Ryanodine Receptor Type 2 Plays a Role in the Development of Cardiac Fibrosis under Mechanical Stretch Through TGFβ-1
Ryanodine Receptor Type 2 Plays a Role in the Development of Cardiac Fibrosis under Mechanical Stretch Through TGFβ-1
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DOI：
10.1536/ihj.16-572
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发表时间：
2017-11-01
影响因子：
1.5
通讯作者：
Zou, Yunzeng
中科院分区：
文献类型：
--
作者：
Ding, Zhiwen;Yuan, Jie;Zou, Yunzeng
Ryanodine receptor 2 （RyR-2）是心肌细胞肌浆网Ca2+释放的主要通道，在心肌收缩功能和心肌肥厚的调控中起重要作用。然而，RyR-2在心肌肥厚发生过程中在心肌纤维化中的作用尚不清楚。在本研究中，我们利用培养的新生大鼠心肌细胞和心脏成纤维细胞，检测RyR-2是否调节心肌细胞分泌的TGF β 1对心脏纤维化的作用。RyR-2仅在心肌细胞中表达，在心肌成纤维细胞中不表达。机械拉伸诱导心肌细胞TGF β 1表达上调，RyR-2敲低显著抑制TGF β 1表达上调。与野生型相比，成纤维细胞中胶原基因的转录水平也有所下降，尽管这两种基因的表达均高于静止心肌细胞（非拉伸）。在TGF β 1中和抗体的抑制下，机械拉伸心肌细胞与非机械拉伸心肌细胞的胶原基因表达无显著差异。这些结果表明，RyR-2调节机械拉伸心肌细胞中TGF β 1的表达，TGF β 1通过旁分泌机制促进心肌成纤维细胞胶原的形成。机械拉伸中RyR-2可通过TGF β 1依赖性旁分泌机制促进心肌纤维化的发生。我们的发现为全面理解RyR-2在调节心脏纤维化中的分子作用提供了更多的见解。
Ryanodine receptor type 2 (RyR-2), the main Ca2+ release channel from sarcoplasmic reticulum in cardiomyocytes, plays a vital role in the regulation ofmyocardial contractile function and cardiac hypertrophy. However, the role of RyR-2 in cardiac fibrosis during the development of cardiac hypertrophy remains unclear.In this study, we examined whether RyR-2 regulates TGF beta 1, which is secreted from cardiomyocytes and exerts on cardiac fibrosis using cultured cardiomyocytes and cardiac fibroblasts of neonatal rats. The expression of RyR-2 was found only in cardiomyocytesbut not in cardiac fibroblasts. Mechanical stretch induced upregulation of TGF beta 1 in cardiomyocytes and RyR-2 knockdown significantly suppressed the upregulation of TGF beta 1 expression. The transcript levels of collagen genes were also decreased in fibroblasts compare with wild type, although the expression of both two kinds was higher than those in stationary cardiomyocytes (non-stretch). With the inhibition of the TGF beta 1-neutralizing antibody, the expression of collagen genes has no significant difference between the mechanically stretched cardiomyocytes and non-stretchedones. These results indicate that RyR-2 regulated TGF beta 1 expression in mechanically stretched cardiomyocytes and TGF beta 1 promoted collagen formation of cardiac fibroblasts by a paracrine mechanism.RyR-2 in mechanical stretch could promote the development of cardiac fibrosis involving TGF beta 1-dependent paracrine mechanism. Our findings provided more insight into comprehensively understanding the molecular role of RyR-2 in regulating cardiac fibrosis.