Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa
Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa
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DOI：
10.1210/en.2003-1699
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发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Maggi, M
中科院分区：
文献类型：
--
作者：
Morelli, A;Filippi, S;Maggi, M
通过实时 RT-PCR 和蛋白质印迹分析，我们发现人类男性生殖道中的 5 型磷酸二酯酶 (PDE5) mRNA 和蛋白质丰度比女性生殖道高几倍。在人海绵体 (CC) 中检测到最高 mRNA 水平（> 1 x 10(7) 分子/杯总 RNA），其中 PDE5 蛋白免疫定位于肌肉和内皮室中。使用先前建立的低促性腺激素性性腺功能减退症兔模型研究了雄激素在调节 PDE5 表达中的可能作用。在该模型中，性腺功能减退减少，睾酮 (T) 补充恢复，CC PDE5 基因和蛋白质表达。此外，补充 T 可以完全挽救甚至增强环 GMP 向代谢物的转化，而不会改变西地那非的 IC50（IC50 = 2.16 +/- 0.62 nM）。在对照 CC 试纸条中，西地那非剂量依赖性地增加电场刺激引起的松弛，EC50 = 3.42 +/- 1.7 nM。西地那非对电场刺激的作用降低，性腺功能减退，T 增加，同样不改变其相对 EC50 值。性腺功能减退兔条带中的 CC 对 NO 供体 NCX4040 的敏感性高于对照或 T 处理的兔条带。此外，西地那非增强了NCX4040在性腺功能正常的兔条中的作用，但在性腺功能减退的兔条中没有增强作用。这表明雄激素上调兔子阴茎中的 PDE5。我们还测量了长期接受雌激素和醋酸环丙孕酮治疗的男性变女性变性个体的人类 CC 中的 PDE5 基因表达和代谢活性。将观察值与性腺正常对照相比，PDE5 mRNA、蛋白质和功能活性显着降低。总之，我们首次证明雄激素对 PDE5 具有正向调节作用，从而为男性生殖道中这种酶的最高丰度提供了可能的解释。
By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (> 1 x 10(7) molecules/mug total RNA) was detected in human corpora cavernosa ( CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone ( T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC50 for sildenafil (IC50 = 2.16 +/- 0.62 nM). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC50 = 3.42 +/- 1.7 nM. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC50 values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover, sildenafil enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract.