Ca2+ 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 (Ca2+) signaling dysfunction, mainly demonstrat...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03742-8 |
| _version_ | 1828098575081406464 |
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| author | Angela S. Maione Pawan Faris Lara Iengo Valentina Catto Luca Bisonni Francesco Lodola Sharon Negri Michela Casella Anna Guarino Gianluca Polvani Marina Cerrone Claudio Tondo Giulio Pompilio Elena Sommariva Francesco Moccia |
| author_facet | Angela S. Maione Pawan Faris Lara Iengo Valentina Catto Luca Bisonni Francesco Lodola Sharon Negri Michela Casella Anna Guarino Gianluca Polvani Marina Cerrone Claudio Tondo Giulio Pompilio Elena Sommariva Francesco Moccia |
| author_sort | Angela S. Maione |
| collection | DOAJ |
| description | 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 (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. Methods and results 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. Conclusions 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. |
| first_indexed | 2024-04-11T08:04:30Z |
| format | Article |
| id | doaj.art-18182d2f699f4083af4d1ace0e1d0059 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-11T08:04:30Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-18182d2f699f4083af4d1ace0e1d00592022-12-22T04:35:36ZengBMCJournal of Translational Medicine1479-58762022-11-0120112010.1186/s12967-022-03742-8Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainideAngela S. Maione0Pawan Faris1Lara Iengo2Valentina Catto3Luca Bisonni4Francesco Lodola5Sharon Negri6Michela Casella7Anna Guarino8Gianluca Polvani9Marina Cerrone10Claudio Tondo11Giulio Pompilio12Elena Sommariva13Francesco Moccia14Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCSDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of PaviaUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCSDepartment of Clinical Electrophysiology and Cardiac Pacing, Centro Cardiologico Monzino IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCSLaboratory of Cardiac Cellular Physiology, Department of Biotechnology and Bioscience, University of Milano-BicoccaDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of PaviaDepartment of Clinical Electrophysiology and Cardiac Pacing, Centro Cardiologico Monzino IRCCSCardiovascular Tissue Bank of Lombardy, Centro Cardiologico Monzino IRCCSCardiovascular Tissue Bank of Lombardy, Centro Cardiologico Monzino IRCCSMedicine, Leon H. Charney Division of Cardiology, Heart Rhythm Center and Cardiovascular Genetics Program, New York University School of MedicineDepartment of Clinical Electrophysiology and Cardiac Pacing, Centro Cardiologico Monzino IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCSDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of PaviaAbstract 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 (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. Methods and results 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. Conclusions 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.https://doi.org/10.1186/s12967-022-03742-8Arrhythmogenic cardiomyopathyCardiac mesenchymal stromal cellsCalcium signallingCaMKIIStore-operated Ca2+ entryFlecainide |
| spellingShingle | Angela S. Maione Pawan Faris Lara Iengo Valentina Catto Luca Bisonni Francesco Lodola Sharon Negri Michela Casella Anna Guarino Gianluca Polvani Marina Cerrone Claudio Tondo Giulio Pompilio Elena Sommariva Francesco Moccia Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide Journal of Translational Medicine Arrhythmogenic cardiomyopathy Cardiac mesenchymal stromal cells Calcium signalling CaMKII Store-operated Ca2+ entry Flecainide |
| title | Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
| title_full | Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
| title_fullStr | Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
| title_full_unstemmed | Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
| title_short | Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
| title_sort | ca2 dysregulation in cardiac stromal cells sustains fibro adipose remodeling in arrhythmogenic cardiomyopathy and can be modulated by flecainide |
| topic | Arrhythmogenic cardiomyopathy Cardiac mesenchymal stromal cells Calcium signalling CaMKII Store-operated Ca2+ entry Flecainide |
| url | https://doi.org/10.1186/s12967-022-03742-8 |
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