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Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3beta activation.

Authors: Li, HJ  Yin, H  Yao, YY  Shen, B  Bader, M  Chao, L  Chao, J 
Citation: Li HJ, etal., Cardiovasc Res. 2007 Jan 1;73(1):130-42. Epub 2006 Oct 27.
Pubmed: (View Article at PubMed) PMID:17137568
DOI: Full-text: DOI:10.1016/j.cardiores.2006.10.014

OBJECTIVE: We assessed the role of glycogen synthase kinase-3beta (GSK-3beta) and kinin B2 receptor in mediating tissue kallikrein's protective effects against cardiac hypertrophy. METHODS: We investigated the effect and mechanisms of tissue kallikrein using hypertrophic animal models of rats as well as mice deficient in kinin B1 or B2 receptor after aortic constriction (AC). RESULTS: Intramyocardial delivery of adenovirus containing the human tissue kallikrein gene resulted in expression of recombinant kallikrein in rat myocardium. Kallikrein gene delivery improved cardiac function and reduced heart weight/body weight ratio and cardiomyocyte size without affecting mean arterial pressure 28 days after AC. Icatibant and adenovirus carrying a catalytically inactive GSK-3beta mutant (Ad.GSK-3beta-KM) abolished kallikrein's effects. Kallikrein treatment increased cardiac nitric oxide (NO) levels and reduced NAD(P)H oxidase activity and superoxide production. Furthermore, kallikrein reduced the phosphorylation of apoptosis signal-regulating kinase1, mitogen-activated protein kinases (MAPKs), Akt, GSK-3beta, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-kappaB (NF-kappaB) activation in the myocardium. Ad.GSK-3beta-KM abrogated kallikrein's actions on GSK-3beta and CREB phosphorylation and NF-kappaB activation, whereas icatibant blocked all kallikrein's effects. The protective role of kinin B2 receptor in cardiac hypertrophy was further confirmed in kinin receptor knockout mice as heart weight/body weight ratio and cardiomyocyte size increased significantly in kinin B2 receptor knockout mice after AC compared to wild type and B1 receptor knockout mice. CONCLUSIONS: These findings indicate that tissue kallikrein, through kinin B2 receptor and GSK-3beta signaling, protects against pressure overload-induced cardiomyocyte hypertrophy by increased NO formation and oxidative stress-induced Akt-GSK-3beta-mediated signaling events, MAPK and NF-kappaB activation.

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CRRD Object Information
CRRD ID: 1641797
Created: 2007-08-22
Species: All species
Last Modified: 2007-08-22
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.