Effect of efonidipine on TGF-β1-induced cardiac fibrosis through Smad2-dependent pathway in rat cardiac fibroblasts

J Pharmacol Sci. 2011;117(2):98-105. doi: 10.1254/jphs.11065fp. Epub 2011 Sep 7.

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 [(3)H]-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 [(3)H]-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 [(3)H]-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, L-Type / metabolism*
  • Calcium Channels, T-Type / metabolism*
  • Dihydropyridines / pharmacology*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibrosis / metabolism
  • Myocardium / metabolism
  • Myocardium / pathology
  • Nifedipine / pharmacology
  • Nitrophenols / pharmacology*
  • Organophosphorus Compounds / pharmacology
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Transfection
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / pharmacology*

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Calcium Channels, T-Type
  • Dihydropyridines
  • Nitrophenols
  • Organophosphorus Compounds
  • RNA, Small Interfering
  • Smad2 Protein
  • Smad2 protein, rat
  • Transforming Growth Factor beta1
  • efonidipine
  • Nifedipine