Myocardin (MYOCD) plays an important role in cardiovascular disease. However, its underlying impact on atherosclerosis remains to be elucidated. ATP binding cassette transporter A1 (ABCA1), a key membrane-associated lipid transporter which maintains intracellular lipid homeostasis, has a protective function in atherosclerosis progress. The purpose of this study was to investigate whether and how the effect of MYOCD on atherosclerosis is associated with ABCA1 in vascular smooth muscle cells (VSMCs). We found both MYOCD and ABCA1 expression were dramatically decreased in atherosclerotic patient aortas compared to control. MYOCD knockdown inhibited ABCA1 expression in human aortic vascular smooth muscle cells (HAVSMCs), leading to reduced cholesterol efflux and increased intracellular cholesterol contents. MYOCD overexpression exerted the opposite effect. Mechanistically, MYOCD regulates ABCA1 expression in an SRF-dependent manner. Consistently, apolipoprotein E-deficient mice treated with MYOCD shRNA developed more plaques in the aortic sinus, which is associated with reduced ABCA1 expression, increased cholesterol retention in the aorta, and decreased high-density lipoprotein cholesterol levels in the plasma. Our data suggest that MYOCD deficiency exacerbates atherosclerosis by downregulating ABCA1 dependent cholesterol efflux from VSMCs, thereby providing a novel strategy for the therapeutic treatment of atherosclerotic cardiovascular disease.

心肌素（MYOCD）在心血管疾病中发挥着重要作用。然而，其对动脉粥样硬化的潜在影响仍有待阐明。 ATP 结合盒转运蛋白 A1 (ABCA1) 是一种关键的膜相关脂质转运蛋白，可维持细胞内脂质稳态，在动脉粥样硬化进展中具有保护功能。本研究的目的是探讨 MYOCD 对动脉粥样硬化的影响是否以及如何与血管平滑肌细胞 (VSMC) 中的 ABCA1 相关。我们发现与对照组相比，动脉粥样硬化患者主动脉中的 MYOCD 和 ABCA1 表达显着降低。 MYOCD 敲低抑制人主动脉血管平滑肌细胞 (HAVSMC) 中 ABCA1 的表达，导致胆固醇流出减少和细胞内胆固醇含量增加。 MYOCD 过度表达产生相反的效果。从机制上讲，MYOCD 以 SRF 依赖性方式调节 ABCA1 表达。一致地，用 MYOCD shRNA 治疗的载脂蛋白 E 缺陷小鼠在主动脉窦中形成更多斑块，这与 ABCA1 表达减少、主动脉中胆固醇滞留增加以及血浆中高密度脂蛋白胆固醇水平降低有关。我们的数据表明，MYOCD 缺陷通过下调 VSMC 中 ABCA1 依赖性胆固醇流出而加剧动脉粥样硬化，从而为动脉粥样硬化性心血管疾病的治疗提供新策略。