TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts

Naoyuki Kitajima, Kunihiro Watanabe, Sachio Morimoto, Yoji Sato, Shigeki Kiyonaka, Masahiko Hoshijima, Yasuhiro Ikeda, Nakaya Michio, Tomomi Ide, Yasuo Mori, Hitoshi Kurose, Motohiro Nishida

Research output: Contribution to journalArticle

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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 Ca2+ 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 Ca2+/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.

Original languageEnglish
Pages (from-to)108-113
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume409
Issue number1
DOIs
Publication statusPublished - May 27 2011

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Dilated Cardiomyopathy
Calcium-Calmodulin-Dependent Protein Kinases
Reactive Oxygen Species
NADPH Oxidase
Calmodulin
Cardiac Myocytes
Heart Ventricles
Dilatation
Phosphotransferases
Chemical activation
GTP-Binding Proteins
Oxidative Stress
Oxidative stress
Up-Regulation
cysteine and glycine-rich protein 3
Rats
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. / Kitajima, Naoyuki; Watanabe, Kunihiro; Morimoto, Sachio; Sato, Yoji; Kiyonaka, Shigeki; Hoshijima, Masahiko; Ikeda, Yasuhiro; Michio, Nakaya; Ide, Tomomi; Mori, Yasuo; Kurose, Hitoshi; Nishida, Motohiro.

In: Biochemical and Biophysical Research Communications, Vol. 409, No. 1, 27.05.2011, p. 108-113.

Research output: Contribution to journalArticle

Kitajima, Naoyuki ; Watanabe, Kunihiro ; Morimoto, Sachio ; Sato, Yoji ; Kiyonaka, Shigeki ; Hoshijima, Masahiko ; Ikeda, Yasuhiro ; Michio, Nakaya ; Ide, Tomomi ; Mori, Yasuo ; Kurose, Hitoshi ; Nishida, Motohiro. / TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. In: Biochemical and Biophysical Research Communications. 2011 ; Vol. 409, No. 1. pp. 108-113.
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AU - Kiyonaka, Shigeki

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