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. 2025 Apr 29;52(1):437.
doi: 10.1007/s11033-025-10532-0.

Regulation of vascular smooth muscle cells phenotype by metformin up-regulated miR-1/ CCND1 axis via targeting AMPK/TGF-β signaling pathway

Yulin Luo #  1 , Mengting Li #  1   2   3 , Jingcan You  1   2   3 , Jun Jiang  4   5 , Min Zeng  6 , Mao Luo  7   8   9
Affiliations

Regulation of vascular smooth muscle cells phenotype by metformin up-regulated miR-1/ CCND1 axis via targeting AMPK/TGF-β signaling pathway

Yulin Luo et al. Mol Biol Rep. .

Abstract

The phenotypic switch of vascular smooth muscle cells (VSMCs), characterized by the tissue-specific expression of certain microRNAs (miRNAs), is a critical factor in the development of diabetic vascular diseases. Metformin, a widely prescribed anti-diabetic medication for type 2 diabetes treatment, activates the adenosine monophosphate-activated protein kinase (AMPK) pathway and exerts a protective effect on vascular endothelium. Although the regulatory effects of metformin on the switch of the vascular smooth muscle cell phenotype have been identified, the specific role of miRNAs in this process remains unclear. We identified a specific miR-1 in response to metformin treatment and determined its effects on both miR-1 and its targets. Subsequently, we investigated the influence of these factors on the metformin-induced phenotype switch in vascular smooth muscle cells, specifically focusing on proliferation and migration, as well as activation of the AMPK/Transforming Growth Factor (TGF-β) axis. This was achieved using various methodologies, including bioinformatics analysis, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, wound scratch assays, and Cell Counting Kit-8 assays. Our findings showed that metformin upregulated miR-1, which directly targets cyclin D1 (CCND1) in VSMCs. Metformin was observed to enhance the expression of contractile phenotype proteins, including α-smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SMMHC), while simultaneously reducing the expression of proliferative phenotype proteins such as CCND1 and proliferating cell nuclear antigen (PCNA). The inhibition of miR-1 was found to reverse the effects of metformin on the phenotypic switch of VSMCs. This occurs partly through the AMPK/TGF-β signaling pathway and inhibits the migration and proliferation of VSMCs.

Keywords: CCND1; Metformin; VSMC phenotype; miR-1.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Informed consent Statement: Not applicable.

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