Document Detail

Tissue Kallikrein Promotes Cardiac Neovascularization by Enhancing Endothelial Progenitor Cell Functional Capacity.
MedLine Citation:
PMID:  22435954     Owner:  NLM     Status:  Publisher    
Tissue kallikrein (TK) has been demonstrated to improve neovasculogenesis after myocardial infarction (MI). In the present study, we examined the role and underlying mechanisms of TK in peripheral endothelial progenitor cell (EPC) function. Peripheral blood-derived mononuclear cells containing EPCs were isolated from rat. The in vitro effects of TK on EPC differentiation, apoptosis, migration, and vascular tube formation capacity were studied in the presence or absence of TK, kinin B2 receptor antagonist (icatibant), and phosphatidylinositol-3 kinase inhibitor (LY294002). Apoptosis was evaluated by flow cytometry analysis using Annexin V-FITC/PI staining as well as western blot analysis of Akt phosphorylation and cleaved caspase-3. Using an MI mouse model, we then examined the in vivo effects of human TK gene adenoviral vector (Ad.hTK) administration on the number of CD34+Flk-1+ progenitors in the peripheral circulation, heart tissue, extent of vasculogenesis and heart function. Administration of TK significantly increased the number of DiI-LDL/UEA-lectin double-positive early EPCs as well as their migration and tube formation properties in vitro. Transduction of TK in cultured EPCs attenuated apoptosis induced by hypoxia, and led to an increase in Akt phosphorylation and a decrease in cleaved caspase-3 levels. The beneficial effects of TK were blocked by pretreatment with icatibant and LY294002. The expression of recombinant human TK in the ischemic mouse heart significantly improved cardiac contractility and reduced infarct size 7 days after gene delivery. Compared with the Ad.Null group, Ad.hTK reduced mortality and preserved left ventricular function by increasing the number of CD34+Flk-1+ EPCs and promoting the growth of capillaries and arterioles in the peri-infarct myocardium. These data provide direct evidence that TK promotes vessel growth by increasing the number of EPCs and enhancing their functional properties through the kinin B2 receptor-Akt signaling pathway. Keywords: endothelial progenitor cells; tissue kallikrein; bradykinin; B2 receptor; myocardial infarction.
Yuyu Yao; Zulong Sheng; Yefei Li; Fengdi Yan; Genshan Ma; Naifeng Liu; Cong Fu; Yongjun Li; Julie Chao; Lee Chao
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-21
Journal Detail:
Title:  Human gene therapy     Volume:  -     ISSN:  1557-7422     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Medical School of Southeast University, Department of Cardiology, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, Nanjing, China, 210009, 86-25-83272038, 86-25-83272038;
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