title: TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts.
abstract: Dilated cardiomyopathy (DCM) is a myocardial disorder that is characterized by dilation and dysfunction of the left ventricle (LV). Accumulating evidence has implicated aberrant Ca(2+) signaling and oxidative stress in the progression of DCM, but the molecular details are unknown. In the present study, we report that inhibition of the transient receptor potential canonical 3 (TRPC3) channels partially prevents LV dilation and dysfunction in muscle LIM protein-deficient (MLP (-/-)) mice, a murine model of DCM. The expression level of TRPC3 and the activity of Ca(2+)/calmodulin-dependent kinase II (CaMKII) were increased in MLP (-/-) mouse hearts. Acitivity of Rac1, a small GTP-binding protein that participates in NADPH oxidase (Nox) activation, and the production of reactive oxygen species (ROS) were also increased in MLP (-/-) mouse hearts. Treatment with pyrazole-3, a TRPC3 selective inhibitor, strongly suppressed the increased activities of CaMKII and Rac1, as well as ROS production. In contrast, activation of TRPC3 by 1-oleoyl-2-acetyl-sn-glycerol (OAG), or by mechanical stretch, induced ROS production in rat neonatal cardiomyocytes. These results suggest that up-regulation of TRPC3 is responsible for the increase in CaMKII activity and the Nox-mediated ROS production in MLP (-/-) mouse cardiomyocytes, and that inhibition of TRPC3 is an effective therapeutic strategy to prevent the progression of DCM.
authors.affiliation: Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kitajima
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sato
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Michio
authors.initials: M
authors.lastname: Nakaya
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D060588:LIM Domain Proteins; D009124:Muscle Proteins; D009479:Neuropeptides; D011720:Pyrazoles; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C090114:cysteine and glycine-rich protein 3; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D002118:Calcium