763 ACTIVATION OF SIRT1 ATTENUATES VASCULAR DYSFUNCTION AND THROMBOSIS IN MTHFR DEFICIENCY

Abstract Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels homocysteine (Hcy) risk. However, heterozygous carriers have an augmented accidents independently from normal Hcy levels, suggesting additional deregulated processes in MTHFR carriers. Here we hypothesize that targeting Sirtuin 1 (SIRT1) alternative mechanism control deficiency condition. Flow Mediated Dilatation (FMD) light transmission aggregometry assay were performed subjects carrying allele after administration resveratrol, most powerful natural clinical usable compound owns SIRT1 activating properties. revealed endothelial dysfunction enhanced platelet aggregation downregulation. activity stimulation by resveratrol intake was able override these abnormalities without affecting levels. Impaired function, bleeding time, wire-induced thrombus formation rescued a Mthfr-deficient (Mthfr+/-) mouse model treatment. Using cell-based high-throughput multiplexed screening (HTS) assay, novel selective synthetic activator, namely ISIDE11, identified. Ex vivo treatment Mthfr+/- mice ISIDE11 rescues vasorelaxation reduces formation, effects abolished inhibitor. Moreover, platelets treated showed normalization their typical hyper-reactivity. These results candidate activation new therapeutic strategy contain cardio cerebrovascular