TY - JOUR
T1 - The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium
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
N1 - Funding Information:
Our special thanks go to Dr. N. Wettschureck and Prof. S. Offermanns (Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany) for continuous support with the animal experiments. The work is part of the dissertation of DH, JH and KS (University of Cologne). This study was supported by the German Heart Foundation/ German Foundation of Heart Research (F/11/07 to HR), the Marga and Walter Boll-Stiftung (to HR) and a grant of the National Institute of Health (NIH R01 61395 to TMW). The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
PY - 2013/8/20
Y1 - 2013/8/20
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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U2 - 10.1016/j.ijcard.2012.04.039
DO - 10.1016/j.ijcard.2012.04.039
M3 - Article
C2 - 22560942
AN - SCOPUS:84881478425
SN - 0167-5273
VL - 167
SP - 1476
EP - 1485
JO - International Journal of Cardiology
JF - International Journal of Cardiology
IS - 4
ER -