The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium

Hannes Reuter, Katharina Seuthe, Yüksel Korkmaz, Sabine Grönke, Dieter Paul Hoyer, Dennis Rottlaender, Carsten Zobel, Klaus Addicks, Johanna Hoyer, Peter Grimminger, Jan Brabender, Thomas M. Wilkie, Erland Erdmann

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis: 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.

Original languageEnglish (US)
Pages (from-to)1476-1485
Number of pages10
JournalInternational Journal of Cardiology
Volume167
Issue number4
DOIs
StatePublished - Aug 20 2013

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Gq-G11 GTP-Binding Protein alpha Subunits
Knockout Mice
Myocardium
Calcineurin
Cardiomegaly
Type 1 Diabetes Mellitus
GATA4 Transcription Factor
Phenotype
Streptozocin
Intraperitoneal Injections
Hyperglycemia
Type 2 Diabetes Mellitus
Protein Kinase C
Hypertrophy
Echocardiography
Real-Time Polymerase Chain Reaction
Protein Isoforms
Staining and Labeling
Glucose
Membranes

Keywords

  • G protein signalling
  • Gα knockout
  • Myocardial hypertrophy
  • NF-κB
  • Protein kinase C
  • Type 1 diabetes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Reuter, H., Seuthe, K., Korkmaz, Y., Grönke, S., Hoyer, D. P., Rottlaender, D., ... Erdmann, E. (2013). The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium. International Journal of Cardiology, 167(4), 1476-1485. https://doi.org/10.1016/j.ijcard.2012.04.039

The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium. / Reuter, Hannes; Seuthe, Katharina; Korkmaz, Yüksel; Grönke, Sabine; Hoyer, Dieter Paul; Rottlaender, Dennis; Zobel, Carsten; Addicks, Klaus; Hoyer, Johanna; Grimminger, Peter; Brabender, Jan; Wilkie, Thomas M.; Erdmann, Erland.

In: International Journal of Cardiology, Vol. 167, No. 4, 20.08.2013, p. 1476-1485.

Research output: Contribution to journalArticle

Reuter, H, Seuthe, K, Korkmaz, Y, Grönke, S, Hoyer, DP, Rottlaender, D, Zobel, C, Addicks, K, Hoyer, J, Grimminger, P, Brabender, J, Wilkie, TM & Erdmann, E 2013, 'The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium', International Journal of Cardiology, vol. 167, no. 4, pp. 1476-1485. https://doi.org/10.1016/j.ijcard.2012.04.039
Reuter, Hannes ; Seuthe, Katharina ; Korkmaz, Yüksel ; Grönke, Sabine ; Hoyer, Dieter Paul ; Rottlaender, Dennis ; Zobel, Carsten ; Addicks, Klaus ; Hoyer, Johanna ; Grimminger, Peter ; Brabender, Jan ; Wilkie, Thomas M. ; Erdmann, Erland. / The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium. In: International Journal of Cardiology. 2013 ; Vol. 167, No. 4. pp. 1476-1485.
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abstract = "Aims/hypothesis: 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.",
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AU - Reuter, Hannes

AU - Seuthe, Katharina

AU - Korkmaz, Yüksel

AU - Grönke, Sabine

AU - Hoyer, Dieter Paul

AU - Rottlaender, Dennis

AU - Zobel, Carsten

AU - Addicks, Klaus

AU - Hoyer, Johanna

AU - Grimminger, Peter

AU - Brabender, Jan

AU - Wilkie, Thomas M.

AU - Erdmann, Erland

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N2 - Aims/hypothesis: 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.

AB - Aims/hypothesis: 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.

KW - G protein signalling

KW - Gα knockout

KW - Myocardial hypertrophy

KW - NF-κB

KW - Protein kinase C

KW - Type 1 diabetes

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