Autophagy regulates β-hydroxybutyrate synthesis to prevent hypertension-associated premature vascular aging

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Hypertension is a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated and exacerbated in hypertension. Nonetheless, our understanding of the mechanisms that cause arteries to prematurely age, thus increasing the cardiovascular risk for hypertensive patients, is yet to be determined. It is well established that the upregulation/reconstitution of autophagy ameliorates the aged phenotype, especially in the vasculature. Nonetheless, the precise mechanisms by which autophagy exerts anti-vascular aging effects, remain to be elucidated. Therefore, the long-term objective of this project is to uncover novel mechanisms by which autophagy ameliorates premature vascular aging associated with hypertension. Evolutionarily, autophagy serves to mobilize macro - and micronutrients in times of starvation and stress. As a result, autophagy has also been recognized as a mediator of hepatic lipid metabolism, which could then liberate substrates for ketogenesis. Previously, we made the seminal observation that autophagy induces the biosynthesis of liver-derived ketone body, 􀈕-hydroxybutyrate (􀈕OHB). Furthermore, we have observed that 􀈕OHB has profound anti-hypertensive effects, including potent vasodilation of isolated resistance arteries, however, data collected from the K99 phase has suggested that this is through a non -canonical signaling mechanism. Therefore, we hypothesize that upregulation of autophagy in liver, stimulates the production of 􀈕OHB, which induces vasodilation, and decreases phenotypes of premature vascular aging associated with hypertension. We will test this hypothesis by executing the following specific aims: 1) 􀈕OHB prevents vascular aging phenotypes by stimulating vasodilation via direct activation of potassium channels on endothelial cells, and 2) decreased autophagic activity in hypertension reduces 􀈕OHB biosynthesis, contributing to high blood pressure and premature vascular aging. To execute these aims, we will investigate mice genetically deficient in specific potassium channels, mice genetically deficient in autophagy protein Atg5, and genetically hypertensive rats. Hypertension will be induced in mice via angiotensin II infusion. Collectively, this application proposes a novel, physiologic mechanism by which autophagy in the liver prevents premature vascular aging and also proposes a pathogenic consequence of decreased autophagic activity in hypertension. As vascular age is a new clinically used index for cardiovascular disease risk, understanding these mechanisms may assist in the development of new therapies to reverse or prevent vascular damage associated with hypertension. Given that hypertension is a major public health burden in the United States, our proposal is very much in accordance with the mission of the National Institutes of Health.