MTMR7 suppresses the phenotypic switching of vascular smooth muscle cell and vascular intimal hyperplasia after injury via regulating p62/mTORC1-mediated glucose metabolism

Abstract Myotubularin-related protein 7 (MTMR7) suppresses the proliferation in various of cell types and is also associated with vascular stenosis-related disease. However, whether MTMR7 regulates the vascular smooth muscle cell (VSMC) and vascular intimal hyperplasia remains unclear. We aimed at exploring the role of MTMR7 in the phenotypic switching of VSMC and vascular intimal hyperplasia after injury. MTMR7 expression was significantly downregulated in injured artery. Compared to wild type (WT) mice, Mtmr7 -transgenic ( Mtmr7 -Tg) mice showed reduced intima/media ratio, decreased percentage of Ki-67-positive cells within neointima, and increased Calponin expression in injured artery. Upregulating MTMR7 by Len- Mtmr7 transfection inhibited platelet derived growth factor (PDGF)-BB-induced proliferation, migration of VSMCs and reversed the decrease in expression of Calponin and SM-MHC. Microarray, single cell sequence, and other bioinformatics analysis revealed that MTMR7 is highly related to glucose metabolism and mammalian target of rapamycin complex 1 (mTORC1). Further experiments confirmed that MTMR7 markedly repressed glycolysis and mTORC1 activity in PDGF-BB-challenged VSMC. Restoring mTORC1 activity abolished MTMR7-mediated suppression of glycolysis, phenotypic shift in VSMC and protection against vascular intimal hyperplasia. Furthermore, upregulating MTMR7 led to dephosphorylation and dissociation of p62 from mTORC1. External expression of p62 also abrogated the inhibitory effects of MTMR7 on glycolysis and phenotypic switching in PDGF-BB-stimulated VSMC. Our study demonstrates that MTMR7 inhibits injury-induced vascular intimal hyperplasia and phenotypic switching of VSMC. Mechanistically, the beneficial effects of MTMR7 are conducted via suppressing p62/mTORC1-mediated glycolysis.