Abstract 210: Beta-carotene Conversion to Vitamin a Delays Atherosclerosis Progression and Accelerates Atherosclerosis Regression

Abstract

β-carotene (BC) from plants is strong antioxidant and is the precursor of vitamin A in animals. Human studies show that elevated BC blood levels correlate with lower incidence of heart disease, but the molecular mechanisms are unclear. While humans accumulate high amounts of BC in blood, rodents completely metabolize BC to vitamin A, precluding the possibility of studying if BC influences heart disease using mouse models. To overcome this, we used a mouse model lacking the enzyme that converts BC to vitamin A (BC oxygenase 1, BCO1) and studied if BC plays a role in atherosclerosis, the main cause of heart disease. We first crossed Bco1 -/- mice with Ldlr -/- mice to generate Bco1 -/- / Ldlr -/- mice. These mice were fed Western diet (WD) containing BC (WD-BC) for 12 wks, accumulated levels of BC in blood comparable to those observed in humans (12±2 μM), as well as in atherosclerotic lesions, while Ldlr -/- mice fed WD-BC only accumulated trace amounts of BC in blood (0.3±0.1 μM). Ldlr -/- mice fed WD-BC showed delayed atherosclerosis progression (40% reduction in plaque size, n=10-12 mice/group) when compared to those fed WD without BC (WD-noBC). These changes were accompanied by decreased plasma cholesterol (35%) and triglyceride (~55%) levels (n=10-12 mice/group). People typically present for treatment of atherosclerotic disease after plaques have advanced. Thus, we next tested whether BC plays a role in atherosclerosis regression after lipid lowering. For this purpose, we utilized a LDLR antisense oligonucleotide (LDLR-ASO) strategy to block expression of the LDLR to induce hypercholesterolemia. Wild-type and Bco1 -/- mice were fed WD-noBC and simultaneously treated with LDLR-ASO for 16 wks. After LDLR-ASO treatment was stopped, plasma cholesterol levels fell from 700mg/mL to 70mg/mL. Mice were also switched to WD-BC or continued with WD-noBC for 3 wks. Wild-type mice, but not Bco1 -/- mice, fed WD-BC showed a reduced content of plaque macrophages (30%) and newly recruited monocytes (25%) (n=7 to 12 mice/group) when compared to those fed WD-noBC. We are currently in the process of elucidating the molecular mechanisms responsible of these beneficial effects of BC on atherosclerosis progression and regression.