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

> **NIH NIH K99** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2020 · $109,840

## Abstract

PROJECT SUMMARY
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. In the current proposal, we have revealed for the first time, that
autophagy induces the synthesis of liver-derived ketone body, β-hydroxybutyrate (βOHB). Furthermore, we
have observed that βOHB has profound anti-hypertensive effects, including potent vasodilation of isolated
resistance arteries via the G protein-coupled receptor Gpr109a and potassium channels. Therefore, we
hypothesize that upregulation of autophagy in liver, stimulates the production of βOHB, 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) autophagy in the liver liberates lipid
substrates for βOHB synthesis, 2) βOHB prevents vascular aging phenotypes by stimulating vasodilation
via endothelial Gpr109a, as well as direct activation of potassium channels, and 3) decreased autophagic
activity in hypertension reduces βOHB synthesis, contributing to high blood pressure and premature
vascular aging. To execute these aims, we will investigate normotensive and genetically hypertensive rats
in vivo, analyze isolated arteries from mice genetically deficient in Gpr109a ex vivo, and culture primary and
immortalized hepatocytes in vitro. 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 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.

## Key facts

- **NIH application ID:** 9953199
- **Project number:** 1K99HL151889-01
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Cameron McCarthy
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $109,840
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953199

## Citation

> US National Institutes of Health, RePORTER application 9953199, Autophagy regulates β-hydroxybutyrate synthesis to prevent hypertension-associated premature vascular aging (1K99HL151889-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953199. Licensed CC0.

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