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.
Funding Information
  • Ningxia High School first-class Discipline (NXYLXK2017B07)
  • Natural Science Foundation of Ningxia Province (2019AAC03081)
  • National Natural Science Foundation of China (No. 81770459, No. 81970369)

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