# Heightened hypoxia and DNA methylation in heart defects of diabetic embryopathy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $743,799

## Abstract

Summary
Maternal diabetes induces congenial heart defects (CHDs) formation and the underlying mechanism is still
unclear. Maternal diabetes induces hypoxia in the developing embryo and short-term gestational hypoxia induces
CHDs. Hypoxia and DNA hypermethylation have been interlinked in human diseases. DNA hypermethylation is
implicated in CHDs including hypoplastic left heart syndrome (HLHS), a complex and severe CHD type. We found
that maternal diabetes enhanced hypoxia and increased DNA methylation in the developing heart. Hypoxia
inducible factor 1 alpha (HIF-1α) up-regulated the two de novo DNA methyltransferase (DNMT3a and DNMT3b)
in cardiac progenitors in the developing mouse hearts or derived from human inducible pluripotent stem cells
(iPSCs). Blockage of DNA hypermethylation by removing DNMT3a and DNMT3b in early cardiac Nkx2.5+
progenitors ameliorated all CHD types in diabetic pregnancy. Thus, we hypothesize that maternal diabetes
induces hypoxia and triggers the activation of the hypoxia inducible factor 1 alpha (HIF-1α) pathway,
which induces DNA hypermethylation by up-regulating DNMT3a/b. Inhibition of hypoxia, HIF-1α or DNA
hypermethylation or double DNMT3a/b deletion abrogates the functional deficits in cardiac progenitors
leading to CHD reduction and improvement of cardiomyocyte and cardiac function. First heart field
defects contribute to HLHS formation and cardiac dysfunction in this severe type of CHDs. To test our
hypothesis, we proposed three specific aims. Aim 1 will determine whether maternal diabetes-induced
hypoxia is responsible for DNA hypermethylation in early cardiac progenitors leading to CHD formation.
We will examine whether hypoxia increases DNA methylation in early cardiac progenitors by up-regulating
DNMT3a/b expression leading to CHDs in diabetic pregnancy. Aim 2 will investigate the role of maternal
diabetes-induced DNA hypermethylation in gene dysregulation that results in functional defects in early
cardiac progenitors and the first heart field. We will determine whether DNA hypermethylation in both heart
fields alters gene expression leading to CHDs and cardiomyocyte dysfunction in diabetic pregnancy by using
DNMT3a/b double deletion in early cardiac progenitors. Aim 3 will determine whether heightened HIF-1α
activity and consequent DNA hypermethylation contribute to cardiomyocyte dysfunction of HLHS in
diabetic pregnancy. We hypothesize that persistent activation of the HIF-1α pathway and DNA hypermethylation
contribute to cardiomyocyte dysfunction in maternal diabetes-induced CHDs. Successful completion will dissect
the critical role of hypoxia and DNA methylation in diabetes-induced CHDs and provide mechanistic insights for
improving cardiomyocyte function in CHD patients.

## Key facts

- **NIH application ID:** 10895575
- **Project number:** 5R01HL160727-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Wei-Bin Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $743,799
- **Award type:** 5
- **Project period:** 2022-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895575

## Citation

> US National Institutes of Health, RePORTER application 10895575, Heightened hypoxia and DNA methylation in heart defects of diabetic embryopathy (5R01HL160727-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10895575. Licensed CC0.

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