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MiR-145 alleviates Hcy-induced VSMC proliferation, migration, and phenotypic switch through repression of the PI3K/Akt/mTOR pathway

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Abstract

The proliferation, migration, and cellular morphology of vascular smooth muscle cells (VSMCs) play important roles in the pathogenesis of atherosclerosis (AS). Homocysteine (Hcy) is a sulfur-containing amino acid, which is an intermediate product of methionine metabolism. Hcy can induce proliferation, migration, and phenotypic switch of VSMCs, but details of these mechanisms are still unclear. The phosphatidylinositol 3-kinase (PI3K/Akt/mTOR) signaling pathway is involved in a host of cellular functions. In this study, we sought to determine if this multifunctional pathway played a role in Hcy-induced proliferation, migration, and phenotypic transformation of VSMCs, which has not been previously reported. miR-145 has been previously reported to suppress the effects of Hcy in VSMCs. In our study, using qRT-PCR, we found that Hcy itself reduced the expression of miR-145 in VSMCs, while overexpression of miR-145 reduced the proliferation, migration, and phenotypic transformation of VSMCs caused by Hcy. Using Western blot analysis, we found that VSMCs exposed to Hcy exhibited significant increases in the levels of PI3K, Akt, and mTOR proteins. Additionally, overexpression of miR-145 dramatically decreased PI3K, Akt, and mTOR expression. Using qRT-PCR we found that miR-145 expression increased after blocking PI3K using an inhibitor. Inhibition of the PI3K signaling pathway also prevented Hcy-induced VSMC proliferation, migration, and phenotypic switch. Taken together, our results suggest that miR-145 could inhibit VSMC proliferation, migration, and phenotype switching by preventing activation of the PI3K/Akt/mTOR signaling pathway.

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Acknowledgements

Thanks to Xi'an Jiaotong University, Ningxia Medical University and the fund Ningxia High School first-class Disciplines (West China first-class Disciplines Basic Medical Sciences at Ningxia Medical University) NXYLXK2017B07, (Natural Science Foundation of Ningxia Province) 2019AAC03081 and National Natural Science Foundation of China (No. 81770459 and No. 81873520).

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Author notes

  1. Minghao Zhang, Fan Li, and Xiuyu Wang contributed equally to this work and should be considered as co-first authors.

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, China

    Minghao Zhang, Yushan Xian, Guan Wang, Zihan Zheng, Chenxu Shang, Bo Wang, Yanhao He & Rong Lin

  2. School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China

    Minghao Zhang, Fan Li, Xiuyu Wang & Jian Gong

  3. Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, China

    Weirong Wang

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  1. Minghao Zhang
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Correspondence to Rong Lin.

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Zhang, M., Li, F., Wang, X. et al. MiR-145 alleviates Hcy-induced VSMC proliferation, migration, and phenotypic switch through repression of the PI3K/Akt/mTOR pathway. Histochem Cell Biol 153, 357–366 (2020). https://doi.org/10.1007/s00418-020-01847-z

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