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.