Aging is associated with vascular stiffness, systolic hypertension, and atherosclerosis. The vascular endothelium plays important paracrine effects on smooth muscle including the production of nitric oxide, reactive oxygen species and cytokines. The paracrine signals from the endothelium may be affected by numerous factors associated with aging including patterns of shear stress, circulating factors and endothelial cell senescence. Deleterious molecular alterations in the endothelium result in impaired responses to various vasodilator stimuli and it is a strong predictor of morbidity and mortality. The enzymes from the class of sirtuins can play an important role in protecting against age-related diseases. Sirtuins include an ancient and diverse protein family with seven members (SIRT1 to 7) that exhibit diversity and complexity in their patterns of cellular localization and sites of action. The sirtuin 6 (SIRT6) plays a particularly important role in protecting against the progeroid phenotypes, as well as the deletion of SIRT6 results in marked bone loss, kypholordosis, and drastic reduction in lifespan. The role of SIRT6 in the regulation of vascular function, however, is not known. Our central hypothesis is that the reduction of age-associated SIRT6 increases histone acetylation and expression of genes pro-oxidative and contributes to vascular dysfunction. Therefore, our overall objective is to establish new interactions between the increases in age-related oxidative stress, vascular dysfunction, and regulation of gene expression by histone acetylation and identify SIRT6 as a new and important regulator of vascular function in health and a contributor to vascular pathological process related to aging.
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