Contribution of p62/SQSTM1 to PDGF-BB-induced myofibroblast-like phenotypic transition in vascular smooth muscle cells lacking Smpd1 gene.
Contribution of p62/SQSTM1 to PDGF-BB-induced myofibroblast-like phenotypic transition in vascular smooth muscle cells lacking Smpd1 gene.
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DOI：
10.1038/s41419-018-1197-2
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发表时间：
2018-11-19
影响因子：
9
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang P;Guan Y;Chen J;Li X;McConnell BK;Zhou W;Boini KM;Zhang Y
越来越多的证据表明自噬在调节动脉粥样硬化形成中血管平滑肌细胞（SMC）稳态中发挥着关键作用。然而，关于自噬在 PDGF-BB 诱导的 SMC 向合成表型和细胞外基质重塑转变中的调节作用知之甚少。我们最近证明酸性鞘磷脂酶（ASM，由 Smpd1 基因编码）控制冠状动脉 SMC 中的自噬成熟。在这里，我们证明 PDGF-BB 刺激会导致 Smpd1−/− SMC 中肌成纤维细胞样的非典型合成表型转变。 PDGF-BB 在 Smpd1−/− SMC 中诱导的这些非典型表型变化的特点是成纤维细胞特异性蛋白 (FSP-1) 表达增加、I 型胶原大量沉积、细胞大小减小、炎症状态升高、细胞因子释放和粘附分子表达增强。从机制上讲，PDGF-BB 会诱导 Akt 激活延长，从而导致自噬体生物合成减少，从而加剧 Smpd1−/− SMC 中 p62/SQSTM1 的积累。更重要的是，Akt 抑制或 p62/SQSTM1 基因沉默减弱了 PDGF-BB 诱导的 Smpd1−/− SMC 中的表型变化。 Smpd1−/− SMC 中 p62/SQSTM1 依赖性肌成纤维细胞样表型转变的首次证明表明，ASM 介导的自噬途径有助于在动脉粥样硬化期间血管重塑的情况下维持动脉平滑肌稳态。
Accumulating evidence indicates a critical role of autophagy in regulating vascular smooth muscle cell (SMC) homeostasis in atherogenesis. However, little is known about the modulatory role of autophagy in PDGF-BB-induced SMC transition towards the synthetic phenotype and extracellular matrix remodeling. We recently demonstrated that acid sphingomyelinase (ASM, encoded by Smpd1 gene) controls autophagy maturation in coronary arterial SMCs. Here, we demonstrate that PDGF-BB stimulation causes a myofibroblast-like non-canonical synthetic phenotype transition in Smpd1−/− SMCs. These non-canonical phenotypic changes induced by PDGF-BB in Smpd1−/− SMCs were characterized by increased expression of fibroblast-specific protein (FSP-1), massive deposition of collagen type I, decreased cell size, elevated inflammatory status with enhanced cytokine release and adhesion molecule expression. Mechanistically, PDGF-BB induces prolonged Akt activation that causes decreased autophagosome biogenesis and thereby exaggerates p62/SQSTM1 accumulation in Smpd1−/− SMCs. More importantly, Akt inhibition or p62/SQSTM1 gene silencing attenuates PDGF-BB-induced phenotypic changes in Smpd1−/− SMCs. This first demonstration of a p62/SQSTM1-dependent myofibroblast-like phenotypic transition in Smpd1−/− SMCs suggests that ASM-mediated autophagy pathway contributes to maintaining the arterial smooth muscle homeostasis in situation of vascular remodeling during atherosclerosis.
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影响因子：
4.7
作者：
Li, Xiang;Han, Wei-Qing;Boini, Krishna M.;Xia, Min;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan
影响因子：
5.6
作者：
Kendall RT;Feghali-Bostwick CA
通讯作者：
Feghali-Bostwick CA
影响因子：
4.7
作者：
Demaria S;Formenti SC
通讯作者：
Formenti SC
DOI：
10.1161/atvbaha.111.232785
发表时间：
2011-10
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Long X;Slivano OJ;Cowan SL;Georger MA;Lee TH;Miano JM
通讯作者：
Miano JM
影响因子：
3.5
作者：
Leger, Andrew J.;Mosquea, Leocadia M.;Yew, Nelson S.
通讯作者：
Yew, Nelson S.