GADD45B and Metabolic Memory in Diabetic Heart Failure

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PROJECT SUMMARY The overall objective of the proposed research project is to determine whether diabetes mellitus epigenetically programs the heart to fail. Diabetes mellitus confers up to a 4-fold increased risk of developing heart failure (HF) independently of coronary artery disease or hypertension. Other etiologies of HF are medically managed with relative efficacy; however, diabetic HF is resistant to these first-line agents. Glycemic control has been proposed to reduce HF risk; however, this remains controversial, and no effective treatment regimen exists for diabetic patients once symptoms of HF develop. Thus, a targeted therapy that reverses diabetes-associated cardiac changes could alter the disease course and improve both quality and duration of life. In order to understand the underlying pathogenesis of HF in a diabetic heart, we have looked to the field of epigenetics, which characterizes the integration of environmental stimuli as stable regulatory influences on gene expression. Specifically, we are interested in determining the extent to which disturbances in the metabolic milieu are caused by or contribute to epigenetic changes. Previous work has identified a connection between alterations in DNA methylation - a common epigenetic mark associated with repressed transcription - and the transcriptional profile in ischemic heart failure. However, the regulatory influences governing cardiac DNA methylation remain poorly understood, as does the impact of DNA methylation on the heart in the context of diabetes mellitus. Our preliminary data reveal a functionally-distinct signature of promoter-associated DNA demethylation in the left ventricle of patients with diabetic HF. Using a combined ‘-omics’ approach, I have subsequently identified Growth Arrest and DNA Damage Inducible 45-beta (GADD45B) as a likely central regulator that is robustly induced in the failing diabetic human and mouse heart. Relatively little is known about GADD45B in the heart, as previous work has focused largely on its regulation of neuronal active DNA demethylation in the context of memory formation. In other tissues, GADD45B has been shown to orchestrate cellular growth and apoptosis in response to oxidative stress, such as those generated via fatty acid oxidation. Accordingly, we hypothesize that GADD45B mediates diabetes-associated cardiac dysfunction via active DNA demethylation of key apoptotic intermediates through a fatty acid-sensitive mechanism. This proposal will test the following two aims: (1) Test the hypothesis that GADD45B can be therapeutically targeted to restore cardiac function in the diabetic heart, and (2) Test the hypothesis that the diabetic milieu potentiates cardiomyocyte GADD45B induction via auto-regulatory DNA demethylation. Completion of this proposal will also provide a foundation for my career as a physician-scientist with a toolbox of both innovative techniques and essential skills.