title: Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes.
abstract: 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.
authors.affiliation: Division of Cardiology, Geneva University Hospitals, 1211 Geneva 14, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Asrih
authors.forename: Stéphany
authors.initials: S
authors.lastname: Gardier
authors.forename: Irène
authors.initials: I
authors.lastname: Papageorgiou
authors.forename: Christophe
authors.initials: C
authors.lastname: Montessuit
mesh_terms: D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D016207:Cytokines; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D009840:Oligomycins; D050799:STAT5 Transcription Factor; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; C092073:cardiotrophin 1; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D005947:Glucose