转录组学联合网络药理学探究高血压通过cGMP/PKG信号通路诱导勃起功能障碍的机制  

Mechanisms of hypertension inducing erectile dysfunction via the cGMP/PKG signaling pathway:An investigation using transcriptomics and network pharmacology

作　　者：冯隽龙 李海松[1] 孙松 王彬[1] 张华南 高子翔 毛鹏鸣[1] 孙龙吉 黄念文 王继升[1] FENG Jun-long;LI Hai-song;SUN Song;WANG Bin;ZHANG Hua-nan;GAO Zi-xiang;MAO Peng-ming;SUN Long-ji;HUANG Nian-wen;WANG Ji-sheng(Department of Andrology,Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing 100700,China;Department of Andrology,Beijing Changping Hospital of Traditional Chinese Medicine,Beijing 102200,China)

机构地区：[1]北京中医药大学东直门医院男科,北京100700 [2]北京市昌平区中医医院男科,北京102200

出　　处：《中华男科学杂志》2024年第9期771-781,共11页National Journal of Andrology

基　　金：中华中医药学会青年人才托举工程项目(CACM-2021-QNRC2-B04);国家中医药管理局李曰庆全国名中医传承工作室建设项目(国中医药人教函【2022】75号)。

摘　　要：目的:运用转录组学与网络药理学探讨高血压诱导勃起功能障碍(ED)的作用机制。方法:将自发性高血压大鼠随机分为模型组和L-精氨酸组(LA组),Wistar Kyoto大鼠为对照组。对照组和模型组大鼠腹腔注射400 mg/kg 9 g/L生理盐水。LA组大鼠腹腔注射400 mg/kg L-精氨酸,每天一次,连续7 d。然后评估所有大鼠的血压和勃起情况。使用ELISA、Western印迹和RT-qPCR评估通路蛋白和mRNA的表达。结果:转录组学联合网络药理学发现,cGMP/PKG信号通路是高血压诱导ED发生的关键信号通路,动物体内实验中,模型组的勃起次数明显低于对照组(P<0.05),Western印迹和RT-qPCR显示,模型组eNOS和PKG蛋白水平低于对照组;模型组sGC蛋白水平显著低于对照组(P<0.05);LA组eNOS、sGC和PKG蛋白水平高于模型组(P<0.05)。结论:高血压抑制了cGMP/PKG信号通路,降低了eNOS、NO、sGC、cGMP和PKG蛋白的表达以及睾酮水平,从而抑制了阴茎血管平滑肌松弛,降低了勃起功能。Objective:To explore the mechanism of hypertension inducing erectile dysfunction(ED)using transcriptomics and network pharmacology.Methods:We randomly divided 12 male rats with spontaneous hypertension(SHT)into an L-arginine(LA)group(n=6)and an SHT model control(MC)group(n=6),took another 6 Wistar Kyoto male rats as normal controls(NC),and treated the animals in the LA group by intraperitoneal injection of LA at 400 mg/kg and those in the latter two groups with physiological saline,once a day,all for 7 days.Then we observed the blood pressure and penile erection of the rats,and determined the expressions of the cGMP/PKG signaling pathway-related proteins and mRNAs in different groups using ELISA,Western blot and RT-qPCR.Results:Transcriptomics combined with network pharmacology showed that the cGMP/PKG signaling pathway played a key role in hypertension-induced ED.In vivo animal experiments revealed a significantly lower frequency of penile erections in the MC than in the NC group(1.33±0.52 vs 2.67±0.51,P<0.05).The protein expressions of eNOS,PKG and sGC were markedly decreased in the model controls compared with those the normal controls(P<0.05),but remarkably upregulated in the LA group compared with those in the MC group(P<0.05).Conclusion:Hypertension decreases the expressions of eNOS,NO,sGC,cGMP and PKG proteins and the level of testosterone by inhibiting the cGMP/PKG signaling pathway,which consequently suppresses the relaxation of the penile vascular smooth muscle and reduces erectile function.

关 键 词：转录组学 网络药理学 高血压 勃起功能障碍 cGMP/PKG信号通路 

分 类 号：R698.1[医药卫生—泌尿科学] R544.1[医药卫生—外科学]