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Acid Sphingomyelinase Regulates AdipoRon-Induced Differentiation of Arterial Smooth Muscle Cells via TFEB Activation
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Acid Sphingomyelinase Regulates AdipoRon-Induced Differentiation of Arterial Smooth Muscle Cells via TFEB Activation
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Acid Sphingomyelinase Regulates AdipoRon-Induced Differentiation of Arterial Smooth Muscle Cells via TFEB Activation
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Journal Article
Acid Sphingomyelinase Regulates AdipoRon-Induced Differentiation of Arterial Smooth Muscle Cells via TFEB Activation
2025
Overview
AdipoRon is a selective adiponectin receptor agonist that inhibits vascular remodeling by promoting the differentiation of arterial smooth muscle cells (SMCs). Our recent studies have demonstrated that activation of TFEB and its downstream autophagy–lysosomal signaling contribute to adipoRon-induced differentiation of SMCs. The present study was designed to examine whether acid sphingomyelinase (ASM; gene symbol Smpd1) is involved in mediating adipoRon-induced activation of TFEB–autophagy signaling and inhibition of proliferation/migration in arterial SMCs. Our results showed that adipoRon induced ASM expression and ceramide production in Smpd1+/+ SMCs, which were abolished in Smpd1−/− SMCs. Compared to Smpd1+/+ SMCs, Smpd1−/− SMCs exhibited less TFEB nuclear translocation and activation of autophagy signaling induced by adipoRon stimulation. SMC differentiation was further characterized by retarded wound healing, reduced proliferation, F-actin reorganization, and MMP downregulation. The results showed that Smpd1−/− SMCs were less responsive to adipoRon-induced differentiation than Smpd1+/+ SMCs. Mechanistically, adipoRon increased the expression of protein phosphatases such as calcineurin and PP2A in Smpd1+/+ SMCs. The calcineurin inhibitor FK506/cyclosporin A or PP2A inhibitor okadaic acid significantly attenuated adipoRon-induced activation of TFEB–autophagy signaling. In addition, adipoRon-induced expressions of calcineurin and PP2A were not observed in Smpd1−/− SMCs. However, activation of calcineurin by lysosomal TRPML1-Ca2+ channel agonist ML-SA1 rescued the activation of TFEB–autophagy signaling and the effects of adipoRon on cell differentiation in Smpd1−/− SMCs. Taken together, these data suggested that ASM regulates adipoRon-induced SMC differentiation through TFEB activation. This study provided novel mechanistic insights into the therapeutic effects of adipoRon on TFEB signaling and pathological vascular remodeling.
Publisher
MDPI AG,MDPI
Subject
/ Acids
/ Animals
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
/ Cell Differentiation - drug effects
/ Cell Movement - drug effects
/ Cell Proliferation - drug effects
/ Enzymes
/ Genes
/ Kinases
/ Mice
/ Muscle, Smooth, Vascular - cytology
/ Muscle, Smooth, Vascular - drug effects
/ Muscle, Smooth, Vascular - metabolism
/ Myocytes, Smooth Muscle - cytology
/ Myocytes, Smooth Muscle - drug effects
/ Myocytes, Smooth Muscle - metabolism
/ Proteins
/ Signal Transduction - drug effects
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