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

Abstract: Objective: We assessed the role of glycogen synthase kinase-3β (GSK-3β) 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-3β mutant (Ad.GSK-3β-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-3β, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-κB (NF-κB) activation in the myocardium. Ad.GSK-3β-KM abrogated kallikrein''s actions on GSK-3β and CREB phosphorylation and NF-κB 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-3β signaling, protects against pressure overload-induced cardiomyocyte hypertrophy by increased NO formation and oxidative stress-induced Akt-GSK-3β-mediated signaling events, MAPK and NF-κB activation. [Copyright &y& Elsevier]