Effect of Efonidipine on TGF-β1–Induced Cardiac Fibrosis Through Smad2-Dependent Pathway in Rat Cardiac Fibroblasts

Bai Lei; Hirofumi Hitomi; Tatsuhiko Mori; Yukiko Nagai; Kazushi Deguchi; Hirohito Mori; Tsutomu Masaki; Daisuke Nakano; Hiroyuki Kobori; Yasushi Kitaura; Akira Nishiyama

doi:10.1254/jphs.11065FP

Full Papers

Effect of Efonidipine on TGF-β1–Induced Cardiac Fibrosis Through Smad2-Dependent Pathway in Rat Cardiac Fibroblasts

Bai Lei, Hirofumi Hitomi, Tatsuhiko Mori, Yukiko Nagai, Kazushi Deguchi, Hirohito Mori, Tsutomu Masaki, Daisuke Nakano, Hiroyuki Kobori, Yasushi Kitaura, Akira Nishiyama

Author information

Bai Lei
Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan
Hirofumi Hitomi
Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan
Tatsuhiko Mori
Department of Internal Medicine III, Osaka Medical College, Japan
Yukiko Nagai
Life Sciences Research Center, Faculty of Medicine, Kagawa University, Japan
Kazushi Deguchi
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
Hirohito Mori
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
Tsutomu Masaki
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
Daisuke Nakano
Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan
Hiroyuki Kobori
Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan
Yasushi Kitaura
Department of Internal Medicine III, Osaka Medical College, Japan
Akira Nishiyama
Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan

Keywords: transforming growth factor beta-1, Smad2, T-type calcium channel, cardiac fibrosis, efonidipine

JOURNAL FREE ACCESS

2011 Volume 117 Issue 2 Pages 98-105

DOI https://doi.org/10.1254/jphs.11065FP

View "Advance Publication" version (September 7, 2011).

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Abstract

Transforming growth factor beta-1 (TGF-β1) plays a critical role in progression of cardiac fibrosis, which may involve intracellular calcium change. We examined effects of efonidipine, a dual T-type and L-type calcium channel blocker (CCB), on TGF-β1–induced fibrotic changes in neonatal rat cardiac fibroblast. T-type and L-type calcium channel mRNAs were highly expressed in cultured cardiac fibroblasts. TGF-β1 (5 ng/mL) significantly increased Smad2 phosphorylation and [³H]-leucine incorporation, which were attenuated by pretreatment with efonidipine (10 μM). Neither R(−)efonidipine (10 μM), selective T-type CCB, nor nifedipine (10 μM), selective L-type CCB, efficaciously inhibited both TGF-β1–induced Smad2 phosphorylation and [³H]-leucine incorporation. However, both were markedly attenuated by combination of R(−)efonidipine and nifedipine, EDTA, or calcium-free medium. Pretreatment with Smad2 siRNA significantly attenuated [³H]-leucine incorporation induced by TGF-β1. These data suggest that efonidipine elicits inhibitory effects on TGF-β1– and Smad2-dependent protein synthesis through both T-type and L-type calcium channel–blocking actions in cardiac fibroblasts.

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