Department of Cardiac Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
Department of Plastic Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
J Clin Lab Anal. 2021 Dec;35(12):e23773. doi: 10.1002/jcla.23773. Epub 2021 Nov 12.
miR-145 is closely related to vascular smooth muscle cells (VSMC) phenotype transformation; however, the regulatory mechanisms through which miR-145 regulates the VSMC phenotype transformation under mechanical stretching are unclear. In this study, we evaluated the roles of miR-145 in VSMCs subjected to mechanical stretching in aortic dissection (AD).
The expression of miR-145 in the aortic vessel wall of model animals and patients with AD was analyzed by quantitative polymerase chain reaction. miR-145-related protein-protein interaction networks and Wikipathways were used to analyze VSMC phenotypic transformation pathways regulated by miR-145. We used gain- and loss-of-function studies to evaluate the effects of miR-145 on VSMC differentiation under mechanical stretch induction and assessed whether Krüppel-like factor 4 (KLF4) was regulated by miR-145 in the aorta under mechanical stretch conditions.
miR-145 was abundantly expressed in the walls of the normal human aorta, but was significantly downregulated in animal models and the walls of patients with dissection. We found that contractile phenotype-related proteins were downregulated in VSMCs subjected to mechanical stretching, whereas the expression of secreted phenotype-related proteins increased. miR-145 overexpression also downregulated contractile phenotype-related proteins in VSMCs and suppressed upregulation of phenotype-related proteins. Finally, under mechanical stretching, KLF4 expression was significantly increased in VSMCs, and overexpression of miR-145 blocked this effect.
Our results confirmed that mechanical stretch-induced phenotypic transformation of VSMCs to promote AD via upregulation of KLF4; this mechanism was regulated by miR-145, which directly modulated KLF4 expression and VSMC differentiation.
miR-145 与血管平滑肌细胞（VSMC）表型转化密切相关；然而，miR-145 在机械拉伸下调节 VSMC 表型转化的调控机制尚不清楚。在这项研究中，我们评估了 miR-145 在主动脉夹层（AD）模型动物和患者的主动脉血管壁中受到机械拉伸时的作用。
通过定量聚合酶链反应分析模型动物和 AD 患者主动脉血管壁中 miR-145 的表达。使用 miR-145 相关的蛋白质-蛋白质相互作用网络和 Wikipathways 分析 miR-145 调节的 VSMC 表型转化途径。我们使用增益和缺失功能研究来评估 miR-145 在机械拉伸诱导下对 VSMC 分化的影响，并评估在机械拉伸条件下 miR-145 是否调节主动脉中的 Krüppel 样因子 4（KLF4）。
miR-145 在正常人类主动脉壁中大量表达，但在动物模型和夹层患者的血管壁中表达明显下调。我们发现，机械拉伸后 VSMCs 中收缩表型相关蛋白表达下调，而分泌表型相关蛋白表达增加。miR-145 的过表达也下调了 VSMCs 中的收缩表型相关蛋白，并抑制了表型相关蛋白的上调。最后，在机械拉伸下，VSMCs 中 KLF4 的表达明显增加，而 miR-145 的过表达阻断了这种作用。
我们的研究结果证实，机械拉伸诱导的 VSMC 表型转化通过上调 KLF4 促进 AD 的发生；这种机制受 miR-145 调节，miR-145 直接调节 KLF4 的表达和 VSMC 的分化。
