title: Cardiac Effects of Attenuating Gsα - Dependent Signaling.
abstract: OBJECTIVE
  Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option.
  
  
  RESULTS
  We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation.
  
  
  CONCLUSIONS
  Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure.
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.|Clinic for Orthopedics and Trauma Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Streit
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Celine S
authors.initials: CS
authors.lastname: Weiss
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Ochs
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Hagenmueller
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Riffel
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Buss
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Heger
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.|Center for Cardiac and Circulatory Diseases, Hoheneggerstr. 9, 76646 Bruchsal, Germany.
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Hardt
mesh_terms: D000318:Adrenergic beta-Agonists; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D048429:Cell Size; D000242:Cyclic AMP / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006339:Heart Rate; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D015398:Signal Transduction; D013318:Stroke Volume; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D000318:Adrenergic beta-Agonists; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol
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