Platelets impair the resolution of inflammation in atherosclerotic plaques in insulin-resistant mice after lipid-lowering

Insulin resistance reduces the benefits of lipid-lowering, as evidenced by higher cardiovascular risk in type 2 diabetes despite LDL-cholesterol reduction. Platelet activation, a key feature in insulin resistance, may hinder inflammation resolution in atherosclerosis. Using an obese, insulin-resistant mouse model, we induced atherosclerosis and treated mice with an apoprotein B oligonucleotide for lipid-lowering, with or without platelet depletion. Platelet depletion increased Fcgr4+ macrophages, reduced necrotic cores, and dampened inflammatory gene expression. Platelets hinder inflammation resolution in insulin resistance during lipid-lowering. Targeting platelet activity may enhance atherosclerosis regression and reduce cardiovascular risk. Overall design: Atherosclerosis, obesity and impaired glucose tolerance were induced in 8-12 weeks old male Ldlr-/- mice by high-fat high-cholesterol diet feeding for progression period (20 weeks, Basline group) and regression period (3 weeks). Atherosclerosis regression was achieved by reversal of hypercholesterolemia using an apolipoprotein B antisense oligonucleotide. During this period, mice received injections of IgG control or anti-CD42b antibody to deplete platelets. Mice were assigned to baseline (BL) or regression groups: ApoB-ASO + IgG or ApoB-ASO + aCD42.