Homocysteine contributes to atherogenic transformation of the aorta in rabbits in the absence of hypercholesterolemia

Abstract Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors such as cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, impairment of its biomechanical properties, and disorganization of aortic collagen in the absence of hypercholesterolemia and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD in the absence of hypercholesterolemia. This led to VCDD-like thin collagen-containing plaques with low levels of macrophages and lipids, massive accumulation of VLDL-triglycerides as well as an impaired K + -induced contraction and acetylcholine-induced relaxation of the aorta compared to rabbits fed VCDD alone. The observed elastin fragmentation and collagen disorganization indicate remodeling of scaffold proteins in response to elevated Hcy. Decreased total protein methylated arginine in blood cells and liver as well as altered metabolic profiles in blood cells, serum, and liver suggest additional mechanisms triggered in response to elevated plasma Hcy levels. We therefore conclude that elevated Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.