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

被引:36
作者
Morisco, Cannine
Marrone, Chiara
Trimarco, Valentina
Crispo, Salvatore
Monti, Maria Gaia
Sadoshima, Junichi
Trimarco, Bruno
机构
[1] Univ Naples Federico II, Dept Medv Clin Sci Cardiovasc Immunol, Dipartimento Med Clin, I-80131 Naples, Italy
[2] Univ Naples Federico II, Dipartimento Neurosci, Naples, Italy
[3] Univ Med & Dent New Jersey, Dept Cell Biol & Mol Med, Newark, NJ USA
关键词
apoptosis; adrenergic agonists; MAP kinase; hypoxia;
D O I
10.1016/j.cardiores.2007.07.012
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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, beta-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 (INK) MAPK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Isoproterenol stimulation failed to induce expression of MKP-1; moreover, insulin resistance induced by long-term beta-adrenergic stimulation inhibited insulin-evoked expression of MKP-1 by impairing insulin-induced phosphorylation of both ERK1/2 and INK 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 beta-adrenergic receptor stimulation impairing some of these pathways affects the cytoprotective action of insulin. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:453 / 464
页数:12
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