ApoE Mimetic Peptide‐MsrA Fusion Protein Restores HDL Function and Ameliorates Atherosclerosis via Circulatory Redox Remodeling in SR‐BI Deficient Mice

ABSTRACT The redox imbalance in circulation can lead to inflammation and cellular damage in vascular walls, which plays a crucial role in atherogenesis. We previously designed an apolipoprotein E (ApoE) mimetic peptide, EpK, which can reduce atherosclerosis in ApoE‐deficient mice by binding high‐density lipoprotein (HDL). Meanwhile, hepatic overexpression of methionine sulfoxide reductase A (MsrA) can exert indirect anti‐atherosclerotic effects. Therefore, exploring biomolecules that directly promote circulatory redox rebalance is significant for the therapy of atherosclerotic cardiovascular diseases (ASCVD). MsrA was recombined with EpK to achieve the secretory expression of EpK‐MsrA. Our experiments revealed that EpK and EpK‐MsrA significantly improved the oxidative state and inflammatory composition of dysfunctional HDL and promoted hepatic cholesterol uptake and excretion, thereby alleviating atherosclerosis and hepatic steatosis in scavenger receptor class B type I deficient (SR‐BI −/− ) mice. Furthermore, compared with EpK, EpK‐MsrA had a stronger anti‐inflammatory and regulatory effect on HDL functional proteins, such as apolipoprotein AI (ApoAI), paraoxonase 1 (PON1), and lecithin cholesterol acyltransferase (LCAT), thereby further reducing atherosclerosis. Additionally, exogenous EpK‐MsrA may be able to regenerate its antioxidant activity through EpK recycling. This study suggests that novel secreted EpK‐MsrA can combine the different antioxidant mechanisms of EpK and MsrA, significantly improve the functional proteins related to lipid metabolism and inflammation, and effectively alleviate atherosclerosis in SR‐BI −/− mice, which may be a promising strategy for the treatment of ASCVD.