$ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide

Background Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium ($ Ca^{2+} $) signaling dysfunction, mainly demonstrated...
Ausführliche Beschreibung

Background Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium ($ Ca^{2+} $) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular $ Ca^{2+} $ oscillations and the $ Ca^{2+} $ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. Methods and results ACM C-MSC show enhanced spontaneous $ Ca^{2+} $ oscillations and concomitant increased $ Ca^{2+} $/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated $ Ca^{2+} $ Entry (SOCE), which leads to enhanced $ Ca^{2+} $ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the $ Ca^{2+} $ handling machinery or CaMKII activity, we demonstrated a causative link between $ Ca^{2+} $ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the $ Ca^{2+} $ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular $ Ca^{2+} $ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. Conclusions Altogether, our results extend the knowledge of $ Ca^{2+} $ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM. Ausführliche Beschreibung