# GAPDH, DNA Repair and Atherosclerosis

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $380,000

## Abstract

Project Summary/Abstract
Accumulated DNA damage is recognized as a causal factor in the initiation and progression of atherosclerosis.
Genomic instability in the vascular smooth muscle cells (SMC) leads to cell apoptosis and contributes to
atherosclerotic plaque vulnerability. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is the major
cellular sensor ultimately responsible for maintaining of cellular homeostasis, however its specific role in
atherogenesis is completely unknown. It has been shown that a key pro-atherogenic lipid OxLDL
downregulated GAPDH in human aortic SMC and that GAPDH expression was markedly decreased in the
atherosclerotic plaque SMC and that low GAPDH level was associated with increased apoptosis. GAPDH
reduced DNA damage and suppressed SMC apoptosis via a novel molecular mechanism involving nuclear
GAPDH interaction with apurinic/apyrimidinic endonuclease 1 (Ape1), the major oxidized DNA repair enzyme.
SMC-specific GAPDH overexpression decreased DNA damage, reduced plaque SMC apoptosis and
decreased atherosclerotic burden. Importantly, atherosclerotic plaques in GAPDH-overexpressing mice had
elevated SMC levels, increased collagen, reduced necrotic cores and thicker SMC-rich fibrous caps suggesting
enhanced plaque stability. The major focus of the current proposal is to study the mechanism mediating
GAPDH-induced anti-atherosclerotic and plaque stabilizing effect and to determine whether GAPDH mimicking
peptide (GMP) reduces atherosclerotic burden and improve plaque stability in atherosclerotic mice. The main
hypothesis is that GAPDH reduces atherosclerotic burden and enhances features of plaque stability via
stimulation of Ape1-dependent DNA repair and suppression of SMC apoptosis. This will test the hypothesis in
following Specific Aims:
Specific Aim 1: To demonstrate that SMC-specific GAPDH regulates DNA repair, apoptosis,
atherosclerotic burden and features of plaque stability and identify mechanism.
Specific Aim 2: To determine whether GAPDH-mimicking peptide (GMP) will activate Ape1, stimulate
DNA repair, suppress cell apoptosis and reduce atherosclerosis.
Proposal will use adeno-associated viruses (AAVs) to perform SMC-targeted GMP cDNA transfer in
atherosclerotic mice. AAV-based vectors are approved to use in humans, therefore the long-term goal is to use
the AAV-GMP vector as an innovative pro-DNA repair and anti-apoptotic therapy to treat unstable
atherosclerosis. Studying of anti-atherosclerotic effects of GAPDH and demonstration that GMP induces
plaque-stabilizing effect will lead to the development of novel targeted therapies to treat atherosclerosis and
prevent acute vascular events.

## Key facts

- **NIH application ID:** 10210430
- **Project number:** 5R01HL142796-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Sergiy Sukhanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210430

## Citation

> US National Institutes of Health, RePORTER application 10210430, GAPDH, DNA Repair and Atherosclerosis (5R01HL142796-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210430. Licensed CC0.

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