Contribution of p62/SQSTM1 to PDGF-BB-induced myofibroblast-like phenotypic transition in vascular smooth muscle cells lacking Smpd1 gene

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.

Activation of TFEB ameliorates dedifferentiation of arterial smooth muscle cells and neointima formation in mice with high-fat diet

“…In mice with genetic deletion of LAMP2, a lysosome associated membrane protein that is critical for lysosome function, aberrant autophagy was observed in SMCs that was linked to luminal stenosis and medial thickening 26 . Our recent studies also demonstrated that impaired autophagy maturation due to lysosome dysfunction contributes to imbalanced SMC homeostasis 7,25,27 . In this study, we speculate if enhancement of both autophagy induction and lysosome biogenesis pathways in SMCs comprises a promising strategy that may efficiently reduce aberrant proliferation and migration of SMCs, and eventually prevent intimal hyperplasia and luminal stenosis.…”

“…SMCs were isolated from mice as previously described 27,66 . Six-week-old male C57BL/6J mice were used in the present study.…”

Downregulation of Lysosomal Acid Ceramidase Mediates HMGB1-Induced Migration and Proliferation of Mouse Coronary Arterial Myocytes

“…Coronary arterial myocytes are the primary cell type in blood vessel walls and play essential roles in pathogenesis of vascular diseases. By transforming from the contractile to the synthetic phenotype, the CAMs exhibit distinct proliferative and migratory abilities and produce pro-inflammatory cytokines (Wang K. et al, 2017;Zhang et al, 2018). HMGB1 was demonstrated to stimulate cell proliferation and migration in a variety of mammalian cells including fibroblasts (Chitanuwat et al, 2013), airway SMCs (Hou et al, 2019), osteosarcoma cells (Guo et al, 2014), and cancer cells (He et al, 2018).…”

The Role of NLRP3 Inflammasome in Radiation-Induced Cardiovascular Injury

“…In vitro co-culture experiments showed that VSMCs co-cultured with irradiated human endothelial cells underwent myofibroblastic transition (Milliat et al, 2006). Zhang and colleagues recently reported that PDGF-BB stimulation of Spmd1-deficient VSMCs induced differentiation to a myofibroblast-like phenotype, as evidenced by marked upregulation of fibroblast-specific protein (FSP-1) expression, massive collagen type I deposition, increased IL-6 release, and upregulation of adhesion molecule expression (Zhang et al, 2018). The underlying mechanism of these effects may be due to prolonged Akt activation, and p62/SQSTM1dependent NRF2 upregulation and nuclear translocation.…”