Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells.
Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells.
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内源性二氧化硫通过抑制血管平滑肌细胞中的 TGF-β/Smad 途径减轻胶原重塑
DOI：
10.1038/srep19503
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发表时间：
2016-01-14
影响因子：
4.6
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Huang Y;Shen Z;Chen Q;Huang P;Zhang H;Du S;Geng B;Zhang C;Li K;Tang C;Du J;Jin H
本研究旨在探讨内源性二氧化硫（SO2）在血管平滑肌细胞（VSMCs）胶原重塑中的作用及其机制。内源性so2合成酶-天冬氨酸转氨酶（AAT） 1或2过表达可提高so2水平，抑制转化生长因子(TGF)-β1诱导的VSMCs中胶原I和III的表达。相比之下，AAT1或AAT2敲低诱导TGF-β1处理的VSMCs发生严重的胶原沉积。此外，AAT1或AAT2过表达抑制前胶原I和III mRNA，上调基质金属蛋白酶(MMP)-13表达，下调MMP-1组织抑制剂水平，反之亦然。在机制上，AAT1或AAT2过表达抑制TGF-β1刺激VSMCs中I型TGF-β受体（t -β ri）和Smad2/3的磷酸化。而TGF-β1/Smad信号通路抑制剂SB431542则可减轻AAT敲除引起的过度胶原沉积。最重要的是，异位表达AAT或外源性添加100 μM so2可阻断AAT缺乏加剧的TGF-β1刺激的VSMCs胶原积累，而100 μM丙酮酸乙酯则没有抑制作用。这些结果表明，内源性so2通过控制TGF-β1/ t -β ri / smad2 /3介导的胶原合成和降解的调节来缓解胶原重塑。
The study was designed to investigate the role of endogenous sulfur dioxide (SO2) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO2synthase aspartate aminotransferase (AAT) 1 or 2 increased SO2levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-β1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-β1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-β receptor (TβRI) and Smad2/3 in TGF-β1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-β1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 μM SO2blocked AAT deficiency-aggravated collagen accumulation in TGF-β1-stimulatd VSMCs, while no inhibition was observed at 100 μM ethyl pyruvate. These findings indicated that endogenous SO2alleviated collagen remodeling by controlling TGF-β1/TβRI/Smad2/3-mediated modulation of collagen synthesis and degradation.