Investigation of anti-atherogenic effects of the alpha-tocopherol long-chain metabolites alpha-13-OH and alpha-13-COOH

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Atherosclerosis and its complications such as stroke and myocardial infarction are a leading cause of death in Western industrialized societies. Hence, research on underlying mechanisms and therapeutic approaches are on greater demand than ever. Based on several results obtained from in vitro and animal studies, vitamin E and in particular its most active form a-tocopherol, was considered as a therapeutic agent for preventing atherosclerosis. However, the promising reports on vitamin E failed to be reproduced in humans.In hepatic a-tocopherol metabolism the long-chain metabolites a-13-OH and a-13-COOH are formed by cytochrome P (CYP)4F2/3A4-dependent omega-hydroxylation followed by omega-oxidation. Our preliminary data promote the hypothesis that the long-chain metabolites of a-tocopherol occur in human serum and are at least bioactive molecules mediating effects more effectively than a-tocopherol. Therefore, anti-atherogenic effects of a-13-OH and a-13-COOH should be investigated in comparison to a-tocopherol in vitro and in vivo.The aim of the project is to unravel the molecular modes of action of the long-chain metabolites of a-tocopherol, namely a-13-OH and a-13-COOH, and their effects on (i) platelet function, (ii) atherosclerosis in the Apoe knockout mouse model, and (iii) atherosclerotic plaque stability in a modified Apoe knockout mouse model. This mouse model is unique in its comparability to human unstable plaques in such characteristics as intraplaque hemorrhage, thin or disrupted fibrous caps, intraluminal thrombosis and neovascularization. In order to comprehensively study the effects of the long-chain metabolites on atherosclerosis, platelet function and plaque stability innovative molecular imaging technologies, molecular biological methods, histological stainings and lipidomic analysis will be used.The investigation of the effects of a-long-chain metabolites on atherosclerosis, plaque stability and platelet function will help to assess the real contribution and the molecular modes of action of vitamin E in cardiovascular complications. The project will provide important information whether the anti-atherogenic properties of a-long-chain metabolites found in vitro can be confirmed in vivo. This will contribute to the complete characterization of the biological effects of a-long-chain metabolites as regulatory molecules and their importance for the pathogenesis of atherosclerosis.