Abstract
Upon vascular injury, vascular smooth muscle cells (VSMCs) change from a contractile phenotype to a synthetic phenotype, thereby leading to atherogenesis and arterial restenosis. Myocardin (MYOCD) is essential for maintaining the contractile phenotype of VSMCs. Deletion of MYOCD in VSMCs triggers autophagy. However, the molecular mechanism underlying the effect of MYOCD on autophagy is not clear. In this study, knockdown of MYOCD in human aortic VSMCs (HA-VSMCs) triggered autophagy and diminished the expression of SMC contractile proteins. Inhibition of autophagy in MYOCD-knockdown cells restored the expression of contractile proteins. MYOCD activated the transcription of miR-30a by binding to the CArG box present in its promoter, as confirmed by luciferase reporter and chromatin immune coprecipitation assays, while miR-30a decreased the expression of autophagy protein-6 (ATG6, also known as beclin1) by targeting its 3′UTR. Restoring the expression of miR-30a in MYOCD-knockdown cells upregulated the levels of contractile proteins. Treatment of VSMCs with platelet-derived growth factor type BB (PDGF-BB) resulted in the transformation of VSMCs to a proliferative phenotype. A low level of miR-30a was observed in PDGF-BB-treated HA-VSMCs, and re-expression of miR-30a led to a decrease in proliferative marker expression. Furthermore, using a wire injury mouse model, we found that miR-30a expression was significantly downregulated in the arterial tissues of mice and that restoration of miR-30a expression at the injured site abolished neointimal formation. Herein, MYOCD could inhibit autophagy by activating the transcription of miR-30a and that miR-30a-mediated autophagy defects could inhibit intimal hyperplasia in a carotid arterial injury model.
Highlights
The switching of vascular smooth muscle cells (VSMCs) from a contractile, quiescent or differentiation phenotype to an adverse, synthetic, proliferative or dedifferentiation phenotype plays an important role in the pathogenesis of various vascular proliferative diseases, including atherosclerosis, restenosis, and aneurysm
In line with previous studies [10], we found that platelet-derived growth factor type BB (PDGF-BB) triggered autophagy in HA-VSMCs, as confirmed by the increase in beclin1 protein and LC3II/LC3I and the decrease in P62 protein (Fig. 5F and G)
Inhibition of autophagy with 3-MA stabilized the expression of SM22α and ACTA2 in PDGF-BB-treated HA-VSMCs (Fig. 5J and K). These results indicated that PDGF-BB could induce HA-VSMC proliferation and trigger autophagy, while inhibition of autophagy could maintain the contractile phenotype
Summary
The switching of vascular smooth muscle cells (VSMCs) from a contractile, quiescent or differentiation phenotype to an adverse, synthetic, proliferative or dedifferentiation phenotype plays an important role in the pathogenesis of various vascular proliferative diseases, including atherosclerosis, restenosis, and aneurysm. Using tamoxifen-treated SMMHC-CreERT2/ MyocdF/F conditional mutant mice, Jianhe Huang et al confirmed that loss of MYOCD markedly decreased the expression of SMC contractile proteins and induced cell autonomous autophagy [4] This phenomenon suggests a new feature of MYOCD in regulating autophagy. It is not clear why the loss of MYOCD causes autophagy activation in SMCs. Increasing evidence has confirmed the critical role of autophagy in the smooth muscle cell phenotype switch. We regions of miR-30a-5p was constructed, and the luciferase found that MYOCD could maintain the expression of SMC assay was performed in MYOCD overexpression or knockdown contractile proteins by upregulating miRNA-30a-5p and inhibiting cells. To further confirm the specific binding of MYOCD to the miR-30a-5p promoter, ChIP assays were
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