Formoso Gloria, Chen Hui, Kim Jeong-a, Montagnani Monica, Consoli Agostino, Quon Michael J
Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Building 10, Room 6C-205, 10 Center Drive MSC 1632, Bethesda, Maryland 20892-1632, USA.
Mol Endocrinol. 2006 May;20(5):1153-63. doi: 10.1210/me.2005-0266. Epub 2005 Dec 22.
Dehydroepiandrosterone (DHEA) is an adrenal steroid and nutritional supplement that may improve insulin sensitivity. Although steroid hormones classically act by regulating transcription, they may also signal through cell surface receptors to mediate nongenomic actions. Because DHEA may augment insulin sensitivity, we hypothesized that DHEA mimics vascular actions of insulin to acutely activate signaling pathways in endothelium-mediating production of nitric oxide (NO) and endothelin 1 (ET-1). Treatment of bovine aortic endothelial cells with either insulin or DHEA (100 nm, 5 min) stimulated significant increases in NO production (assessed with NO-selective fluorescent dye diaminofluorescein 2). These responses were abolished by pretreatment of cells with L-NAME (nitro-L-arginine methyl ester; NO synthase inhibitor) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. Under similar conditions, insulin- or DHEA-stimulated phosphorylation of Akt (Ser473) and endothelial nitric oxide synthase (Ser1179) was inhibited by pretreatment of cells with wortmannin (but not MAPK kinase inhibitor PD98059). Acute DHEA treatment also caused phosphorylation of MAPK (Thr202/Tyr204) that was inhibitable by PD98059 (but not wortmannin). DHEA treatment of bovine aortic endothelial cells (100 nM, 5 min) stimulated a 2-fold increase in ET-1 secretion that was abolished by pretreatment of cells with PD98059 (but not wortmannin). We conclude that DHEA has acute, nongenomic actions in endothelium to stimulate production of the vasodilator NO via PI 3-kinase-dependent pathways and secretion of the vasoconstrictor ET-1 via MAPK-dependent pathways. Altering the balance between PI 3-kinase- and MAPK-dependent signaling in vascular endothelium may determine whether DHEA has beneficial or harmful effects relevant to the pathophysiology of diabetes.
脱氢表雄酮（DHEA）是一种肾上腺类固醇和营养补充剂，可能会改善胰岛素敏感性。尽管类固醇激素通常通过调节转录发挥作用，但它们也可能通过细胞表面受体发出信号，介导非基因组作用。由于DHEA可能增强胰岛素敏感性，我们推测DHEA模拟胰岛素的血管作用，以急性激活内皮细胞中一氧化氮（NO）和内皮素1（ET-1）产生的信号通路。用胰岛素或DHEA（100 nM，5分钟）处理牛主动脉内皮细胞，可刺激NO产生显著增加（用NO选择性荧光染料二氨基荧光素2评估）。用L-NAME（硝基-L-精氨酸甲酯；NO合酶抑制剂）或渥曼青霉素[磷脂酰肌醇（PI）3激酶抑制剂]预处理细胞可消除这些反应。在类似条件下，用渥曼青霉素（而非丝裂原活化蛋白激酶激酶抑制剂PD98059）预处理细胞可抑制胰岛素或DHEA刺激的Akt（Ser473）和内皮型一氧化氮合酶（Ser1179）磷酸化。急性DHEA处理还会导致丝裂原活化蛋白激酶（Thr202/Tyr204）磷酸化，该磷酸化可被PD98059抑制（而非渥曼青霉素）。用DHEA处理牛主动脉内皮细胞（100 nM，5分钟）可刺激ET-1分泌增加2倍，用PD98059（而非渥曼青霉素）预处理细胞可消除这种增加。我们得出结论，DHEA在内皮细胞中具有急性非基因组作用，通过PI 3激酶依赖性途径刺激血管舒张剂NO的产生，并通过丝裂原活化蛋白激酶依赖性途径刺激血管收缩剂ET-1的分泌。改变血管内皮细胞中PI 3激酶和丝裂原活化蛋白激酶依赖性信号之间的平衡，可能决定DHEA对糖尿病病理生理学是有益还是有害。
