Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes

Autor: Christophe Albert Montessuit, Mohamed Asrih, Stéphany Gardier, Irène Papageorgiou
Rok vydání: 2012
Předmět:
Male
Oligomycin
medicine.medical_treatment
Glucose Transporter Type 1/metabolism
Rats
Sprague-Dawley
chemistry.chemical_compound
STAT5 Transcription Factor
Glucose/metabolism
Insulin
Myocytes
Cardiac
Phosphorylation
Cells
Cultured
Pyruvate Dehydrogenase (Lipoamide)/metabolism
ddc:616
Glucose Transporter Type 1
Glucose Transporter Type 4
Myocytes
Cardiac/metabolism
Cell Hypoxia
Cytokines
Cytokines/physiology
Cardiology and Cardiovascular Medicine
Glucose Transporter Type 4/metabolism
Signal Transduction
medicine.medical_specialty
Biology
Insulin resistance
Stress
Physiological
Ca2+/calmodulin-dependent protein kinase
Internal medicine
medicine
Animals
Pyruvate Dehydrogenase (Lipoamide)
Molecular Biology
Protein kinase B
Insulin/physiology
STAT5 Transcription Factor/antagonists & inhibitors/metabolism
Glucose transporter
AMPK
Biological Transport
Oligomycins/pharmacology
medicine.disease
Rats
Insulin receptor
Endocrinology
Glucose
chemistry
biology.protein
Oligomycins
Protein Processing
Post-Translational
Zdroj: Journal of Molecular and Cellular Cardiology, Vol. 56 (2013) pp. 106-115
ISSN: 1095-8584
0022-2828
Popis: Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that is increased in the metabolic syndrome due to overexpression in the adipocytes. The effects of CT-1 on cardiomyocyte substrate metabolism remain unknown. We therefore determined the effects of CT-1 on basal and stimulated glucose transport in cardiomyocytes exposed to a low dose (1nM) or a high dose (10nM). Dose-response curves for insulin showed that 1nM CT-1 reduced insulin responsiveness, while 10nM CT-1 increased insulin responsiveness. In either condition insulin sensitivity was unaffected. Similarly 1nM CT-1 reduced the stimulation of glucose transport in response to metabolic stress, induced by the mitochondrial poison oligomycin, while 10nM CT-1 increased this response. Reduction of stimulated glucose transport by 1nM CT-1 was associated with overexpression of SOCS-3, a protein known to hinder proximal insulin signaling, and increased phosphorylation of STAT5. In cardiomyocytes exposed to 1nM CT-1 there was also reduced phosphorylation of Akt and AS160 in response to insulin, and of AMPK in response to oligomycin. Insulin-stimulated glucose transport and signaling were restored by inhibition of STAT5 activity. On the other hand in cardiomyocytes exposed to 10nM CT-1 there was increased phosphorylation of the AS160 and Akt in response to insulin. Most importantly, basal and oligomycin-stimulated phosphorylation of AMPK was markedly increased in cardiomyocytes exposed to 10nM CT-1. The enhancement of basal and stimulated-glucose transport was abolished in cardiomyocytes treated with the calmodulin-dependent kinase II (CaMKII) inhibitor KN93, and so was AMPK phosphorylation. This suggests that activation of CaMKII mediates activation of AMPK by a high dose of CT-1 independently of metabolic stress. Our results point to a role for CT-1 in the regulation of myocardial glucose metabolism and implicate entirely separate mechanisms in the inhibitory or stimulatory effects of CT-1 on glucose transport at low or high concentrations respectively.
Databáze: OpenAIRE
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