Abstract
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.
Highlights
Vascular smooth muscle cell (SMC) is a highly specialized and differentiated cell and major constitute of blood vessels
Neither rapamycin nor its combination with Platelet-derived growth factor-BB (PDGF-BB) had any effect on FSP-1 in Smpd1+/+ SMCs. These results suggested that restoration of autophagy may at least partially prevent PDGF-BB-induced myofibroblast-like transition in Smpd1−/− SMCs
FSP-1 gene expression was more drastically reduced by p62/ SQSTM1 silencing compared to IL-6, which might indicate that FSP-1 gene requires a higher threshold of p62/ SQSTM1 level for its gene induction. These findings suggest that Akt-p62/SQSTM1 pathway contributes to the myofibroblast transition of Smpd1−/− SMCs upon PDGF-BB stimulation
Summary
Vascular smooth muscle cell (SMC) is a highly specialized and differentiated cell and major constitute of blood vessels. SMCs within the adult blood vessel possess contractile phenotype and exhibit a very low synthetic activity. SMCs can switch from a differentiated (contractile) phenotype to a dedifferentiated (synthetic) state that SMCs become proliferative and migratory. Zhang et al Cell Death and Disease (2018)9:1145 acquired a phenotype intermediate between fibroblasts and SMCs. Zhang et al Cell Death and Disease (2018)9:1145 acquired a phenotype intermediate between fibroblasts and SMCs They are contractile cells expressing α-smooth muscle actin (α-SMA), the actin isoform typical of vascular SMCs, and have a flattened and irregular morphology. The signaling pathways and mediators through which the SMCs switch to the inflammatory myofibroblasts remain largely undefined
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