Ritonavir protects against the development of atherosclerosis in APOE *3-Leiden mice

Objective: The use of the HIV-protease inhibitor ritonavir (RTV) is associated with induction of hypertriglyceridemia, which is a cardiovascular risk factor. Therefore, we investigated the effect of RTV on atherosclerosis development in APOE*3-Leiden transgenic mice, a model for human-like lipoprotein metabolism and atherosclerosis. Methods and results: APOE*3-Leiden mice were fed a Western-type diet without or with RTV (35. mg/kg/day) for 19 weeks. RTV increased plasma TG levels throughout the study (∼2-fold; P<. 0.05). Despite these increased TG levels, RTV decreased the atherosclerotic lesion area in the aortic root (-57%; P<. 0.05), concomitant with reduced macrophage area (-72%; P<. 0.01) and decreased lesion severity. This could not be explained by reduced inflammatory markers in plasma (i.e. serum amyloid A, E-selectin and fibrinogen), nor by decreased lipid accumulation in macrophages or increased cholesterol efflux from macrophages, as assessed using peritoneal macrophages in vitro. Rather, whereas RTV did not affect plasma total cholesterol levels, RTV decreased (V)LDL-cholesterol and increased cholesterol in apoE-rich large HDL. Conclusion: Despite inducing hypertriglyceridemia, RTV decreases atherosclerotic lesion area and severity, associated with decreased (V)LDL-cholesterol and increased atheroprotective apoE-rich large HDL.