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

Tools

Item Type:	Article
Title:	Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3β activation
Creators Name:	Li, H.J., Yin, H., Yao, Y.Y., Shen, B., Bader, M., Chao, L. and Chao, J.
Abstract:	OBJECTIVE: We assessed the role of glycogen synthase kinase-3{beta} (GSK-3{beta}) 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-3{beta} mutant (Ad.GSK-3{beta}-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-3{beta}, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-kappaB (NF-kappaB) activation in the myocardium. Ad.GSK-3{beta}-KM abrogated kallikrein's actions on GSK-3{beta} 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-3{beta} signaling, protects against pressure overload-induced cardiomyocyte hypertrophy by increased NO formation and oxidative stress-induced Akt-GSK-3{beta}-mediated signaling events, MAPK and NF-kappaB activation.
Keywords:	Tissue Kallikrein, Kinin B2 Receptor, Hypertrophy, Glycogen Synthase Kinase-3{beta}, Nuclear Factor-KappaB, Animals, Mice, Rats
Source:	Cardiovascular Research
ISSN:	0008-6363
Publisher:	Elsevier
Volume:	73
Number:	1
Page Range:	130-142
Date:	1 January 2007
Official Publication:	https://doi.org/10.1016/j.cardiores.2006.10.014
PubMed:	View item in PubMed

Repository Staff Only: item control page