Journal
CARDIOVASCULAR RESEARCH
Volume 80, Issue 3, Pages 354-364Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn223
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Funding
- National Institutes of Health [HL-29373, DK-066350]
- National Center for Research Resources [C06 RR015455]
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR015455] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK066350] Funding Source: NIH RePORTER
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We investigated the role of the Akt-glycogen synthase kinase (GSK)-3 beta 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). Human tissue kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3 beta (Ad.GSK-3 beta S9A), 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-3 beta phosphorylation in conjunction with decreased GSK-3 beta 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-3 beta S9A. 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-3 beta S9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, tissue kallikrein decreased GSK-3 beta activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells. 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-3 beta and VEGF signalling pathways.
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