Introduction: The exact contribution of Wnt/β-catenin pathway to arrhythmogenic right ventricular cardiomyopathy (ARVC) pathophysiology is still unknown. Therefore, determining the regulatory mechanism of Wnt/β-catenin signaling in the molecular pathogenesis of ARVC could give crucial insights into the molecular pathogenesis of the onset ARVC disease.
Methods and results: We generated three patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) lines from peripheral blood mononuclear cells obtained from two patients harboring a PKP2 heterozygous mutation (UKJi001-A and UKJi006-A) and one a healthy control (UKJi004-A) donor. Through the examination of CMs from both lines PKP2-iPSC and were subjected to high fatty acid (HFA) in the presence/absence of CHIR99021(acts as Wnt activator) for one week, we were able under HFA to ascertain the following: (1) significant desmosomal abnormalities in the CMs as revealed by electron microscopy (p< 0.01) and the analysis of PKP2 (p< 0.05) and plakoglobin (p< 0.05); (2) the impact of desmosomal remodeling on the associated intercalated disc structure gap junction (p< 0.001); (3) the accumulation of lipid droplets in CMs of both lines PKP2-iPSC, and the upregulation of the proadipogenic factor PPARγ (p< 0.001); (4) inhibition in mitochondrial respiration and ATP production (p< 0.001); and (5) a decrease in the levels of Wnt1 (p< 0.05) and ß-catenin-1 (p< 0.01) in CMs of both lines PKP2-iPSC. It's interesting to note that co-incubating CHIR 99021, a potent and highly selective inhibitor of glycogen synthase kinase 3 (GSK-3), may mitigate the adverse effects of lipotoxicity on CMs by restoring the Wnt1/ß-catenin-1 level and reducing the pGSK-3ß level.
Conclusion: Finally, the results of our study demonstrate the ability of lipogenic stress to worsen the ARVC phenotype and Wnt/β-catenin signaling may have a role in the molecular pathogenesis of ARVC disease. Elucidation of the precise regulatory mechanism of Wnt/β-catenin signaling in ARVC molecular pathogenesis could provide fundamental insights for a new mechanism based therapeutic strategy to delay the onset or progression of this cardiac disease.
