MicroRNA-144 silencing attenuates intimal hyperplasia by directly targeting PTEN

Abstract

Background Intimal hyperplasia contributed by phenotypic switching of vascular smooth muscle cell (VSMC) plays an important role in the pathogenesis of various cardiovascular diseases. MicroRNA-144 (miR-144) is recently reported to be implicated in the development of atherosclerosis. However, the individual role of miR-144 in VSMCs phenotypic modulation and intimal hyperplasia currently still remains unknown. Methods and Results Here we found that miR-144 expression was upregulated in carotid arteries with intimal hyperplasia that subjected to wire injury and the consistent results were obtained with dedifferentiated VSMCs upon platelet-derived growth factor-BB (PDGF-BB) stimulation. Loss-of-function study showed that miR-144 knockdown decreased the ability of VSMC proliferation tested by Brdu and CCK8, and reduced the migrate capability analyzed by Transwell, whereas increased the differentiated SMC marker gene expression examined by RT-PCR. The above results were reversed by miR-144 overexpression. Mechanistically, we have demonstrated that PTEN was the direct target of miR-144 that was responsible for the alleviated effect of miR-144 inhibition on phenotypic switching of VSMCs. Notably, mice injected with miR-144 inhibitor attenuated the formation of neointimal lesions in response to wire injury and maintained the mature SMC marker expression inhibited the proliferation and migration of VSMCs. Conclusion Our research exhibited that miR-144 knockdown attenuated intimal hyperplasia through inhibiting the VSMC phenotypic switching, which was partially mediated by directly targeting to PTEN. Taken together, these evidences suggested that miR-144 may act as a promising therapeutic target for arterial restenosis.

Keywords

• mir-144
• vascular smooth muscle cells
• pten
• phenotypic switching
• intimal hyperplasia