Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression

• Published in: Cardiovascular research Vol. 76; no. 3; pp. 453 - 464
• Main Authors: Morisco, Carmine, Marrone, Chiara, Trimarco, Valentina, Crispo, Salvatore, Monti, Maria Gaia, Sadoshima, Junichi, Trimarco, Bruno
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2007; Oxford University Press
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; Apoptosis - physiology; Biological and medical sciences; Cardiology. Vascular system; Caspase 3 - metabolism; Cell Hypoxia - physiology; Cells, Cultured; Dual Specificity Phosphatase 1 - metabolism; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance - physiology; Isoproterenol - pharmacology; MAP Kinase Kinase 4 - metabolism; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Receptors, Adrenergic, beta - metabolism; Signal Transduction - physiology; Adrenergic agonists; MAP kinase; Hypoxia; Apoptosis; Heart; Agonist; Oxygen; Enzyme; Mitogen-activated protein kinase; Phosphoric monoester hydrolases; Esterases; Gene expression; Insulin; Phlebology; Myocyte; Cytoprotector; Hydrolases; Insulin resistance; Circulatory system; Cardiology
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1016/j.cardiores.2007.07.012

Abstract Objective Insulin protects cardiomyocytes from apoptosis. Insulin resistance usually refers to a defect in the ability of insulin to stimulate glucose uptake. It is unknown, however, whether or not insulin resistance compromises the cell-protective effect of the hormone. Caspases are a family of cysteine proteases that regulate apoptosis. We explored the effects of insulin resistance on hypoxia-induced caspase-3 activation in cardiomyocytes. Methods Experiments were performed in cultured neonatal rat cardiomyocytes. Insulin resistance was induced by treating cardiac myocytes with isoproterenol, a β-adrenergic receptor agonist. Results Twelve hours of hypoxia-induced caspase-3 cleavage, which was inhibited by treatment with insulin, while pre-treatment with isoproterenol abolished the insulin effect. Hypoxia-induced cleavage of caspase-3 was mediated by p38 mitogen-activated protein kinase (MAPK). Insulin inhibited hypoxia-induced phosphorylation of p38 through MAPK phosphatase-1 (MKP-1). Insulin-induced MKP-1 expression was mediated by extracellular signal-regulated protein kinases (ERK) 1/2, c-Jun NH2-terminal kinases (JNK) MAPK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Isoproterenol stimulation failed to induce expression of MKP-1; moreover, insulin resistance induced by long-term β-adrenergic stimulation inhibited insulin-evoked expression of MKP-1 by impairing insulin-induced phosphorylation of both ERK1/2 and JNK without affecting Akt kinase activity. Furthermore, concomitant activation of Akt, ERK 1/2, and JNK was required for insulin to exert its protective effect against the hypoxia-induced cleavage of caspase-3. Conclusions The results of this study lead to the conclusions that, in cardiac myocytes, antiapoptotic signals induced by insulin are mediated by more than one signaling pathway, and that long-term β-adrenergic receptor stimulation impairing some of these pathways affects the cytoprotective action of insulin.