Abstract
Accumulating evidence indicate a critical role of acid sphingomyelinase (gene symbol Smpd1), a lysosomal hydrolase metabolizes sphingomyelin into ceramide, in controlling autophagic flux and vascular smooth muscle cell (SMC) homeostasis in atherogenesis. However, it remains elusive whether or not acid sphingomyelinase and autophagy play a modulatory role in SMC transition towards myofibroblast phenotype and extracellular matrix remodeling. In primary cultured SMCs from mouse coronary arteries, we demonstrated that PDGF‐BB stimulation produced an augmented proliferation in Smpd1−/− SMCs compared to Smpd1+/+ SMCs. More interestingly, PDGF‐BB induced more pronounced upregulation of fibroblast specific protein (FSP‐1), deposition of collagen type I, and expression of TGFβ1 in SMCs when Smpd1 is deleted. The increases in fibroblast markers in Smpd1−/− SMCs by PDGF‐BB were also accompanied by markedly elevated inflammatory status as shown by increased release of inflammatory cytokines (IL6 and IL18), expression of ICAM‐1, and monocyte adhesion. These data suggest that PDGF‐BB promotes a phenotypic transition in SMCs toward a myofibroblast‐like phenotype in the absence of acid sphingomyelinase function. Mechanistically, PDGF‐BB induced an exacerbated accumulation of autophagy substrate p62 in Smpd1−/− SMCs compared to Smpd1+/+ SMCs. In addition to impaired autophagic flux, autophagosome formation in Smpd1−/− SMCs was also suppressed by PDGF‐BB due to prolonged activation of Akt‐mTOR signaling, which further contributes to exacerbated p62 accumulation. Lastly, Akt inhibition or p62 gene silencing attenuated PDGF‐BB‐induced phenotypic changes observed in Smpd1−/− SMCs. Together, our data demonstrate, for the time, a p62‐dependent myofibroblast‐like phenotypic transition in Smpd1−/− SMCs, which indicates that acid sphingomyelinase‐regulated autophagy signaling plays a crucial role in maintaining the arterial smooth muscle homeostasis.Support or Funding InformationNational Heart, Lung, and Blood Institute grants (HL122769, HL122937) and the Young Scientists Fund of National Nature Science Foundation of China (No. 81202095).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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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