Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice

Autores
Keller, Kirsten; Maass, Martina; Dizayee, Sara; Leiss, Veronika; Annala, Suvi; Köth, Jessica; Seemann, Wiebke K.; Müller Ehmsen, Jochen; Mohr, Klaus; Nürnberg, Bernd; Engelhardt, Stefan; Herzig, Stefan; Birnbaumer, Lutz; Matthes, Jan
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Gαi2 knockout on cardiac function and survival in a murine heart failure model of cardiac β1-adrenoceptor overexpression. Methods and results β1-transgenic mice lacking Gαi2 (β1-tg/Gαi2 -/-) were compared with wild-type mice and littermates either overexpressing cardiac β1-adrenoceptors (β1-tg) or lacking Gαi2 (Gαi2 -/-). At 300 days, mortality of mice only lacking Gαi2 was already higher compared with wild-type or β1-tg, but similar to β1-tg/Gαi2 -/-, mice. Beyond 300 days, mortality of β1-tg/Gαi2 -/- mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, β1-tg, and Gαi2 -/- mice, but significant impairment for β1-tg/Gαi2 -/- mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gαi3 was significantly up-regulated in Gαi2 knockout mice (protein compared with wild type: 340 ± 90% in Gαi2 -/- and 394 ± 80% in β1-tg/Gαi2 -/-, respectively). Conclusions Gαi2 deficiency combined with cardiac β1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, β1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gαi2. We propose an enhanced effect of increased β1-adrenergic drive by the lack of protection via Gαi2. Gαi3 up-regulation was not sufficient to compensate for Gαi2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.
Fil: Keller, Kirsten. Universitat Zu Köln; Alemania
Fil: Maass, Martina. University Hospital of Cologne; Alemania
Fil: Dizayee, Sara. Universitat Zu Köln; Alemania
Fil: Leiss, Veronika. Eberhard Karls University Hospitals and Clinics; Alemania
Fil: Annala, Suvi. Universitat Zu Köln; Alemania
Fil: Köth, Jessica. Universitat Zu Köln; Alemania
Fil: Seemann, Wiebke K.. Universitat Zu Köln; Alemania
Fil: Müller Ehmsen, Jochen. Asklepios Klinik Altona; Alemania
Fil: Mohr, Klaus. Universitaet Bonn; Alemania
Fil: Nürnberg, Bernd. Eberhard Karls University Hospitals and Clinics; Alemania
Fil: Engelhardt, Stefan. Universitat Technical Zu Munich; Alemania
Fil: Herzig, Stefan. Universitat Zu Köln; Alemania
Fil: Birnbaumer, Lutz. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Matthes, Jan. Universitat Zu Köln; Alemania
Materia
Adrenergic Receptor
Cardiomyopathy
Cardioprotection
Heart Failure
Inhibitory G Protein
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/37874
Acceder
id CONICETDig_382f1036d4379b286ef162b09ebdeaf5
oai_identifier_str oai:ri.conicet.gov.ar:11336/37874
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing miceKeller, KirstenMaass, MartinaDizayee, SaraLeiss, VeronikaAnnala, SuviKöth, JessicaSeemann, Wiebke K.Müller Ehmsen, JochenMohr, KlausNürnberg, BerndEngelhardt, StefanHerzig, StefanBirnbaumer, LutzMatthes, JanAdrenergic ReceptorCardiomyopathyCardioprotectionHeart FailureInhibitory G Proteinhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Aims Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Gαi2 knockout on cardiac function and survival in a murine heart failure model of cardiac β1-adrenoceptor overexpression. Methods and results β1-transgenic mice lacking Gαi2 (β1-tg/Gαi2 -/-) were compared with wild-type mice and littermates either overexpressing cardiac β1-adrenoceptors (β1-tg) or lacking Gαi2 (Gαi2 -/-). At 300 days, mortality of mice only lacking Gαi2 was already higher compared with wild-type or β1-tg, but similar to β1-tg/Gαi2 -/-, mice. Beyond 300 days, mortality of β1-tg/Gαi2 -/- mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, β1-tg, and Gαi2 -/- mice, but significant impairment for β1-tg/Gαi2 -/- mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gαi3 was significantly up-regulated in Gαi2 knockout mice (protein compared with wild type: 340 ± 90% in Gαi2 -/- and 394 ± 80% in β1-tg/Gαi2 -/-, respectively). Conclusions Gαi2 deficiency combined with cardiac β1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, β1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gαi2. We propose an enhanced effect of increased β1-adrenergic drive by the lack of protection via Gαi2. Gαi3 up-regulation was not sufficient to compensate for Gαi2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.Fil: Keller, Kirsten. Universitat Zu Köln; AlemaniaFil: Maass, Martina. University Hospital of Cologne; AlemaniaFil: Dizayee, Sara. Universitat Zu Köln; AlemaniaFil: Leiss, Veronika. Eberhard Karls University Hospitals and Clinics; AlemaniaFil: Annala, Suvi. Universitat Zu Köln; AlemaniaFil: Köth, Jessica. Universitat Zu Köln; AlemaniaFil: Seemann, Wiebke K.. Universitat Zu Köln; AlemaniaFil: Müller Ehmsen, Jochen. Asklepios Klinik Altona; AlemaniaFil: Mohr, Klaus. Universitaet Bonn; AlemaniaFil: Nürnberg, Bernd. Eberhard Karls University Hospitals and Clinics; AlemaniaFil: Engelhardt, Stefan. Universitat Technical Zu Munich; AlemaniaFil: Herzig, Stefan. Universitat Zu Köln; AlemaniaFil: Birnbaumer, Lutz. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Matthes, Jan. Universitat Zu Köln; AlemaniaOxford University Press2015-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/37874Keller, Kirsten; Maass, Martina; Dizayee, Sara; Leiss, Veronika; Annala, Suvi; et al.; Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice; Oxford University Press; Cardiovascular Research; 108; 3; 12-2015; 348-3560008-6363CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/cvr/cvv235info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/cardiovascres/article/108/3/348/557401info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:20:12Zoai:ri.conicet.gov.ar:11336/37874instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:20:12.705CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
title Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
spellingShingle Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
Keller, Kirsten
Adrenergic Receptor
Cardiomyopathy
Cardioprotection
Heart Failure
Inhibitory G Protein
title_short Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
title_full Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
title_fullStr Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
title_full_unstemmed Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
title_sort Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice
dc.creator.none.fl_str_mv Keller, Kirsten
Maass, Martina
Dizayee, Sara
Leiss, Veronika
Annala, Suvi
Köth, Jessica
Seemann, Wiebke K.
Müller Ehmsen, Jochen
Mohr, Klaus
Nürnberg, Bernd
Engelhardt, Stefan
Herzig, Stefan
Birnbaumer, Lutz
Matthes, Jan
author Keller, Kirsten
author_facet Keller, Kirsten
Maass, Martina
Dizayee, Sara
Leiss, Veronika
Annala, Suvi
Köth, Jessica
Seemann, Wiebke K.
Müller Ehmsen, Jochen
Mohr, Klaus
Nürnberg, Bernd
Engelhardt, Stefan
Herzig, Stefan
Birnbaumer, Lutz
Matthes, Jan
author_role author
author2 Maass, Martina
Dizayee, Sara
Leiss, Veronika
Annala, Suvi
Köth, Jessica
Seemann, Wiebke K.
Müller Ehmsen, Jochen
Mohr, Klaus
Nürnberg, Bernd
Engelhardt, Stefan
Herzig, Stefan
Birnbaumer, Lutz
Matthes, Jan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adrenergic Receptor
Cardiomyopathy
Cardioprotection
Heart Failure
Inhibitory G Protein
topic Adrenergic Receptor
Cardiomyopathy
Cardioprotection
Heart Failure
Inhibitory G Protein
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Aims Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Gαi2 knockout on cardiac function and survival in a murine heart failure model of cardiac β1-adrenoceptor overexpression. Methods and results β1-transgenic mice lacking Gαi2 (β1-tg/Gαi2 -/-) were compared with wild-type mice and littermates either overexpressing cardiac β1-adrenoceptors (β1-tg) or lacking Gαi2 (Gαi2 -/-). At 300 days, mortality of mice only lacking Gαi2 was already higher compared with wild-type or β1-tg, but similar to β1-tg/Gαi2 -/-, mice. Beyond 300 days, mortality of β1-tg/Gαi2 -/- mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, β1-tg, and Gαi2 -/- mice, but significant impairment for β1-tg/Gαi2 -/- mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gαi3 was significantly up-regulated in Gαi2 knockout mice (protein compared with wild type: 340 ± 90% in Gαi2 -/- and 394 ± 80% in β1-tg/Gαi2 -/-, respectively). Conclusions Gαi2 deficiency combined with cardiac β1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, β1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gαi2. We propose an enhanced effect of increased β1-adrenergic drive by the lack of protection via Gαi2. Gαi3 up-regulation was not sufficient to compensate for Gαi2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.
Fil: Keller, Kirsten. Universitat Zu Köln; Alemania
Fil: Maass, Martina. University Hospital of Cologne; Alemania
Fil: Dizayee, Sara. Universitat Zu Köln; Alemania
Fil: Leiss, Veronika. Eberhard Karls University Hospitals and Clinics; Alemania
Fil: Annala, Suvi. Universitat Zu Köln; Alemania
Fil: Köth, Jessica. Universitat Zu Köln; Alemania
Fil: Seemann, Wiebke K.. Universitat Zu Köln; Alemania
Fil: Müller Ehmsen, Jochen. Asklepios Klinik Altona; Alemania
Fil: Mohr, Klaus. Universitaet Bonn; Alemania
Fil: Nürnberg, Bernd. Eberhard Karls University Hospitals and Clinics; Alemania
Fil: Engelhardt, Stefan. Universitat Technical Zu Munich; Alemania
Fil: Herzig, Stefan. Universitat Zu Köln; Alemania
Fil: Birnbaumer, Lutz. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Matthes, Jan. Universitat Zu Köln; Alemania
description Aims Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Gαi2 knockout on cardiac function and survival in a murine heart failure model of cardiac β1-adrenoceptor overexpression. Methods and results β1-transgenic mice lacking Gαi2 (β1-tg/Gαi2 -/-) were compared with wild-type mice and littermates either overexpressing cardiac β1-adrenoceptors (β1-tg) or lacking Gαi2 (Gαi2 -/-). At 300 days, mortality of mice only lacking Gαi2 was already higher compared with wild-type or β1-tg, but similar to β1-tg/Gαi2 -/-, mice. Beyond 300 days, mortality of β1-tg/Gαi2 -/- mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, β1-tg, and Gαi2 -/- mice, but significant impairment for β1-tg/Gαi2 -/- mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gαi3 was significantly up-regulated in Gαi2 knockout mice (protein compared with wild type: 340 ± 90% in Gαi2 -/- and 394 ± 80% in β1-tg/Gαi2 -/-, respectively). Conclusions Gαi2 deficiency combined with cardiac β1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, β1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gαi2. We propose an enhanced effect of increased β1-adrenergic drive by the lack of protection via Gαi2. Gαi3 up-regulation was not sufficient to compensate for Gαi2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.
publishDate 2015
dc.date.none.fl_str_mv 2015-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/37874
Keller, Kirsten; Maass, Martina; Dizayee, Sara; Leiss, Veronika; Annala, Suvi; et al.; Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice; Oxford University Press; Cardiovascular Research; 108; 3; 12-2015; 348-356
0008-6363
CONICET Digital
CONICET
url http://hdl.handle.net/11336/37874
identifier_str_mv Keller, Kirsten; Maass, Martina; Dizayee, Sara; Leiss, Veronika; Annala, Suvi; et al.; Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice; Oxford University Press; Cardiovascular Research; 108; 3; 12-2015; 348-356
0008-6363
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/cvr/cvv235
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/cardiovascres/article/108/3/348/557401
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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