Suppression of miR-4463 promotes phenotypic switching in VSMCs treated with Ox-LDL
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REGULAR ARTICLE
Suppression of miR-4463 promotes phenotypic switching in VSMCs treated with Ox-LDL Xueqin Wang 1,2 & Hui Li 3 & Yuetian Zhang 1 & Qi Liu 4 & Xiaolei Sun 5 & Xuemei He 6 & Qian Yang 7 & Ping Yuan 8 & Xiangyu Zhou 5 Received: 15 March 2020 / Accepted: 5 November 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Vascular smooth muscle cell (VSMC) phenotypic switching is a hallmark of vascular remodeling that contributes to atherosclerotic diseases. MicroRNA 4463 (miR-4463) has been implicated in the development of arteriosclerosis obliterans, whereas the underlying mechanisms in VSMCs have not been fully addressed. In this study, we assessed whether miR-4463 is involved in the phenotypic switching process in VSMCs. Oxidized low-density lipoprotein (Ox-LDL, 50 mg/L) was used to simulate the oxidative stress condition, and miR-4463 expression in VSMCs was detected by a quantitative polymerase chain reaction. To determine the effect of Ox-LDL-mediated regulation of miR-4463 on the phenotypic switching of VSMCs, cell counting kit-8, cell migration assays, and cytoskeleton test were performed. After using specific antagonists of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), the relationship between miR-4463 and its downstream signaling proteins was explored. Ox-LDL induced oxidative stress to promote VSMC transformation from contraction to secretion, which clearly decreased the level of miR-4463. Then, downregulated miR-4463 enhanced the migration and phenotypic transformation of VSMCs and activated the phosphorylation of JNK and ERK; these effects were increased after Ox-LDL induction. As expected, inhibiting the two signaling proteins blocked the effect of the miR-4463 inhibitor combined with Ox-LDL. In addition, inhibition of miR-4463 led to the upregulation of basic fibroblast growth factor (bFGF) expression. The results of this study demonstrate that miR-4463 is a novel regulator of VSMC function in hypoxic conditions and modulates VSMC phenotypic switching via the JNK and ERK signaling pathways; bFGF may be the target gene of miR-4463. Keywords Ox-LDL . miR-4463 . VSMC . Phenotypic switching . Migration
Introduction Atherosclerosis (AS) is a chronic inflammatory disease that is characterized by remodeling of the tunica media and tunica
intima and eventually leads to loss of elasticity of the vessel wall and arterial occlusion formation. Among the functional cells attributed to the pathogenesis of AS, the phenotypic switching of vascular smooth muscle cells (VSMCs) is
Xueqin Wang and Hui Li contributed equally to this work. * Xiangyu Zhou [email protected]
5
Department of Thyroid and Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Luzhou 646000, China
6
Medical Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
1
Department of Basic Surgery, People’s
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