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Developmental biology - Heart

Reprogramming Congestive Heart Failure

Learning from fetal heart function, epigenetic reprogramming can reduce adult heart oxidative stress...


Congestive heart failure (CHF) is a terminal disease affecting nearly 6 million Americans and is indicated when the heart is unable to pump sufficiently to maintain blood flow to meet the body's needs. Management of CHF is limited to symptomatic treatments as the mechanisms causing it are not known. Ischemic cardiomyopathy is the result of restricted blood flow to the coronary arteries. It occurs during a heart attack and starves the heart muscle of oxygen.

Now, researchers at the University of Alabama at Birmingham describe an underlying mechanism that reprograms the hearts of patients with ischemic cardiomyopathy pointing the way toward a future with more personalized care.

The study used heart tissue samples collected by UAB doctors during surgeries to implant small mechanical pumps alongside hearts of patients with end-stage heart failure. As a routine part of this procedure, a small piece of heart tissue is excised and ultimately thrown away as medical waste. This current study collected these tissue samples from the left ventricles of five ischemic cardiomyopathy patients and six non-ischemic cardiomyopathy patients, all men between the ages of 49 and 70.

Led by Adam Wende PhD of the UAB Department of Pathology, the team collected surgical tissue which revealed that epigenetic changes had occurred in these adult hearts. This was likely due to heart cells attempting to reprogram their use of oxygen in order to use less oxygen. Epigenetics are gene modifications known to alter gene activity without changing DNA sequences. One well-established epigenetic change is adding or removing methyl groups to DNA's cytosine base. Generally, hyper-methylation is associated with reducing gene function (or expression), and hypo-methylation with increasing gene function.

Fetal heart in utero and at birth

(LEFT) Fetal heart without oxygen (RIGHT) Neonate heart using oxygen. Image credit: Wikimedia.

Wende and colleagues found an epigenetic signature in the heart of patients with ischemic cardiomyopathy different from non-ischemic hearts. This modification reflects a well known metabolic change where the heart's preference for oxygen switches to an anaerobic metabolism - one not needing oxygen. Oxygen is metabolic fuel for our hearts. This anaerobic (or "without oxygen") system operates in fetal hearts still in the womb surrounded by fluid. Only after birth, does the newborn heart quickly adapt to metabolizing oxygen.
"Altogether, we believe that epigenetic changes encode a so-called 'metabolic plasticity' in failing hearts, the reversal of which may repair [or attempt to repair] the ischemic and failing heart."

Adam Wende PhD, Assistant Professor, University of Alabama at Birmingham (UAB), Department of Pathology, Birmingham, Alabama, USA.

Researchers found increased DNA methylation directly reduced genetic ability to metabolize oxygen. However, the transcription factor KLF15 does regulate metabolic gene function, but is suppressed by epigenetic regulator EZH2.
EZH2 offers a new target for future heart based therapy. Co-author Sooryanarayana Varambally has spent 15 years studying EZH2, making progress treating cancers with inhibitors that regulate EZH2.

This current study is published in Nature - Laboratory Investigation. In addition to a wide range of bioinformatic tools, first author Mark Pepin used the publicly available R program to analyze multi-Omic datasets and compare their findings to animal-based studies as well as other public databases. Wende: "Supplying the coding scripts is our way of demonstrating the rigor and reproducibility that should be expected of any bioinformatics study."

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.

Authors: Mark E. Pepin, Chae-Myeong Ha, David K. Crossman, Silvio H. Litovsky, Sooryanarayana Varambally, Joseph P. Barchue, Salpy V. Pamboukian, Nikolaos A. Diakos, Stavros G. Drakos, Steven M. Pogwizd and Adam R. Wende. Pepin is a sixth year MD PhD student at UAB and is currently completing the PhD portion of his training in the Medical Scientist Training Program.



Acknowledgements
Financial support was provided by National Institutes of Health grants DK076169, HL133011, TR001417, MD008620, HL135121, HL132067, HD071866 and HL137240; the American Heart Association Heart Failure Strategically Focused Research Network grant 16SFRN29020000; and the Nora Eccles Treadwell Foundation.



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Aug 22, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




A comparison of healthy heart with contracted muscle (left) and a weakened heart with over-stretched muscle (right). Image Credit: Wiki-Media.


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