Esobi Ikechukwu C, Oladosu Olanrewaju, Echesabal-Chen Jing, Powell Rhonda R, Bruce Terri, Stamatikos Alexis
Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA.
Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA.
J Lipids. 2023 Jun 16;2023:8241899. doi: 10.1155/2023/8241899. eCollection 2023.
Recent evidence suggests that the majority of cholesterol-laden cells found in atherosclerotic lesions are vascular smooth muscle cells (VSMC) that have transdifferentiated into macrophage-like cells (MLC). Furthermore, cholesterol-laden MLC of VSMC origin have demonstrated impaired ABCA1-dependent cholesterol efflux, but it is poorly understood why this occurs. A possible mechanism which may at least partially be attributed to cholesterol-laden MLC demonstrating attenuated ABCA1-dependent cholesterol efflux is a miR-33a expression, as a primary function of this microRNA is to silence ABCA1 expression, but this has yet to be rigorously investigated. Therefore, the VSMC line MOVAS cells were used to generate miR-33a knockout (KO) MOVAS cells, and we used KO and wild-type (WT) MOVAS cells to delineate any possible proatherogenic role of miR-33a expression in VSMC. When WT and KO MOVAS cells were cholesterol-loaded to convert into MLC, this resulted in the WT MOVAS cells to exhibit impaired ABCA1-dependent cholesterol efflux. In the cholesterol-loaded WT MOVAS MLC, we also observed a delayed restoration of the VSMC phenotype when these cells were exposed to the ABCA1 cholesterol acceptor, apoAI. These results imply that miR-33a expression in VSMC drives atherosclerosis by triggering MLC transdifferentiation via attenuated ABCA1-dependent cholesterol efflux.
最近的证据表明，在动脉粥样硬化病变中发现的大多数富含胆固醇的细胞是已转分化为巨噬细胞样细胞（MLC）的血管平滑肌细胞（VSMC）。此外，源自VSMC的富含胆固醇的MLC已证明其ABCA1依赖性胆固醇流出受损，但人们对其发生原因知之甚少。一种可能至少部分归因于富含胆固醇的MLC表现出ABCA1依赖性胆固醇流出减弱的机制是miR-33a表达，因为这种微小RNA的主要功能是使ABCA1表达沉默，但这一点尚未得到严格研究。因此，使用VSMC系MOVAS细胞生成miR-33a基因敲除（KO）的MOVAS细胞，我们用KO和野生型（WT）MOVAS细胞来描述miR-33a表达在VSMC中可能存在的促动脉粥样硬化作用。当WT和KO MOVAS细胞被加载胆固醇以转化为MLC时，这导致WT MOVAS细胞表现出ABCA1依赖性胆固醇流出受损。在加载胆固醇的WT MOVAS MLC中，当这些细胞暴露于ABCA1胆固醇受体载脂蛋白AI时，我们还观察到VSMC表型的恢复延迟。这些结果表明，VSMC中的miR-33a表达通过减弱ABCA1依赖性胆固醇流出触发MLC转分化，从而推动动脉粥样硬化的发展。
