國家衛生研究院 NHRI:Item 3990099045/13443
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    题名: Mechanoresponsive smad5 enhances MiR-487a processing to promote vascular endothelial proliferation in response to disturbed flow
    作者: Wang, WL;Chen, LJ;Wei, SY;Shih, YT;Huang, YH;Lee, PL;Lee, CI;Wang, MC;Lee, DY;Chien, S;Chiu, JJ
    贡献者: Institute of Cellular and Systems Medicine
    摘要: MicroRNAs (miRs) and bone morphogenetic protein receptor-specific Smads are mechano-responsive molecules that play vital roles in modulating endothelial cell (EC) functions in response to blood flow. However, the roles of interplay between these molecules in modulating EC functions under flows remain unclear. We elucidated the regulatory roles of the interplay between miR-487a and Smad5 in EC proliferation in response to different flow patterns. Microarray and quantitative RT-PCR showed that disturbed flow with low and oscillatory shear stress (OS, 0.5 +/- 4 dynes/cm(2)) upregulates EC miR-487a in comparison to static controls and pulsatile shear stress (12 +/- 4 dynes/cm(2)). MiR-487a expression was higher in ECs in the inner curvature (OS region) than the outer curvature of the rat aortic arch and thoracic aorta and also elevated in diseased human coronary arteries. MiR-487a expression was promoted by nuclear phospho-Smad5, which bound to primary-miR-487a to facilitate miR-487a processing. Algorithm prediction and luciferase reporter and argonaute 2-immunoprecipitation assays demonstrated that miR-487a binds to 3 ' UTR of CREB binding protein (CBP) and p53. Knockdown and overexpression of miR-487a decreased and increased, respectively, phospho-Rb and cyclin A expressions through CBP and p53. A BrdU incorporation assay showed that miR-487a enhanced EC proliferation under OS in vitro and in disturbed flow regions of experimentally stenosed rat abdominal aorta in vivo. These results demonstrate that disturbed flow with OS induces EC expression of miR-487a through its enhanced processing by activated-Smad5. MiR-487 inhibits its direct targets CBP and p53 to induce EC cycle progression and proliferation. Our findings suggest that EC miR-487 may serve as an important molecular target for intervention against disturbed flow-associated vascular disorders resulting from atherosclerosis.
    日期: 2021-04-20
    關聯: Frontiers in Cell and Developmental Biology. 2021 Apr 20;9:Article number 647714.
    Link to: http://dx.doi.org/10.3389/fcell.2021.647714
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2296-634X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000646605000001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85105382389
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