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- Title
Ca<sup>2+</sup> dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide.
- Authors
Maione, Angela S.; Faris, Pawan; Iengo, Lara; Catto, Valentina; Bisonni, Luca; Lodola, Francesco; Negri, Sharon; Casella, Michela; Guarino, Anna; Polvani, Gianluca; Cerrone, Marina; Tondo, Claudio; Pompilio, Giulio; Sommariva, Elena; Moccia, Francesco
- Abstract
<bold>Background: </bold>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 (Ca2+) 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 Ca2+ oscillations and the Ca2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes.<bold>Methods and Results: </bold>ACM C-MSC show enhanced spontaneous Ca2+ oscillations and concomitant increased Ca2+/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca2+ Entry (SOCE), which leads to enhanced Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE.<bold>Conclusions: </bold>Altogether, our results extend the knowledge of Ca2+ 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.
- Subjects
HEART cells; FLECAINIDE; GENE silencing; CARDIOMYOPATHIES; TISSUE remodeling; ADIPOGENESIS
- Publication
Journal of Translational Medicine, 2022, Vol 20, Issue 1, p1
- ISSN
1479-5876
- Publication type
journal article
- DOI
10.1186/s12967-022-03742-8