title: Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Keller
authors.affiliation: Department of Internal Medicine III, University Hospital of Cologne, Cologne, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Maass
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Dizayee
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Leiss
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Suvi
authors.initials: S
authors.lastname: Annala
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Köth
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Wiebke K
authors.initials: WK
authors.lastname: Seemann
authors.affiliation: Asklepios Klinik Altona, Hamburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Müller-Ehmsen
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herzig
authors.affiliation: Laboratory of Neurobiology, NIEHS, NIH (Department of Health and Human Services), Durham, USA.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany jan.matthes@uni-koeln.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Matthes
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000172:deficiency* / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D013318:Stroke Volume; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C547788:Adrb1 protein, mouse; D018342:Receptors, Adrenergic, beta-1; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse; C417708:Gnai3 protein, mouse
keywords: Adrenergic receptor; Cardiomyopathy; Cardioprotection; Heart failure; Inhibitory G protein