$ 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
Gespeichert in:
| Autor*in: |
Maione, Angela S. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2022 |
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| Übergeordnetes Werk: |
Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 20(2022), 1 vom: 12. Nov. |
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| Übergeordnetes Werk: |
volume:20 ; year:2022 ; number:1 ; day:12 ; month:11 |
| Links: |
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| DOI / URN: |
10.1186/s12967-022-03742-8 |
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| Katalog-ID: |
SPR051124033 |
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| 100 | 1 | |a Maione, Angela S. |e verfasserin |0 (orcid)0000-0003-1460-7033 |4 aut | |
| 245 | 1 | 0 | |a $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
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| 520 | |a 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. | ||
| 650 | 4 | |a Arrhythmogenic cardiomyopathy |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cardiac mesenchymal stromal cells |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Calcium signalling |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a CaMKII |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Store-operated Ca |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a entry |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Flecainide |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Faris, Pawan |4 aut | |
| 700 | 1 | |a Iengo, Lara |4 aut | |
| 700 | 1 | |a Catto, Valentina |4 aut | |
| 700 | 1 | |a Bisonni, Luca |4 aut | |
| 700 | 1 | |a Lodola, Francesco |4 aut | |
| 700 | 1 | |a Negri, Sharon |4 aut | |
| 700 | 1 | |a Casella, Michela |4 aut | |
| 700 | 1 | |a Guarino, Anna |4 aut | |
| 700 | 1 | |a Polvani, Gianluca |4 aut | |
| 700 | 1 | |a Cerrone, Marina |4 aut | |
| 700 | 1 | |a Tondo, Claudio |4 aut | |
| 700 | 1 | |a Pompilio, Giulio |4 aut | |
| 700 | 1 | |a Sommariva, Elena |4 aut | |
| 700 | 1 | |a Moccia, Francesco |4 aut | |
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10.1186/s12967-022-03742-8 doi (DE-627)SPR051124033 (SPR)s12967-022-03742-8-e DE-627 ger DE-627 rakwb eng Maione, Angela S. verfasserin (orcid)0000-0003-1460-7033 aut $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Arrhythmogenic cardiomyopathy (dpeaa)DE-He213 Cardiac mesenchymal stromal cells (dpeaa)DE-He213 Calcium signalling (dpeaa)DE-He213 CaMKII (dpeaa)DE-He213 Store-operated Ca (dpeaa)DE-He213 entry (dpeaa)DE-He213 Flecainide (dpeaa)DE-He213 Faris, Pawan aut Iengo, Lara aut Catto, Valentina aut Bisonni, Luca aut Lodola, Francesco aut Negri, Sharon aut Casella, Michela aut Guarino, Anna aut Polvani, Gianluca aut Cerrone, Marina aut Tondo, Claudio aut Pompilio, Giulio aut Sommariva, Elena aut Moccia, Francesco aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 12. Nov. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:12 month:11 https://dx.doi.org/10.1186/s12967-022-03742-8 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 12 11 |
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10.1186/s12967-022-03742-8 doi (DE-627)SPR051124033 (SPR)s12967-022-03742-8-e DE-627 ger DE-627 rakwb eng Maione, Angela S. verfasserin (orcid)0000-0003-1460-7033 aut $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Arrhythmogenic cardiomyopathy (dpeaa)DE-He213 Cardiac mesenchymal stromal cells (dpeaa)DE-He213 Calcium signalling (dpeaa)DE-He213 CaMKII (dpeaa)DE-He213 Store-operated Ca (dpeaa)DE-He213 entry (dpeaa)DE-He213 Flecainide (dpeaa)DE-He213 Faris, Pawan aut Iengo, Lara aut Catto, Valentina aut Bisonni, Luca aut Lodola, Francesco aut Negri, Sharon aut Casella, Michela aut Guarino, Anna aut Polvani, Gianluca aut Cerrone, Marina aut Tondo, Claudio aut Pompilio, Giulio aut Sommariva, Elena aut Moccia, Francesco aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 12. Nov. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:12 month:11 https://dx.doi.org/10.1186/s12967-022-03742-8 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 12 11 |
| allfields_unstemmed |
10.1186/s12967-022-03742-8 doi (DE-627)SPR051124033 (SPR)s12967-022-03742-8-e DE-627 ger DE-627 rakwb eng Maione, Angela S. verfasserin (orcid)0000-0003-1460-7033 aut $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Arrhythmogenic cardiomyopathy (dpeaa)DE-He213 Cardiac mesenchymal stromal cells (dpeaa)DE-He213 Calcium signalling (dpeaa)DE-He213 CaMKII (dpeaa)DE-He213 Store-operated Ca (dpeaa)DE-He213 entry (dpeaa)DE-He213 Flecainide (dpeaa)DE-He213 Faris, Pawan aut Iengo, Lara aut Catto, Valentina aut Bisonni, Luca aut Lodola, Francesco aut Negri, Sharon aut Casella, Michela aut Guarino, Anna aut Polvani, Gianluca aut Cerrone, Marina aut Tondo, Claudio aut Pompilio, Giulio aut Sommariva, Elena aut Moccia, Francesco aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 12. Nov. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:12 month:11 https://dx.doi.org/10.1186/s12967-022-03742-8 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 12 11 |
| allfieldsGer |
10.1186/s12967-022-03742-8 doi (DE-627)SPR051124033 (SPR)s12967-022-03742-8-e DE-627 ger DE-627 rakwb eng Maione, Angela S. verfasserin (orcid)0000-0003-1460-7033 aut $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Arrhythmogenic cardiomyopathy (dpeaa)DE-He213 Cardiac mesenchymal stromal cells (dpeaa)DE-He213 Calcium signalling (dpeaa)DE-He213 CaMKII (dpeaa)DE-He213 Store-operated Ca (dpeaa)DE-He213 entry (dpeaa)DE-He213 Flecainide (dpeaa)DE-He213 Faris, Pawan aut Iengo, Lara aut Catto, Valentina aut Bisonni, Luca aut Lodola, Francesco aut Negri, Sharon aut Casella, Michela aut Guarino, Anna aut Polvani, Gianluca aut Cerrone, Marina aut Tondo, Claudio aut Pompilio, Giulio aut Sommariva, Elena aut Moccia, Francesco aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 12. Nov. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:12 month:11 https://dx.doi.org/10.1186/s12967-022-03742-8 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 12 11 |
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10.1186/s12967-022-03742-8 doi (DE-627)SPR051124033 (SPR)s12967-022-03742-8-e DE-627 ger DE-627 rakwb eng Maione, Angela S. verfasserin (orcid)0000-0003-1460-7033 aut $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Arrhythmogenic cardiomyopathy (dpeaa)DE-He213 Cardiac mesenchymal stromal cells (dpeaa)DE-He213 Calcium signalling (dpeaa)DE-He213 CaMKII (dpeaa)DE-He213 Store-operated Ca (dpeaa)DE-He213 entry (dpeaa)DE-He213 Flecainide (dpeaa)DE-He213 Faris, Pawan aut Iengo, Lara aut Catto, Valentina aut Bisonni, Luca aut Lodola, Francesco aut Negri, Sharon aut Casella, Michela aut Guarino, Anna aut Polvani, Gianluca aut Cerrone, Marina aut Tondo, Claudio aut Pompilio, Giulio aut Sommariva, Elena aut Moccia, Francesco aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 12. Nov. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:12 month:11 https://dx.doi.org/10.1186/s12967-022-03742-8 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 12 11 |
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Maione, Angela S. misc Arrhythmogenic cardiomyopathy misc Cardiac mesenchymal stromal cells misc Calcium signalling misc CaMKII misc Store-operated Ca misc entry misc Flecainide $ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
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$ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide Arrhythmogenic cardiomyopathy (dpeaa)DE-He213 Cardiac mesenchymal stromal cells (dpeaa)DE-He213 Calcium signalling (dpeaa)DE-He213 CaMKII (dpeaa)DE-He213 Store-operated Ca (dpeaa)DE-He213 entry (dpeaa)DE-He213 Flecainide (dpeaa)DE-He213 |
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$ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
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$ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
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Maione, Angela S. |
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Journal of translational medicine |
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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 |
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Elektronische Aufsätze |
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Maione, Angela S. |
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$ ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in arrhythmogenic cardiomyopathy and can be modulated by flecainide |
| title_auth |
$ 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. © The Author(s) 2022 |
| abstractGer |
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. © The Author(s) 2022 |
| abstract_unstemmed |
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. © The Author(s) 2022 |
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$ Ca^{2+} $ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide |
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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 |
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