Abstract
Ischemic cardiomyopathy (ICM) is the clinical endpoint of coronary heart disease and a leading cause of heart failure. Despite growing demands to develop personalized approaches to treat ICM, progress is limited by inadequate knowledge of its pathogenesis. Since epigenetics has been implicated in the development of other chronic diseases, the current study was designed to determine whether transcriptional and/or epigenetic changes are sufficient to distinguish ICM from other etiologies of heart failure. Specifically, we hypothesize that genome-wide DNA methylation encodes transcriptional reprogramming in ICM. RNA-sequencing analysis was performed on human ischemic left ventricular tissue obtained from patients with end-stage heart failure, which enriched known targets of the polycomb methyltransferase EZH2 compared to non-ischemic hearts. Combined RNA sequencing and genome-wide DNA methylation analysis revealed a robust gene expression pattern consistent with suppression of oxidative metabolism, induced anaerobic glycolysis, and altered cellular remodeling. Lastly, KLF15 was identified as a putative upstream regulator of metabolic gene expression that was itself regulated by EZH2 in a SET domain-dependent manner. Our observations therefore define a novel role of DNA methylation in the metabolic reprogramming of ICM. Furthermore, we identify EZH2 as an epigenetic regulator of KLF15 along with DNA hypermethylation, and we propose a novel mechanism through which coronary heart disease reprograms the expression of both intermediate enzymes and upstream regulators of cardiac metabolism such as KLF15.
Highlights
Coronary heart disease (CHD) is the leading cause of death and disability in developed countries
Successes of fibrinolytic and non-invasive therapies have markedly improved survival post-myocardial infarction, cardiac function often declines until patients develop symptoms of congestive heart failure, a terminal outcome known as ischemic cardiomyopathy (ICM)
To ensure that our analysis of ischemic cardiomyopathy (ICM) vs. non-ischemic heart failure (NICM) was not confounded by other patient metrics, we collected a wide array of patient demographics and comorbidities (Fig. 1a)
Summary
Coronary heart disease (CHD) is the leading cause of death and disability in developed countries. It is well-recognized that up to 40% of the myocardial segments affected by coronary artery stenosis remain viable [4, 5] This ischemic myocardium adapts to chronic hypoperfusion by suppressing myofibrillar protein expression and reducing its energetic demand, a process termed colliquative myocytolysis [6]. These morphologic changes are accompanied by metabolic adaptation of cardiac tissue to a “fetal-like” state, wherein the heart preferentially consumes glucose over fatty acids for its energy supply [7,8,9]. Hypoxia and nutrient availability contribute to the reactivation of this transcriptional program, as is the case during its in utero development, the mechanisms through which cardiac nutrient-sensing produces global changes in metabolic gene expression remain poorly understood [10, 11]
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