miRNA-145 inhibits VSMC proliferation by targeting CD40

Abstract

Recent studies have demonstrated functions of miR-145 in vascular smooth muscle cells (VSMCs) phenotypes and vascular diseases. In this study, we aim to determine whether CD40 is involved in miR-145 mediated switch of VSMC phenotypes. In cultured VSMCs, the effects of miR-145 and CD40 on TNF-α, TGF-β, and Homocysteine (Hcy) induced cell proliferation were evaluated by over-expression of miR-145 or by siRNA-mediated knockdown of CD40. We also used ultrasound imaging to explore the effect of miR-145 on carotid artery intima-media thickness (CIMT) in atherosclerotic cerebral infarction (ACI) patients. The results showed 50 ng/mL TNF-α, 5 ng/mL TGF-β, and 500 μmol/L Hcy significantly increased the expression of CD40, both at mRNA and protein levels, and also induced the proliferation of VSMCs. We found that over-expression of miR-145 significantly inhibited the expression of CD40 and the differentiation of VSMCs, and over-expression of miR-145 decreased IL-6 levels in VSMC supernatants. In ACI patients, the lower expression of miR-145 was associated with thicker CIMT and higher levels of plasma IL-6. Our results suggest that the miR-145/CD40 pathway is involved in regulating VSMC phenotypes in TNF-α, TGF-β, and Hcy induced VSMCs proliferation model. Targeting miR-145/CD40 might be a useful strategy for treating atherosclerosis.

Integrated Analyses Reveal Overexpressed Notch1 Promoting Porcine Satellite Cells’ Proliferation through Regulating the Cell Cycle

“…miR-935 suppresses tumorigenesis of gastric signet ring cell carcinoma by targeting Notch1 [ 78 ]. miRNA-145 inhibits VSMC proliferation by targeting CD40 [ 79 ]. VSMC differentiation signals potentially can be fine-tuned or amplified by miR-143/145 through Notch and SRF in parallel pathways [ 80 ].…”

MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling

“…Recently, studies have demonstrated that PDGF-bb treatment differentially regulated the expression of miRNAs in VSMCs. In some studies, PDGF-bb treatment induced the up-regulation of miRNAs such as miR-15b, miR-541 and miR-146b-5p [ 22 – 24 ]; while in other experiments, PDGF-bb treatment suppressed the expression of miRNAs such as miR-599, miR-21 and miR-145 [ 14 , 25 , 26 ]. In the present study, we showed that PDGF-bb treatment suppressed the expression of miR-137.…”

“…MiR-503 was found to inhibit PDGF-bb-induced human aortic VSMCs proliferation and migration via targeting the insulin receptor [ 13 ]. MiR-145 was found to have inhibitory effects on the VSMCs proliferation, and this inhibitory effect was mediated via targeting the CD40 [ 14 ]. On the other hand, miR-34a was found to promote proliferation of human pulmonary artery smooth muscle cells by targeting platelet-derived growth factor alpha [ 15 ], and miR-181b activated the PI3K and MAPK signaling pathways, which subsequently promoted VSMCs proliferation [ 16 ].…”

The Role of MicroRNAs in Arterial Stiffness and Arterial Calcification. An Update and Review of the Literature

“…Moreover, miR-133 indirectly decreases the activity of KLF4 via downregulating the transcription factor Sp-1 (Torella et al, 2011 ). Suppression of CD40, a type I transmembrane glycoprotein receptor, is another mechanism through which miR-145 contributes to the contractile phenotype of VSMC and inhibits TNF-α -mediated VSMC proliferation (Guo et al, 2016 ). Finally, miR-143/145 deficiency negatively regulate vascular tone through impaired vasodilation which is considered to result from increased VSMC switch to the dedifferentiated phenotype (Noratal et al, 2012 ).…”