Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

“…In six-month-old PKP2-Hz mice AnkB was 24% reduced (1.0 ± 0.07 vs. 0.76 ± 0.08; p ≤ 0.05), SERCA2a 46% ( p = 0.08) and Casq2 31%(1.0 ± 0.087 vs. 0.69 ± 0.04; p ≤ 0.05; Figure S2). Notably, impaired AnkB expression has been recently associated with human ACM [28].…”

Arrhythmogenic cardiomyopathy: pathogenesis, pro-arrhythmic remodelling, and novel approaches for risk stratification and therapy

“… 55 Upon treatment with SB216763, ACM features like fibrosis formation, downregulation of Cx43 and plakoglobin, and contractile dysfunction were almost completely reversed back to control conditions. 55 , 119 These results indicate the importance of the Wnt/β-catenin pathway in progression of ACM. However, continuous activation of the Wnt/β-catenin pathway increases the risk of developing cancer, limiting the clinical applicability of this therapeutic strategy.…”

“…In addition, in ACM fish treated with SB216763, maladaptive remodelling of ion channels underlying action potential formation was reversed. 55 Comparable results were obtained in a mouse model which expressed patient-specific mutations in Ank2 , 119 in cultured buccal mucosa cells, 44 in neonatal rat ventricular myocytes transfected with the same 2057-del2-plakoglobin mutation and in iPSC-CMs of ACM patients with a PKP2 mutation. 55 Upon treatment with SB216763, ACM features like fibrosis formation, downregulation of Cx43 and plakoglobin, and contractile dysfunction were almost completely reversed back to control conditions.…”

“…As explained above, current research focuses on both the Wnt/β signalling pathway and the NFκB pathway. 59 , 119 Using plakoglobin mutant zebrafish, Asimaki et al 55 identified SB216763, an inhibitor of GSK3β and activator of the Wnt/β-catenin pathway, as a pharmacological modulator capable of preventing and rescuing the ACM phenotype in zebrafish. In addition, in ACM fish treated with SB216763, maladaptive remodelling of ion channels underlying action potential formation was reversed.…”

Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine

“…To date, more than 15 genes have been linked to ACM, of which five genes encode desmosomal proteins located in the intercalated disk, including desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), plakophilin-2 (PKP2), and plakoglobin (JUP) (McKoy et al, 2000;Rampazzo et al, 2002;Gerull et al, 2004;Pilichou et al, 2006;Syrris et al, 2006;Vimalanathan et al, 2018;Roberts et al, 2019). Mutations in PKP2, DSP, and DSG2 are the most common causes, accounting for about 45% of all ACM probands, and all other genes are relatively rare (Padron-Barthe et al, 2017).…”