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, Michio Nakaya, Tomomi Ide, Yasuo Mori, Hitoshi Kurose, Motohiro Nishida

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

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

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'TRPC3-mediated Ca<sup>2+</sup> influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts'. Together they form a unique fingerprint.

Cite this