Effect of efonidipine on TGF-β1-induced cardiac fibrosis through Smad2-dependent pathway in rat cardiac fibroblasts.
Effect of efonidipine on TGF-β1-induced cardiac fibrosis through Smad2-dependent pathway in rat cardiac fibroblasts.
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DOI：
10.1254/jphs.11065fp
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发表时间：
2011
影响因子：
3.5
通讯作者：
Nishiyama A
中科院分区：
文献类型：
--
作者：
Lei B;Hitomi H;Mori T;Nagai Y;Deguchi K;Mori H;Masaki T;Nakano D;Kobori H;Kitaura Y;Nishiyama A
转化生长因子β 1（Transforming growth factor beta 1，TGF-β1）在心肌纤维化的发生发展中起着重要作用，可能与细胞内钙离子的变化有关。我们研究了依福地平（一种T型和L型双重钙通道阻滞剂（CCB））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（5 ng/mL）显著增加Smad 2磷酸化和[3 H]-亮氨酸掺入，而依福地平（10 μM）预处理可减弱这一作用。选择性T型CCB的R（−）依福地平（10 μM）和选择性L型CCB的硝苯地平（10 μM）均不能有效抑制TGF-β1诱导的Smad 2磷酸化和[3 H]-亮氨酸掺入。然而，R（-）依福地平和硝苯地平、EDTA或无钙培养基联合使用可显著减弱这两种作用。Smad 2 siRNA预处理显著抑制TGF-β1诱导的[3 H]-亮氨酸掺入。这些数据表明，依非地平通过阻断T型和L型钙通道抑制心脏成纤维细胞中TGF-β1和Smad 2依赖的蛋白合成。
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.