Hyperhomocysteinemia and atherosclerosis: molecular mechanisms and pathophysiology

Cardiovascular diseases, which are in the majority of cases a consequence of atherosclerosis, are the leading cause of death worldwide. However, only about half of all cases of atherosclerosis incidence can be explained by the major risk factor for atherosclerosis, hypercholesterolemia, together with other established risk factors. Hyperhomocysteinemia (HHcy), which is characterized by elevated levels of homocysteine (Hcy) in the blood, is a novel independent risk factor for atherosclerosis, which increases cardiovascular risk in combination with hypercholesterolemia and strongly correlates with cardiovascular mortality. HHcy is present in 5-10% of the general population and increases in the elderly to 30%. Thus, understanding HHcy contribution to the development of atherosclerosis is of immense importance. However, neither trigger(s) nor mechanisms linking HHcy to cardiovascular pathology are currently known. In a pilot study conducted as a cooperation project between University of Graz and Medical University of Graz using a rabbit model that exhibits similar development of atherosclerosis to humans, we have observed that indeed HHcy induced by dietary intervention in the absence of hypercholestertolemia resulted in the formation of atherosclerotic plaques. Combination of HHcy- and hypercholesterolemia- inducing diets triggered even faster and more severe plaque development than hypercholesterolemia alone. Notably, these plaques were much softer, indicative of their more vulnerable nature that can lead to plaque rupture. Rabbits, unlike rodents, do not need to be genetically modified to be susceptible for the development of atherosclerosis, due to similar to humans lipoprotein metabolism, and thus may better reflect consequences of HHcy on the arterial wall. We want to understand mechanisms that mediate the alterations of the arterial wall and contribute to atherosclerosis development in response to HHcy. We hypothesize that S-adenosyl-L-homocysteine (AdoHcy) accumulation and inhibition of methylation is responsible for these alterations. We propose using rabbit model and cell culture experiments to dissect mechanisms responsible for the development of HHcy-associated alterations of the arterial wall in the absence or presence of hypercholesterolemia. Comparison of differences and similarities of atherogenic transformations of the aortic wall in response to HHcy, hypercholesterolemia and their combination as well as modulation of key HHcy-associated metabolites and pathways will indicate mechanisms responsible for these alterations and potential triggers. Analysis of cell culture responses to homocysteine and AdoHcy will further elaborate mechanisms triggered by elevated homocysteine. Usage of primary human cells will show whether mechanisms identified in the rabbit model are applicable to the situation in humans. This comprehensive analysis is expected to yield a better understanding of the pathological alterations of the arterial wall in response to HHcy and to provide mechanistic insight into the critical cellular events involved. That altogether will aid in better prognosis, diagnosis and therapy of cardiovascular diseases.