Abstract
Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.
Highlights
Coronary stents are routinely placed in the treatment of coronary artery disease (CAD)
Vascular injury caused by angioplasty, stenting, or bypass surgery triggers phenotypic switch of vascular smooth muscle cells (VSMCs) and subsequent abnormal proliferation and migration of VSMCs, leading to excessive formation of neointima, which contributes to occlusive vascular diseases such as atherosclerosis, intimal hyperplasia associated with restenosis, and vein graft stenosis [6,7,8,9]
To investigate whether MIA SH3 Domain ER Export Factor 3 (MIA3) is associated with VSMC proliferation, we treated the cultured human aortic smooth muscle cells (HASMCs) with FBS, and our data revealed that MIA3 is expressed in VSMCs and the mRNA and protein level of MIA3 in cultured proliferating HASMCs are significantly increased compared with the serum-starved quiescent HASMCs, whereas SMC contractile gene a-SMA was significantly reduced (Figures 1A–C)
Summary
Coronary stents are routinely placed in the treatment of coronary artery disease (CAD). Knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. This preliminary study provides new insights into the role and molecular mechanisms of MIA3 controlling function of VSMC and PVAT and identifies a novel potential target for suppression of neointimal formation.The authors declare that all supporting data are available within the article and its online supplementary file. Following wash with PBS for three times, slides were mounted with vectashield mounting medium containing DAPI (Vector Laboratories, Burlingame, CA, USA) and imaged using fluorescent microscope. In the cell counting assay, VSMCs transfected with MIA3 siRNA or overexpressing vector and scramble siRNA or control empty vector were seeded at an initial density of 2 × 104 per well in a 12-well plate in VSMC culture medium with 10% FBS, and the cells were harvested and counted at the designated time points. Statistical analyses were performed in SPSS version 13.0 (SPSS, Inc., Chicago, IL). p < 0.05 was considered to indicate a statistically significant difference
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