Fibbi Benedetta, Morelli Annamaria, Marini Mirca, Zhang Xin-Hua, Mancina Rosa, Vignozzi Linda, Filippi Sandra, Chavalmane Aravinda, Silvestrini Enrico, Colli Enrico, Adorini Luciano, Vannelli Gabriella Barbara, Maggi Mario
Andrology Unit, Department of Clinical Physiopathology, University of Florence, V.le G. Pieraccini, 6, 50139 Florence, Italy.
J Androl. 2008 Jan-Feb;29(1):70-84. doi: 10.2164/jandrol.107.003152. Epub 2007 Aug 15.
Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil-containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose-dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, alpha-smooth muscle actin, SM22alpha, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR, likely by interfering with RhoA/ROCK signaling within the penis.
与正常血压的Wistar-Kyoto大鼠相比，自发性高血压大鼠（SHR）的特征是勃起功能受损以及收缩相关的RhoA/Rho相关卷曲螺旋蛋白激酶（RhoA/ROCK）通路过度活跃。通过测量海绵体神经电刺激后的海绵体内压与平均动脉压（ICP:MAP）比值，我们证实了这些发现，并表明SHR对西地那非（经口灌胃25mg/kg）的反应性也受到阻碍。阿托伐他汀（5和30mg/kg）为期2周的治疗改善了西地那非诱导的SHR海绵体（CC）中ICP:MAP的升高，并使RhoA和ROCK2的过表达恢复正常。相反，其他基因，如神经元型一氧化氮合酶（NOS）、内皮型NOS和磷酸二酯酶5未受影响。在源自CC的人胎儿平滑肌细胞（hfPSMC）中，阿托伐他汀抑制RhoA膜转位和ROCK活性，以及RhoA依赖性生物学功能，如细胞迁移和细胞增殖。香叶基香叶基焦磷酸以剂量依赖性方式挽救了阿托伐他汀对迁移的影响，提示RhoA香叶基香叶基化参与其中。在hfPSMC中，阿托伐他汀降低了RhoA依赖性基因如ROCK2、结蛋白、α-平滑肌肌动蛋白、SM22α和心肌素的表达。与阿托伐他汀相反，艾洛骨化醇是一种维生素D类似物，它也干扰SHR膀胱中的RhoA激活，但无法恢复阴茎对西地那非的反应性。总之，阿托伐他汀而非艾洛骨化醇可改善SHR中由西地那非诱导的阴茎勃起，可能是通过干扰阴茎内的RhoA/ROCK信号传导实现的。
