# Sirtuin 3 Inactivation and SOD2 Acetylation in Vascular Dysfunction and Hypertension

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $626,254

## Abstract

Project Summary
Vascular dysfunction plays a key role in hypertension and cardiovascular disease associated with inactivation of
mitochondrial deacetylase Sirt3, but mitochondria-targeted treatments are not available. Sirt3 inactivation induces
inhibition of mitochondrial superoxide dismutase (SOD2) and impairs fatty acid metabolism leading to mitochondrial
oxidative stress and formation of harmful lipid peroxidation products, isolevuglandins (isoLG). We suggest that a feed-
forward cycle between Sirt3 inactivation and mitochondrial isoLG promotes vascular dysfunction and hypertension.
We developed new mitochondria-targeted isoLG scavenger, mito2HOBA, which protects Sirt3 activity and attenuates
hypertension. In this proposal, we will advance this research by defining the novel role of mitochondrial isoLG in
Sirt3 inactivation and vascular dysfunction, and we will establish the therapeutic potential of targeting mitochondrial
isoLG. Our overall objective is to define the specific mechanism of isoLG-mediated Sirt3 inactivation and directly test
the therapeutic potential of targeting mitochondrial isoLG using new transgenic mice, new mitochondria-targeted
drugs, and vascular tissue from patients with essential hypertension. We will pursue the following aims:
AIM 1.Test the hypothesis that inactivation of endothelial Sirt3 induces endothelial dysfunction which is prevented
by targeting mitochondrial isoLG. In this aim we will examine the pathophysiological role of endothelial
 Sirt3 impairment and mitochondrial isoLG in endothelium specific Sirt3 depleted (EcSirt3KO) and wild-type
 male and female mice. We will define the role of Sirt3 inactivation and mitochondrial isoLG in endothelial
 inflammation, cell senescence, endothelial barrier disruption, and impaired relaxation.
AIM 2.Test the hypothesis that inactivation of smooth muscle Sirt3 induces vascular dysfunction, and blocking
mitochondrial isoLG improves vascular function. We will study the role of smooth muscle Sirt3 impairment
 in smooth muscle Sirt3 depleted (SmcSirt3KO) mice. The specific roles of SOD2-K68 acetylation and metabolic
 dysfunction will be tested in available SOD2-deacetylation mimetic SOD2K68R and Sirt3-/--SODK68R mice. The
 role of mitochondrial isoLG in smooth muscle hypertrophy, inflammation and aortic remodeling will be defined.
AIM 3. Determine the therapeutic potential of targeting Sirt3 inactivation and mitochondrial isoLG in mouse models
and human vascular tissue from patients with essential hypertension. We will test (A) if treatment with novel
 mitochondria-targeted isoLG scavengers, such as mito2HOBA, after onset of hypertension increases Sirt3
 activity and improves vascular function in mouse models, and (B) if targeting mitochondrial isoLG in vascular
 tissues from hypertensive human subjects ex vivo reduces inflammation, improves Sirt3 activity, and relaxation.
We are in an ideal position to perform these interdisciplinary studies. We developed new Sirt3 transge...

## Key facts

- **NIH application ID:** 10185288
- **Project number:** 1R01HL157583-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Sergey Dikalov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $626,254
- **Award type:** 1
- **Project period:** 2021-04-21 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185288

## Citation

> US National Institutes of Health, RePORTER application 10185288, Sirtuin 3 Inactivation and SOD2 Acetylation in Vascular Dysfunction and Hypertension (1R01HL157583-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10185288. Licensed CC0.

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