Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins
Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins
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DOI：
10.1073/pnas.0306631101
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发表时间：
2004-05-25
影响因子：
11.1
通讯作者：
Gravanis, A
中科院分区：
文献类型：
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作者：
Charalampopoulos, L;Tsatsanis, C;Gravanis, A
中枢神经系统和肾上腺产生的神经活性类固醇脱氢表雄酮 (DHEA)、其硫酸酯硫酸脱氢表雄酮 (DHEAS) 和四氢孕酮 (Allo) 似乎对海马和皮质神经元缺血和兴奋毒性损伤具有保护作用。我们假设它们还可能对肾上腺髓质（交感神经系统的重要组成部分）以及与其主要产生部位相邻的组织发挥保护作用。 DHEA、DHEAS 和 Allo 保护大鼠嗜铬细胞和大鼠嗜铬细胞瘤 PC12 细胞系（一种用于研究肾上腺髓质细胞凋亡和存活的既定模型），抵抗血清剥夺诱导的细胞凋亡。它们的作用具有时间和剂量依赖性，EC50 分别为 1.8、1.1 和 1.5 nM。将 DHEA DHEAS 和 Allo 的抗凋亡作用与一长串结构相关的化合物进行比较，发现其具有结构特异性，主要限于雄烯的构象 3beta-OH-Delta5 和孕烷的构象 3alpha-OH。事实上，3-酮、Delta(4) 或 C7 羟基化雄烯和 313 孕烷是无效的。 DHEA(S) 和 Allo 的促生存作用不依赖于 N-甲基-D-天冬氨酸、GABA(A)、sigma1 或雌激素受体。它涉及抗凋亡 Bcl-2 蛋白，它们的作用是其作用的必要条件，因为 Bcl-2 反义寡核苷酸逆转了它们的作用。最后，DHEA(S) 和 Allo 激活 cAMP 反应元件结合蛋白和 NF-kappabeta，它们是抗凋亡 Bcl-2 蛋白表达的上游效应子。他们还激活了抗凋亡激酶 PKCα/β，这是 Bcl-2 蛋白的翻译后激活剂。我们的研究结果表明，衰老或压力过程中 DHEA(S) 和 Allo 的下降可能会使肾上腺髓质无法免受促凋亡挑战。
The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEA sulfate (DHEAS), and allopregnanolone (Allo), produced by the CNS and the adrenals, appear to exert a protective effect in hippocampal and cortical neuron ischemia- and excito-toxicity-induced injury. We hypothesized that they may also play a protective role on the adrenal medulla, an important part of the sympathetic nervous system, and the tissue adjacent to their primary site of production. DHEA, DHEAS, and Allo protected rat chromaffin cells and the rat pheochromocytoma PC12 cell line, an established model for the study of adrenomedullary cell apoptosis and survival, against serum deprivation-induced apoptosis. Their effects were time- and dose-dependent, with EC50 1.8, 1.1, and 1.5 nM, respectively. The antiapoptotic effect of DHEA DHEAS and Allo was compared to that of a long list of structurally related compounds and was found to be structure-specific, confined mainly to conformation 3beta-OH-Delta5 for androstenes and 3alpha-OH for pregnanes. Indeed, 3-keto, Delta(4), or C7 hydroxylated androstenes and 313 pregnanes were ineffective. The prosurvival effect of DHEA(S) and Allo was N-methyl-D-aspartate-, GABA(A)-, sigma1-, or estrogen receptor-independent. It involved the antiapoptotic Bcl-2 proteins, their role being sine qua non for their action because Bcl-2 antisense oligonucleotides reversed their effects. Finally, DHEA(S) and Allo activated cAMP response element-binding protein and NF-kappabeta, upstream effectors of antiapoptotic Bcl-2 protein expression. They also activated the antiapoptotic kinase PKCalpha/beta, a posttranslational activator of Bcl-2 protein. Our findings suggest that decline of DHEA(S) and Allo during aging or stress may leave the adrenal medulla unprotected against proapoptotic challenges.