Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology

Sobuj Mia; Ravi Sonkar; Lamario Williams; Mary N Latimer; David R Rawnsley; Samir Rana; Jin He; Pieterjan Dierickx; Teayoun Kim; Min Xie; Kirk M Habegger; Masato Kubo; Lufang Zhou; Morten B Thomsen; Sumanth D Prabhu; Stuart J Frank; Paul S Brookes; Mitchell A Lazar; Abhinav Diwan; Martin E Young

doi:10.1016/j.jacbts.2023.03.016

Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology

JACC Basic Transl Sci. 2023 Jun 14;8(9):1141-1156. doi: 10.1016/j.jacbts.2023.03.016. eCollection 2023 Sep.

Authors

Sobuj Mia¹, Ravi Sonkar¹, Lamario Williams¹, Mary N Latimer¹, David R Rawnsley², Samir Rana¹, Jin He¹, Pieterjan Dierickx^{3

4}, Teayoun Kim⁵, Min Xie¹, Kirk M Habegger⁵, Masato Kubo^{6

7}, Lufang Zhou¹, Morten B Thomsen⁸, Sumanth D Prabhu², Stuart J Frank^{5

9}, Paul S Brookes¹⁰, Mitchell A Lazar^{3

11}, Abhinav Diwan^{2

12}, Martin E Young¹

Affiliations

¹ Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
² Departments of Medicine, Cell Biology and Physiology, Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.
³ Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁵ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Research Institute for Biomedical Science, Tokyo University of Science, Chiba, Japan.
⁷ Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences (IMS), RIKEN Yokohama Institute, Kanagawa, Japan.
⁸ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Demark.
⁹ Endocrinology Section, Birmingham VAMC Medical Service, Birmingham, Alabama, USA.
¹⁰ Department of Anesthesiology and Perioperative Medicine, University of Rochester, Rochester, New York, USA.
¹¹ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹² John Cochran VA Medical Center, St. Louis, Missouri, USA.

Abstract

Circadian clocks temporally orchestrate biological processes critical for cellular/organ function. For example, the cardiomyocyte circadian clock modulates cardiac metabolism, signaling, and electrophysiology over the course of the day, such that, disruption of the clock leads to age-onset cardiomyopathy (through unknown mechanisms). Here, we report that genetic disruption of the cardiomyocyte clock results in chronic induction of the transcriptional repressor E4BP4. Importantly, E4BP4 deletion prevents age-onset cardiomyopathy following clock disruption. These studies also indicate that E4BP4 regulates both cardiac metabolism (eg, fatty acid oxidation) and electrophysiology (eg, QT interval). Collectively, these studies reveal that E4BP4 is a novel regulator of both cardiac physiology and pathophysiology.

Keywords: chronobiology; electrophysiology; heart failure; metabolism.

Abstract

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