title: The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium.
abstract: OBJECTIVE
  Pathological cardiac hypertrophy is an early phenotype in both types 1 and 2 diabetes. The primary stimulus for hypertrophic growth in diabetes is yet unknown and may involve neurohumoral stimulation of Gq-coupled receptors as well as direct glucose-dependent mechanisms. To discriminate between these hypertrophic stimuli we analyzed hypertrophic signalling pathways in wildtype and Gα11-knockout mice.
  
  
  METHODS
  Experimental diabetes was induced in wildtype and knockout mice by intraperitoneal injection of streptozotocin. 8 weeks after induction of diabetes myocardial function and structure was assessed by echocardiography before sacrifice. To identify prohypertrophic signalling pathways expression and translocation of protein kinase C isoforms α, βII, δ, ε and ζ were analyzed by immunohistochemical staining and immunoblot analysis after tissue fractionation. Changes in calcineurin signalling were identified by immunoblot analysis and functional assays. Expression levels of transcription factors GATA4 and NF-κB were quantified by real-time RT-PCR.
  
  
  RESULTS
  Diabetic wildtype mice developed myocardial hypertrophy with preserved cardiac function. Calcineurin signalling was not different between the two groups. However, diabetic wildtype mice showed increased protein levels of PKC-α and PKC-ζ, translocation of PKC-α, -δ and -ε to cellular membranes and higher levels of NF-κB expression. In contrast, diabetic Gα11-knockout mice showed no altered phenotype and no changes in NF-κB or PKC expression, although translocation of PKC-ε occurred as in wildtypes.
  
  
  CONCLUSIONS
  Gα11 is essential for the development of cardiac hypertrophy in type 1-diabetes. Stimulation of hypertrophic signalling through PKC-α, PKC-δ, PKC-ζ, and NF-κB appears to be receptor-dependent, whereas PKC-ε is activated by hyperglycemia, independent of Gα11.
authors.affiliation: Department of Internal Medicine III, University of Cologne, Kerpener Str 62, 50937 Cologne, Germany. Hannes.Reuter@uk-koeln.de
authors.forename: Hannes
authors.initials: H
authors.lastname: Reuter
authors.forename: Katharina
authors.initials: K
authors.lastname: Seuthe
authors.forename: Yüksel
authors.initials: Y
authors.lastname: Korkmaz
authors.forename: Sabine
authors.initials: S
authors.lastname: Grönke
authors.forename: Dieter Paul
authors.initials: DP
authors.lastname: Hoyer
authors.forename: Dennis
authors.initials: D
authors.lastname: Rottlaender
authors.forename: Carsten
authors.initials: C
authors.lastname: Zobel
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Johanna
authors.initials: J
authors.lastname: Hoyer
authors.forename: Peter
authors.initials: P
authors.lastname: Grimminger
authors.forename: Jan
authors.initials: J
authors.lastname: Brabender
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wilkie
authors.forename: Erland
authors.initials: E
authors.lastname: Erdmann
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D043802:GTP-Binding Protein alpha Subunits, Gq-G11