Novel Mechanistic Roles for Ankyrin-G in Cardiac Remodeling and Heart Failure

Michael A Makara; Jerry Curran; Ellen R Lubbers; Nathaniel P Murphy; Sean C Little; Hassan Musa; Sakima A Smith; Sathya D Unudurthi; Murugesan V S Rajaram; Paul M L Janssen; Penelope A Boyden; Elisa A Bradley; Thomas J Hund; Peter J Mohler

doi:10.1016/j.jacbts.2018.07.008

Novel Mechanistic Roles for Ankyrin-G in Cardiac Remodeling and Heart Failure

JACC Basic Transl Sci. 2018 Nov 12;3(5):675-689. doi: 10.1016/j.jacbts.2018.07.008. eCollection 2018 Oct.

Authors

Michael A Makara^{1

2}, Jerry Curran^{1

2}, Ellen R Lubbers^{1

2}, Nathaniel P Murphy^{1

2}, Sean C Little^{1

2}, Hassan Musa^{1

2}, Sakima A Smith^{1

2

3}, Sathya D Unudurthi^{1

4}, Murugesan V S Rajaram^{1

5}, Paul M L Janssen^{1

2}, Penelope A Boyden⁶, Elisa A Bradley^{1

3}, Thomas J Hund^{1

4}, Peter J Mohler^{1

2

3}

Affiliations

¹ Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center and College of Medicine, Columbus, Ohio.
² Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center and College of Medicine, Columbus, Ohio.
³ Department of Internal Medicine, The Ohio State University Wexner Medical Center and College of Medicine, Columbus, Ohio.
⁴ Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus, Ohio.
⁵ Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University College of Engineering, Columbus, Ohio.
⁶ Department of Pharmacology, Columbia University, New York, New York.

Abstract

Ankyrin polypeptides are intracellular proteins responsible for targeting cardiac membrane proteins. Here, the authors demonstrate that ankyrin-G plays an unexpected role in normal compensatory physiological remodeling in response to myocardial stress and aging; the authors implicate disruption of ankyrin-G in human heart failure. Mechanistically, the authors illustrate that ankyrin-G serves as a key nodal protein required for cardiac myofilament integration with the intercalated disc. Their data define novel in vivo mechanistic roles for ankyrin-G, implicate ankyrin-G as necessary for compensatory cardiac physiological remodeling under stress, and implicate disruption of ankyrin-G in the development and progression of human heart failure.

Keywords: AnkG, ankyrin-G; DSP, desmoplakin; ECG, electrocardiogram; HF, heart failure; LV, left ventricular; Nav1.5; PBS, phosphate-buffered saline; PKP2, plakophilin-2; TAC, transverse aortic constriction; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; WT, wild-type; ankyrin; arrhythmia; cKO, cardiomyocyte-specific knockout; cytoskeleton; heart failure; ion channel.

Abstract

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