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Cardiovascular Research 2007 73(1):130-142; doi:10.1016/j.cardiores.2006.10.014
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Copyright © 2006, European Society of Cardiology

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

Huey-Jiun Lia, Hang Yina, Yu-Yu Yaoa, Bo Shena, Michael Baderb, Lee Chaoa and Julie Chaoa,*

aDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29425, USA
bThe Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

* Corresponding author. Tel.: +1 843 792 9927; fax: +1 843 792 4850. Email address: chaoj{at}musc.edu

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-{kappa}B (NF-{kappa}B) activation in the myocardium. Ad.GSK-3β-KM abrogated kallikrein's actions on GSK-3β 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-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-{kappa}B activation.

KEYWORDS Tissue kallikrein; Kinin B2 receptor; Hypertrophy; Glycogen synthase kinase-3β; Nuclear factor-{kappa}B

* Huey-Jiun Li and Hang Yin have equal contributions.

Time for primary review 19 days


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