Abstract
Fabry disease is a life-threatening X-linked genetic disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. As a result of the enzyme deficiency, glycosphingolipids (GSLs)with terminal α-D-galactosyl moieties, primarily globotriaosylceramide (Gb3), accumulate leading to dysfunction of multiple cell/organ systems. Arrhythmias and left ventricle hypertrophy are the most prominent cardiac manifestations of Fabry disease, and can precipitate heart failure and cause the early death of the patients. The pathogenesis of the arrhythmias and cardiac hypertrophy in Fabry disease is unclear. The only available specific treatment for Fabry disease, enzyme replacement therapy (ERT) has limited effect on preventing or reversing cardiac manifestations, especially arrhythmias. Therefore, there is a demand for developing new therapeutic approaches. We generated induced pluripotent stem cell (iPSC) from classic male hemizygous Fabry patients and differentiated them into functional cardiomyocytes. These Fabry disease patient-derived cardiac cells showed slow spontaneous beating, mimicking bradycardia in the donor patients. Molecular analysis revealed upregulated expression of the membrane Ca2+ sensor L-type calcium channels (LTCC), hyperphosphorylation of ryanodine receptor (RyR2) and decreased expression of phospholamban in Fabry patient iPSCderived cardiomyocytes. Ca2+ imaging showed abnormal sarcoplasmic reticulum (SR) Ca2+ release and uptake in the Fabry patient cardiomyocytes. In addition, a LTCC inhibitor, verapamil improved the beating rate of Fabry disease patient cardiac clusters in vitro. We conclude that abnormal calcium (Ca2+) handing/homeostasis contributes to cardiac arrhythmia and possibly cardiac hypertrophy in Fabry disease and targeting the Ca2+ cycling pathway may be an effective treatment of heart disease in Fabry patients.
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