Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan.
J Pharmacol Sci. 2011;117(2):98-105. doi: 10.1254/jphs.11065fp. Epub 2011 Sep 7.
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.
转化生长因子-β1（TGF-β1）在心脏纤维化的进展中起着关键作用，这可能涉及细胞内钙变化。我们研究了双重 T 型和 L 型钙通道阻滞剂（CCB）依福地平对 TGF-β1诱导的新生大鼠心脏成纤维细胞纤维化变化的影响。T 型和 L 型钙通道 mRNA 在培养的心脏成纤维细胞中高度表达。TGF-β1（5ng/ml）显著增加 Smad2 磷酸化和[（3）H]亮氨酸掺入，依福地平（10µM）预处理可减弱这种作用。非洛地平（10µM），一种选择性 T 型 CCB，尼卡地平（10µM），一种选择性 L 型 CCB，均不能有效抑制 TGF-β1诱导的 Smad2 磷酸化和[（3）H]亮氨酸掺入。然而，R(-)efonidipine 和 nifedipine 的联合、EDTA 或无钙培养基均可显著减弱其作用。Smad2 siRNA 预处理可显著减弱 TGF-β1诱导的[（3）H]亮氨酸掺入。这些数据表明，依福地平通过心脏成纤维细胞中的 T 型和 L 型钙通道阻断作用，对 TGF-β1 和 Smad2 依赖性蛋白合成产生抑制作用。
