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MiR-126-5p promotes contractile switching of aortic smooth muscle cells by targeting VEPH1 and alleviates Ang II-induced abdominal aortic aneurysm in mice

Abstract

Abdominal aortic aneurysm (AAA) is a potential lethal disease that is defined by an irreversible dilatation (>50%) of the aorta. During AAA expansion, the aortic wall is often remodeled, which is featured by extracellular matrix (ECM) degeneration, medial and adventitial inflammation, depletion and phenotypic switching of vascular smooth muscle cells (SMCs). Recent studies have suggested microRNAs as vital regulators for vascular SMC function. Our earlier work demonstrated an anti-AAA role of miR-126-5p in ApoE/− mice infused with angiotensin (Ang) II. The present study aimed to further elucidate its role in AAA pathogenesis with a focus on aortic SMC phenotypic switching. Ventricular zone expressed PH domain containing 1 (VEPH1) was identified as a novel negative regulator for vascular SMC differentiation by our group, and its expression was negatively correlated to miR-126-5p in mouse abdominal aortas based on the present microarray data. In vivo, in addition attenuating Ang II infusion-induced aortic dilation and elastin degradation, miR-126-5p agomirs also significantly reduced the expression of VEPH1. In vitro, to induce synthetic transition of human aortic smooth muscle cells (hAoSMCs), cells were stimulated with 1 μM Ang II for 24 h. Ectopic overexpression of miR-126-5p restored the differentiation of hAoSMCs—the expression of contractile/differentiated SMC markers, MYH11, and α-SMA, increased, whilst that of synthetic/dedifferentiated SMC markers, PCNA and Vimentin, decreased. Both mus and homo VEPH1 genes were validated as direct targets for miR-126-5p. VEPH1 re-expression impaired miR-126-5p-induced differentiation of hAoSMCs. In addition, Ang II-induced upregulation in matrix metalloproteinase (MMP)-9 and MMP2, two key proteases responsible for ECM degradation, in mouse aortas and hAoSMCs was reduced by miR-126-5p overexpression as well. Collectively, these results reveal an important, but previously unexplored, role of miR-126-5p in inhibiting AAA development-associated aortic SMC dedifferentiation.

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Fig. 1: MiR-126-5p agomirs limit murine AAA formation and reduced VEPH1 expression.
Fig. 2: Overexpression of miR-126-5p inhibits MMP activation induced by Ang II in hAoSMCs.
Fig. 3: Overexpression of miR-126-5p suppresses Ang II-induced synthetic phenotype of hAoSMCs.
Fig. 4: MiR-126-5p negatively regulates VEPH1 expression in hAoSMCs.
Fig. 5: MiR-126-5p directly targets both mus and homo VEPH1 mRNA.
Fig. 6: Re-expression of VEPH1 impaired miR-126-5p-triggered hAoSMC differentiation.

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Correspondence to Lei Li.

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This study was approved by the Ethic Committee of Dalian Medical University. The animal experiments conformed to the NIH Guide for Care and Use of Laboratory Animals.

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Shi, X., Ma, W., Pan, Y. et al. MiR-126-5p promotes contractile switching of aortic smooth muscle cells by targeting VEPH1 and alleviates Ang II-induced abdominal aortic aneurysm in mice. Lab Invest 100, 1564–1574 (2020). https://doi.org/10.1038/s41374-020-0454-z

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