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

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-022-03742-8.