Advancing our understanding of AnkRD1 in cardiac development and disease

This editorial refers to ‘Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction’ by N. Piroddi et al., pp. 1458–1472. The ankyrin repeat domain 1 protein (AnkRD1), also known as cardiac ankyrin repeat protein is a highly conserved, multifunctional protein with hypothesized roles in cardiogenesis, mechanosensing, regulation of gene expression, intracellular signalling, and cardiac stress-response.1 AnkRD1 is a member of the muscle ankyrin repeat family and is predominantly expressed in cardiomyocytes with dual localization in the nucleus and at the sarcomere at the I-band. Mechanical stimuli lead to translocation from the sarcomere into the nucleus. AnkRD1 knockout and overexpression models have failed to clearly indicate the role of AnkRD1 in vivo. AnkRD1 knockout mice fail to exhibit significant hypertrophy, even after stimulation with phenylephrine and demonstrated impaired wound healing.2,3 However, studies of previous AnkRD1 overexpression models have yielded conflicting results. One transgenic model demonstrated less hypertrophy in response to pressure overload or isoproterenol infusion through inhibition of the extracellular signal-regulated kinase (ERK) and transforming growth factor beta (TGF-β) signalling pathways.4 However, another model utilizing viral upregulation showed pathologic remodelling in response to transverse aortic constriction through the nuclear factor of activated T-cell (NFAT) and calcineurin pathways.5 Both of these overexpression models only examine the role of AnkRD1 in the adult heart. AnkRD1 has been suggested to be linked to human diseases. It has been shown to be upregulated in dilated cardiomyopathy, ischaemic cardiomyopathy, and arrhythmogenic cardiomyopathy, as well as end-stage heart failure of any cause.6–9 Further, variants in AnkRD1 have been identified in both hypertrophic and dilated cardiomyopathies. These variants are thought to cause disease through modulation of AnkRD1 binding to partners essential for mechanosensing and subsequent nuclear translocation of AnkRD1. Variants in AnkRD1 have also been linked to congenital atrial septal defects.10 While results of previous overexpression experiments have yielded inconsistent results, the link between AnkRD1 and human disease is clear and warrants further study of the role of AnkRD1 in cardiac development, physiology, and pathophysiology. An original research article by Piroddi et al.11 seeks to expand our current understanding of the role of AnkRD1 in cardiac development and physiology (Figure 1). Their research utilized a novel, cardiomyocyte-specific AnkRD1 overexpression murine model which overexpressed AnkRD1 beginning E7.5. Notably, this is the first study to longitudinally examine the effects of AnkRD1 overexpression on embryonic through adult cardiac function. This study demonstrates the importance AnkRD1 in cardiogenesis, as its overexpression caused structural malformation of embryonic hearts including sinus venosus defects, altered rotation, anomalous veno-atrial connections, and misshapen fossae ovalis. However, perturbations in cardiac physiology continue to progress and evolve as mice aged into adulthood. Young mice initially exhibited preserved ejection fraction, but eventually developed a heart failure phenotype, demonstrating a transition from adaptive to maladaptive remodelling. Adult AnkRD1 overexpression mice exhibited progressive loss of sarcomere stability and structure resulting in late diastolic dysfunction. Notably, this diastolic dysfunction was characterized by changes in lusitropy, not passive stiffening. Furthermore, immunofluorescence microscopy demonstrates the dynamic temporally regulated nucleo-sarcoplasmic sublocalization of AnkRD1. This work is the first to longitudinally examine the effect of AnkRD1 throughout cardiac development and provides a compelling, mechanistic link between human cardiac pathophysiology and AnkRD1. While this work provides critical understanding of the role of AnkRD1 in heart development and disease, there is still a need to investigate modulators of AnkRD1 function in order to understand its role in a variety of human disease states. AnkRD1 has been linked to both congenital and acquired conditions, including total anomalous pulmonary venous return and both dilated and hypertrophic cardiomyopathies. Mice from this study demonstrated preserved ejection fraction and retained myofibril force similar to hypertrophic cardiomyopathy, but eventually developed sarcomeric loss, more similar to dilated cardiomyopathy supporting the suggestion that AnkRD1 is involved in the pathogenesis of multiple disease phenotypes. While the mechanisms contributing to the phenotypic diversity of are not known, it has been suggested that the manifestation is determined by several factors, including alterations in binding partners and signalling modulators of AnkRD1, with attention given to the response to haemodynamic changes, due to the important role of AnkRD1 in mechanosensing.1 Continued research is essential to further improve our understanding of normal cardiac physiology and the link between AnkRD1 and the pathophysiology of diverse cardiac diseases. The authors are supported by National Institutes of Health grants (HL135754, HL135096, HL139348, and HL134824 to P.J.M.); a grant from the Ohio State Frick Center for Heart Failure and Arrhythmia, the Linda and Joe Chlapaty Center for Atrial Fibrillation, the Leducq Foundation, and JB Project. Conflict of interest: none declared. Diverse functions of AnkRD1. AnkRD1 plays important roles in embryonic cardiac development, inflammation, sarcomeric organization, mechanosensing, adaptive remodelling, wound healing/fibrosis, and regulation of apoptosis. Findings described by Piroddi et al. via their AnkRD1 overexpression model are indicated in bold. AnkRD1, ankyrin repeat domain 1; ANF, atrial natriuretic factor; Bcl2, B-cell lymphoma 2; cTnC, cardiac troponin C; ERK, extracellular signal-regulated kinase; GATA4, GATA binding protein 4; MMP13, matrix metalloproteinase 13; MLC-2v, myosin light chain-2; Nkx2, NK2 homeobox 1; NFAT, nuclear factor of activated T-cell; NFκB, nuclear factor κ-light-chain-enhancer of activated B cells; TGF-β, transforming growth factor beta; p53, tumour protein 53; YB-1, Y-box binding protein 1. The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.