Homocysteine Leads to Decreased Acylcarnitine Levels in the Heart in a Rabbit Model of Atherosclerosis

Cardiovascular disease, the leading cause of death worldwide, is mainly a result of atherosclerosis. However, 50% of all cases of atherosclerosis still cannot be explained by known risk factors including hypercholesterolemia. Hyperhomocysteinemia, an elevation of homocysteine (Hcy) levels in the blood, is an independent risk factor for atherosclerosis, aggravates atherosclerosis in the presence of hypercholesterolemia and strongly correlates with cardiovascular mortality. We showed that a diet deficient in vitamins and choline required for Hcy degradation (VCDD) leads to cholesterol-independent atherogenic transformation of the aorta and aortic lipid accumulation in balloon-injured rabbit model of atherosclerosis (Almer et al, 2022, Biomed Pharmacother). Elevation of plasma Hcy by intravenous injections of Hcy into VCDD-fed rabbits results in further atherogenic changes, degradation of aortic lipid droplets, decreased total protein methylated arginine and altered metabolomic profiles compared to rabbits fed VCDD only (Tehlivets et al, 2024, Biomed Pharmacother). Here we show that feeding VCDD with or without intravenous injections of Hcy leads to dysregulation of lipid metabolism in blood cells, heart and aorta in rabbits. Hcy has a graded effect on lipid metabolism deregulating glycerolipid, cholesterol, ceramide, acylcarnitine and fatty acid metabolism in different tissues. Accumulation of triglycerides in response to VCDD and their decrease in response to VCDD in combination with Hcy injections in blood cells and heart, accumulation of cholesterol in blood cells, heart and aorta, accumulation of ceramides and fatty acids in blood cells and drastic drop in myocardial acylcarnitines suggest mechanisms how elevated Hcy may contribute to development of CVD.