)-3beta signalling pathway in mediating the protective effects of tissue kallikrein on myocardial injury by promoting angiogenesis and blood flow in rats after myocardial infarction (MI).
METHODS AND RESULTS: Human tissue kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3beta (Ad.GSK-3betaS9A), was injected into rat myocardium after MI. The expression of recombinant human kallikrein in rat heart significantly improved cardiac function and reduced infarct size 10 days after gene delivery. Kallikrein administration significantly increased myocardial blood flow as well as capillary and arteriole densities in the infarcted myocardium. Kallikrein increased cardiac Akt and GSK-3beta phosphorylation in conjunction with decreased GSK-3beta activity and the upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). All of kallikrein's effects on the myocardium were abrogated by Ad.DN-Akt and Ad.GSK-3betaS9A. Moreover, in cultured human aortic endothelial cells, tissue kallikrein stimulated capillary tube formation and promoted cell migration; however, these effects were blocked by Ad.DN-Akt, Ad.GSK-3betaS9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, tissue kallikrein decreased GSK-3beta activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells.
CONCLUSION: These data provide the first direct evidence that tissue kallikrein protects against acute-phase MI by promoting neovascularization, restoring regional blood flow and improving cardiac function through the kinin B2 receptor-Akt-GSK-3beta and VEGF signalling pathways.
Authors:
Yu-Yu Yao; Hang Yin; Bo Shen; Robert S Smith; Yuying Liu; Lin Gao; Lee Chao; Julie Chao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-08-09
Journal Detail:
Title:  Cardiovascular research     Volume:  80     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-17     Completed Date:  2009-03-10     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  354-64     Citation Subset:  IM    
Affiliation:
Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210029, People's Republic of China.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Animals
Cell Movement / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Disease Models, Animal
Endothelium, Vascular / cytology,  drug effects,  metabolism
Glycogen Synthase Kinase 3 / metabolism*
Heart / drug effects*,  physiology
Humans
Male
Myocardial Infarction / metabolism
Myocardium / metabolism
Neovascularization, Physiologic / drug effects*
Proto-Oncogene Proteins c-akt / metabolism*
Rats
Rats, Wistar
Regional Blood Flow / drug effects
Signal Transduction / drug effects*
Tissue Kallikreins / genetics,  metabolism*,  pharmacology*
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Grant Support
ID/Acronym/Agency:
C06 RR015455/RR/NCRR NIH HHS; DK-066350/DK/NIDDK NIH HHS; HL-29373/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Vascular Endothelial Growth Factor A; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.4.21.35/Tissue Kallikreins
Comments/Corrections
Comment In:
Cardiovasc Res. 2008 Dec 1;80(3):328-9   [PMID:  18835841 ]

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


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