# Glucose-Mediated Remodeling of Cardiac DNA Methylation

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $371,250

## Abstract

Despite overall reductions in heart disease, the increased risk of developing heart failure has
remained 2-fold greater among people with diabetes. Evidence from our laboratory and others has
identified that fluctuations in glucose level and uptake directly contributes to cardiovascular disease
(CVD) by modifying proteins, DNA, and gene expression. In the case of glucose, clinical studies have
shown that following tight glycemic control, susceptibility to disease progression is sustained years or
even decades in a process termed “glycemic memory”. A long-term goal of our laboratory is to
understand the role of glucose in the formation of glycemic memory and determine if these changes
alter disease progression. Recently the mechanism of epigenetic regulation, which consists of
modifications of the histone proteins that help package DNA and direct modifications of the DNA (e.g.
methylation), is linked to glycemic memory. A critical barrier in determining the molecular
mechanisms has been the ability to place the marks in the intact heart to test disease susceptibility.
Two novel advances have taken place over the last 2-5 years that place the glucose-mediated protein
post-translational modification, O-GlcNAcylation, at the forefront of this quest. Specifically, O-
GlcNAcylation is part of the histone code. Secondly, the proteins that regulate O-GlcNAcylation
interact with the proteins that tailor DNA methylation, providing a second link between glucose and
epigenetics. The objective of the current proposal is to determine the mechanism by which
fluctuations in glucose alter DNA methylation and how these changes alter gene expression and
cardiac function. As diabetes and heart failure are diseases with strong metabolic components, we
will focus on how glucose-mediated epigenetic changes alter metabolism and energetics in acquired
heart disease. We have developed two novel mouse models to test this hypothesis. The first builds
upon our model of inducible cardiomyocyte-specific expression of the glucose transporter, GLUT4,
and the second is a new model of cardiomyocyte O-GlcNAc regulation. Thus uniquely allowing us to
directly test the role that cardiomyocyte glucose delivery and GlcNAcylation have on CVD. Our
preliminary data define persistent DNA methylation changes that increase susceptibility to pressure-
overload hypertrophy. In this proposal we will: determine the mechanism of altered DNA methylation
(Aim 1), determine if these epigenetic modifications alter contractile and metabolic dysfunction in
response to a common diabetic co-morbidity of hypertension (Aim 2), and determine if O-GlcNAc
alone is sufficient to increase disease susceptibility (Aim 3). Collectively, the completion of these
studies will provide fundamental insights into the mechanistic basis for glucose in the regulation of
cardiac gene expression contributing to the development of diabetic CVD.

## Key facts

- **NIH application ID:** 9989889
- **Project number:** 5R01HL133011-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Adam Raymond Wende
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989889

## Citation

> US National Institutes of Health, RePORTER application 9989889, Glucose-Mediated Remodeling of Cardiac DNA Methylation (5R01HL133011-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989889. Licensed CC0.

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