Copyright © 2007, European Society of Cardiology
Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression
aDipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy
bDipartimento di Neuroscienze, Università Federico II, Napoli, Italy
cDepartment of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey, USA
*Corresponding author. Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy, Via S. Pansini n. 5, 80131 Napoli, ITALY. Tel./fax: +39 081 7462256. cmorisco{at}yahoo.com
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.
KEYWORDS Apoptosis; Adrenergic agonists; MAP kinase; Hypoxia
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