title: Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3beta activation.
abstract: OBJECTIVE
  We assessed the role of glycogen synthase kinase-3beta (GSK-3beta) 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-3beta mutant (Ad.GSK-3beta-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-3beta, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-kappaB (NF-kappaB) activation in the myocardium. Ad.GSK-3beta-KM abrogated kallikrein's actions on GSK-3beta 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-3beta signaling, protects against pressure overload-induced cardiomyocyte hypertrophy by increased NO formation and oxidative stress-induced Akt-GSK-3beta-mediated signaling events, MAPK and NF-kappaB activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29425, USA.
authors.forename: Huey-Jiun
authors.initials: HJ
authors.lastname: Li
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Yao
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D020840:Tissue Kallikreins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D009566:Nitrates; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D009243:NAD; D013481:Superoxides; D009249:NADP; D038362:Glycogen Synthase Kinase 3; D020840:Tissue Kallikreins