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

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 kinase 1, mitogen-activated protein kinases (MAPKs), Akt, GSK-3 beta, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-kappa B (NF-kappa B) activation in the myocardium. Ad.GSK-3 beta-KM abrogated kallikrein's actions on GSK-3 beta and CREB phosphorylation and NF-kappa B 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-kappa B activation. (c) 2006 European Society of Cardiology. Published by Elsevier B.V.