Morisco Carmine, Marrone Chiara, Trimarco Valentina, Crispo Salvatore, Monti Maria Gaia, Sadoshima Junichi, Trimarco Bruno
Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy.
Cardiovasc Res. 2007 Dec 1;76(3):453-64. doi: 10.1016/j.cardiores.2007.07.012. Epub 2007 Jul 25.
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.
Experiments were performed in cultured neonatal rat cardiomyocytes. Insulin resistance was induced by treating cardiac myocytes with isoproterenol, a beta-adrenergic receptor agonist.
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 beta-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.
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.
胰岛素可保护心肌细胞免于凋亡。胰岛素抵抗通常是指胰岛素刺激葡萄糖摄取能力的缺陷。然而，胰岛素抵抗是否会损害该激素的细胞保护作用尚不清楚。半胱天冬酶是一类调节凋亡的半胱氨酸蛋白酶。我们探讨了胰岛素抵抗对缺氧诱导的心肌细胞中半胱天冬酶 -3 激活的影响。
实验在培养的新生大鼠心肌细胞中进行。用β-肾上腺素能受体激动剂异丙肾上腺素处理心肌细胞以诱导胰岛素抵抗。
缺氧 12 小时可诱导半胱天冬酶 -3 裂解，胰岛素处理可抑制此过程，而预先用异丙肾上腺素处理则消除了胰岛素的作用。缺氧诱导的半胱天冬酶 -3 裂解由 p38 丝裂原活化蛋白激酶（MAPK）介导。胰岛素通过 MAPK 磷酸酶 -1（MKP -1）抑制缺氧诱导的 p38 磷酸化。胰岛素诱导的 MKP -1 表达由细胞外信号调节蛋白激酶（ERK）1/2、c -Jun N 端激酶（JNK）MAPK 和磷脂酰肌醇 3 -激酶（PI3K）/Akt 途径介导。异丙肾上腺素刺激未能诱导 MKP -1 的表达；此外，长期β-肾上腺素能刺激诱导的胰岛素抵抗通过损害胰岛素诱导的 ERK1/2 和 JNK 磷酸化而抑制胰岛素诱发的 MKP -1 表达，而不影响 Akt 激酶活性。此外，胰岛素发挥其对缺氧诱导的半胱天冬酶 -3 裂解的保护作用需要 Akt、ERK 1/2 和 JNK 的协同激活。
本研究结果得出以下结论：在心肌细胞中，胰岛素诱导的抗凋亡信号由多个信号通路介导，长期β-肾上腺素能受体刺激损害其中一些通路会影响胰岛素的细胞保护作用。
