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
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-
B (NF-B) activation in the myocardium. Ad.GSK-3β-KM abrogated kallikrein's actions on GSK-3β and CREB phosphorylation and NF-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-B activation.
KEYWORDS Tissue kallikrein; Kinin B2 receptor; Hypertrophy; Glycogen synthase kinase-3β; Nuclear factor-B
Huey-Jiun Li and Hang Yin have equal contributions.
Time for primary review 19 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y.-Y. Yao, H. Yin, B. Shen, R. S. Smith Jr, Y. Liu, L. Gao, L. Chao, and J. Chao Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3{beta} pathway Cardiovasc Res, September 4, 2008; (2008) cvn223v2. [Abstract] [Full Text] [PDF]
|
|