Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, USA.
Cell Death Dis. 2018 Nov 19;9(12):1145. doi: 10.1038/s41419-018-1197-2.
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.
越来越多的证据表明自噬在动脉粥样硬化发生过程中调节血管平滑肌细胞 (SMC) 稳态方面起着关键作用。然而，自噬在血小板衍生生长因子-BB (PDGF-BB) 诱导的 SMC 向合成表型和细胞外基质重塑的转化中所起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 刺激导致 Smpd1 SMC 中出现肌成纤维细胞样非典型合成表型转化。PDGF-BB 在 Smpd1 SMC 中诱导的这些非典型表型变化的特征是成纤维细胞特异性蛋白 (FSP-1) 的表达增加、I 型胶原大量沉积、细胞体积减小、炎症状态增强，细胞因子释放和粘附分子表达增加。在机制上，PDGF-BB 诱导 Akt 的持续激活，导致自噬体生物发生减少，从而使 Smpd1 SMC 中的 p62/SQSTM1 积累增加。更重要的是，Akt 抑制或 p62/SQSTM1 基因沉默可减弱 PDGF-BB 诱导的 Smpd1 SMC 中的表型变化。这是首次在 Smpd1 SMC 中证明 p62/SQSTM1 依赖性肌成纤维细胞样表型转化，表明 ASM 介导的自噬途径有助于在动脉粥样硬化期间的血管重塑过程中维持动脉平滑肌的稳态。
