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.