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Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway.
Cardiovasc Res. 2008 Dec 01; 80(3):354-64.CR

Abstract

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+Show Affiliations

Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210029, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18689794

Citation

Yao, Yu-Yu, et al. "Tissue Kallikrein Promotes Neovascularization and Improves Cardiac Function By the Akt-glycogen Synthase Kinase-3beta Pathway." Cardiovascular Research, vol. 80, no. 3, 2008, pp. 354-64.
Yao YY, Yin H, Shen B, et al. Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway. Cardiovasc Res. 2008;80(3):354-64.
Yao, Y. Y., Yin, H., Shen, B., Smith, R. S., Liu, Y., Gao, L., Chao, L., & Chao, J. (2008). Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway. Cardiovascular Research, 80(3), 354-64. https://doi.org/10.1093/cvr/cvn223
Yao YY, et al. Tissue Kallikrein Promotes Neovascularization and Improves Cardiac Function By the Akt-glycogen Synthase Kinase-3beta Pathway. Cardiovasc Res. 2008 Dec 1;80(3):354-64. PubMed PMID: 18689794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway. AU - Yao,Yu-Yu, AU - Yin,Hang, AU - Shen,Bo, AU - Smith,Robert S,Jr AU - Liu,Yuying, AU - Gao,Lin, AU - Chao,Lee, AU - Chao,Julie, Y1 - 2008/08/09/ PY - 2008/8/12/pubmed PY - 2009/3/11/medline PY - 2008/8/12/entrez SP - 354 EP - 64 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 80 IS - 3 N2 - 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/18689794/Tissue_kallikrein_promotes_neovascularization_and_improves_cardiac_function_by_the_Akt_glycogen_synthase_kinase_3beta_pathway_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvn223 DB - PRIME DP - Unbound Medicine ER -