Simoncini Tommaso, Mannella Paolo, Fornari Letizia, Varone Gaetano, Caruso Antonella, Genazzani Andrea R
Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy.
Endocrinology. 2003 Aug;144(8):3449-55. doi: 10.1210/en.2003-0044.
Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones in humans, and their levels progressively decline with age. Epidemiological studies suggest that DHEA/DHEAS concentrations may be inversely related to cardiovascular risk, but disagreement exists on this issue. Preliminary studies show that DHEA regulates vascular function, but few data have been published on the mechanisms. We show that DHEA administration to human endothelial cells triggers nitric oxide synthesis, due to enhanced expression and stabilization of endothelial nitric oxide synthase (eNOS). Additionally, DHEA rapidly activates eNOS, through a nontranscriptional mechanism that depends on ERK1/2 MAPK, but not on phosphatidylinositol 3-kinase/Akt. DHEA is not converted to estrogens or androgens by endothelial cells, and its genomic and nongenomic effects are not blocked by antagonists of the estrogen, progesterone, glucocorticoid, or androgen receptors, suggesting that DHEA acts through a specific receptor. Oral DHEA administration to ovariectomized Wistar rats dose-dependently restores aortic eNOS levels and eNOS activity, confirming the effects of DHEA in vivo. Our present data suggest that DHEA may have direct genomic and nongenomic effects on the vascular wall that are not mediated by other steroid hormone receptors, leading to eNOS activation and induction.
脱氢表雄酮（DHEA）及其硫酸酯（DHEAS）是人体内主要的循环甾体激素，其水平会随着年龄的增长而逐渐下降。流行病学研究表明，DHEA/DHEAS浓度可能与心血管风险呈负相关，但在这个问题上存在分歧。初步研究表明，DHEA可调节血管功能，但关于其机制的报道较少。我们发现，给人内皮细胞施用DHEA可触发一氧化氮合成，这是由于内皮型一氧化氮合酶（eNOS）的表达增强和稳定性增加所致。此外，DHEA通过一种不依赖于转录的机制快速激活eNOS，该机制依赖于ERK1/2丝裂原活化蛋白激酶（MAPK），而不依赖于磷脂酰肌醇3激酶/蛋白激酶B（PI3K/Akt）。内皮细胞不会将DHEA转化为雌激素或雄激素，其基因组和非基因组效应也不会被雌激素、孕激素、糖皮质激素或雄激素受体的拮抗剂所阻断，这表明DHEA通过一种特异性受体发挥作用。给去卵巢的Wistar大鼠口服DHEA可剂量依赖性地恢复主动脉eNOS水平和eNOS活性，证实了DHEA在体内的作用。我们目前的数据表明，DHEA可能对血管壁具有直接的基因组和非基因组效应，且不受其他甾体激素受体介导，从而导致eNOS激活和诱导。
