Abstract 103: Cycling Of Plasma Cholesterol Increases The Rate Of Atherosclerosis Progression And Alters The Chromatin Landscape Of Bone Marrow Monocytes

Abstract

Background: Coronary artery disease (CAD) is the leading cause of death worldwide. Although statins decrease CAD risk by lowering LDL cholesterol (LDL-C), only half of statin users adhere to treatment. Of those who discontinue, 75% resume statin therapy at a later time. Thus, many undergo recurring cycles of lower to higher LDL-C. High variability in LDL-C is an independent predictor of CVD events, but the direct effects of plasma cholesterol cycles on atherosclerosis plaque progression, or regression, remain unknown. Methods: Ldlr-/- mice were fed a high fat/cholesterol-western diet (WD) for 16 weeks to develop advanced plaques (Baseline; BL). A first round of cholesterol lowering was attained with ApoB anti-sense oligonucleotide injections. Some animals were harvested after 4 weeks of cholesterol lowering (Regression; Reg) while the remaining continued on WD for 4 more weeks after stopping ASO injections, so that cholesterol levels were again increased (Cycled progression; CyP). Another round of cholesterol lowering followed for 4 weeks (Cycled regression; CyR). Mice that had continuous high levels of cholesterol were used as controls (progression; P). Results: Animals subjected to high cholesterol cycles (CyP) showed increased rates of macrophage (CD68+cell) accumulation in atherosclerotic plaques. This increase was two times greater than commonly seen when plasma cholesterol remained elevated. Plaques in CyP also showed a proinflammatory phenotype and increased monocyte recruitment. Despite this, a subsequent round of cholesterol lowering (CyR) effectively regressed plaques. ATAC-seq analysis of bone marrow (BM) monocytes showed distinct landscapes of chromatin accessibility between the groups, particularly with CyP showing a seemingly paradoxical and strong pattern of closed chromatin at inflammatory genes, such as IL-6, TLR-4 , and Ifnar2 , though plaque macrophages were more inflammatory. Conclusion: Cholesterol cycling aggravates atherosclerosis when high levels are regained vs. when they are sustained. Interestingly, plaque macrophages and BM monocytes may be differentially affected by cholesterol cycles. These results may be particularly relevant to patients with intermittent adherence to statins and higher risk for CVD.