PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress.
PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress.
复制标题
DOI：
10.1042/bj20121344
复制
发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Hill BG
中科院分区：
文献类型：
--
作者：
Salabei JK;Cummins TD;Singh M;Jones SP;Bhatnagar A;Hill BG
血管损伤和慢性动脉疾病导致血管平滑肌细胞（VSMCs）暴露于浓度增加的生长因子。生长因子触发VSMC表型转变的机制尚不清楚。由于细胞重编程启动的生长因子不仅需要参与细胞增殖的基因的诱导，但也去除收缩蛋白，我们假设自噬是一个重要的调节VSMC表型。用血小板衍生生长因子（PDGF）-BB处理VSMC导致收缩表型标志物钙调蛋白和α-平滑肌肌动蛋白表达减少，合成表型标志物骨桥蛋白和波形蛋白表达上调。通过LC 3-II丰度、LC 3斑点形成和电子显微镜评估，自噬被PDGF暴露激活。用3-甲基腺嘌呤、spautin-1或巴弗洛霉素抑制自噬稳定了收缩表型。尤其是spautin-1可显著稳定PDGF处理的细胞中的α-平滑肌细胞肌动蛋白和钙调蛋白，并防止肌动蛋白丝的解体，减少细胞外基质的产生，消除VSMC的过度增殖和迁移。有趣的是，用PDGF处理细胞可以防止由于暴露于脂质过氧化产物4-羟基壬烯醛而导致的蛋白质损伤和细胞死亡。这些结果证明了由PDGF诱导的独特形式的自噬对于获得合成表型和在发现发生在血管病变中的高氧化应激条件下的存活是必需的。
Vascular injury and chronic arterial diseases result in exposure of vascular smooth muscle cells (VSMCs) to increased concentrations of growth factors. The mechanisms by which growth factors trigger VSMC phenotype transitions remain unclear. Because cellular reprogramming initiated by growth factors requires not only the induction of genes involved in cell proliferation but also the removal of contractile proteins, we hypothesized that autophagy is an essential modulator of VSMC phenotype. Treatment of VSMCs with platelet-derived growth factor (PDGF)-BB resulted in decreased expression of the contractile phenotype markers calponin and α-smooth muscle actin and upregulation of the synthetic phenotype markers osteopontin and vimentin. Autophagy, as assessed by LC3-II abundance, LC3 puncta formation and electron microscopy, was activated by PDGF exposure. Inhibition of autophagy with 3-methyladenine, spautin-1, or bafilomycin stabilized the contractile phenotype. In particular, spautin-1 led to a remarkable stabilization α-smooth muscle cell actin and calponin in PDGF-treated cells and prevented actin filament disorganization, diminished production of extracellular matrix and abrogated VSMC hyperproliferation and migration. Interestingly, treatment of cells with PDGF prevented protein damage and cell death due to exposure to the lipid peroxidation product, 4-hydroxynonenal. These results demonstrate a distinct form of autophagy induced by PDGF that is essential for attaining the synthetic phenotype and for survival under conditions of high oxidative stress found to occur in vascular lesions.