Abstract
Previous studies have linked human polymorphisms of ALDH2 to cardiovascular diseases but the underlying mechanisms remain elusive. Here we investigated the role of ALDH2 in atherosclerosis using a murine model of low density lipoprotein receptor (LDLR) and ALDH2 double knockout mice. Surprisingly, we found that double KO mice had significantly decreased areas of atherosclerotic plaque and less macrophages in mouse aorta comparing to LDLR KO mice. Bone marrow transplant experiments also supported an important role of macrophages in this phenotype. Moreover, in vitro experiments using bone marrow derived macrophages (BMDM) showed that macrophages from ALDH2 KO had decreased uptake of ox-LDL through downregulation of phagocytic genes in LDLR-/-background. CO-IP, IF experiments, and RNA-seq in macrophages demonstrated that LDLR regulated ALDH2 entering into nucleus and regulated genes related to autophagy, AMPK activation, and mitochondrial functions. Our findings shed light on novel roles of ALDH2 in the pathogenesis of atherosclerosis through modulating macrophages functions by interactions of LDLR and AMPK - beyond the conventional roles of detoxification of reactive aldehydes.
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