Abstract
Human antigen R (HuR) is a widespread RNA-binding protein involved in homeostatic regulation and pathological processes in many diseases. Atherosclerosis is the leading cause of cardiovascular disease and acute cardiovascular events. However, the role of HuR in atherosclerosis remains unknown. In this study, mice with smooth muscle-specific HuR knockout (HuRSMKO) were generated to investigate the role of HuR in atherosclerosis. HuR expression was reduced in atherosclerotic plaques. As compared with controls, HuRSMKO mice showed increased plaque burden in the atherosclerotic model. Mechanically, HuR could bind to the mRNAs of adenosine 5′-monophosphate-activated protein kinase (AMPK) α1 and AMPKα2, thus increasing their stability and translation. HuR deficiency reduced p-AMPK and LC3II levels and increased p62 level, thereby resulting in defective autophagy. Finally, pharmacological AMPK activation induced autophagy and suppressed atherosclerosis in HuRSMKO mice. Our findings suggest that smooth muscle HuR has a protective effect against atherosclerosis by increasing AMPK-mediated autophagy.
Highlights
Atherosclerosis is a chronic and systemic vascular inflammatory process, the pathological basis of coronary artery disease, myocardial infarction, and stroke[1]
As compared with the normal chow diet (ND) group, for the high-fat diet (HFD) group, Human antigen R (HuR) was downregulated in atherosclerotic lesions (Fig. 1C)
In this study, the expression of HuR was decreased in atherosclerotic plaques from ApoE−/− mice with an HFD
Summary
Atherosclerosis is a chronic and systemic vascular inflammatory process, the pathological basis of coronary artery disease, myocardial infarction, and stroke[1]. It remains the leading cause of death worldwide. Developing new strategies to prevent plaque formation and rupture has become an important research area. Atherosclerosis is initiated by endothelial dysfunction and vascular inflammation caused by cardiovascular risk factors such as hyperlipidemia and hypertension. Lipoproteins in the blood enter the arterial wall from the damaged endothelial cells[2,3]. Inflammatory factors can stimulate monocytes and vascular smooth muscle
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