5型磷酸二酯酶抑制剂(PDE5I)已成为治疗勃起功能障碍(ED)的一线药物。然而,其对高血压ED的有效率仅为60%-70%。若何进步ED医治的疗效是今朝研讨的重点。
探讨淫羊藿苷能否通过影响翻译后蛋白-蛋白相互作用调节内皮型一氧化氮合成酶(eNOS)活性来改善自发性高血压大鼠(SHR)的勃起功能。
12周龄健康雄性SHR大鼠和Wistar-Kyoto大鼠(WKY)随机分为4组:SHR对照组,SHR+淫羊藿苷(10mg/kg·d灌胃)治疗组,WKY对照组,WKY+淫羊藿苷(10mg/kg·d灌胃)治疗组(n=5)。4周后,最大阴茎海绵体内压/平均动脉压(ICPmax/MAP),热休克蛋白90(Hsp90)的表达,caveolin-1,钙调蛋白,p-eNOS,测量阴茎海绵体组织中的eNOS以及一氧化氮(NO)和cGMP的含量。通过免疫沉淀检测eNOS与Hsp90,caveolin-1和钙调蛋白之间的相互作用。
在3V和5V电刺激下,SHR+淫羊藿苷治疗组的ICPmax/MAP(0.08±0.01,0.23±0.07,0.40±0.05)明显高于SHR组(0.03±0.01,0.13±0.03,0.21±0.02)(P<0.05)。与SHR组相比,HSP90、钙调蛋白、P-eNOS,eNOS,WKY组和SHR+淫羊藿苷治疗组大鼠阴茎海绵体组织中P-eNOS/eNOS明显升高(P<0.05),caveolin-1的表达显著降低(P<0.05)。SHR+淫羊藿苷治疗组NO含量(2.16±0.22μmol/g)和cGMP浓度(3.69±0.12pmol/mg)明显高于SHR组(1.01±0.14μmol/g,2.31±0.22pmol/mg)(P<.05)。与SHR组相比,SHR+淫羊藿苷治疗组大鼠海绵体中eNOS和HSP90的相互作用显著增加(P<0.05),eNOS和caveolin-1之间的相互作用显著降低(P<0.01),eNOS和钙调蛋白之间的相互作用没有明显变化。
上调SHR海绵体中HSP90和钙调蛋白的表达并抑制Caveolin-1,促进eNOS与HSP90的相互作用,抑制eNOS与caveolin-1的相互作用,增加p-eNOS/eNOS,可能是淫羊藿苷改善SHR勃起功能的机制。
Type 5 phosphodiesterase inhibitor (PDE5I) has become the first-line treatment for erectile dysfunction (ED). However, its effective rate for hypertension ED is only 60%-70%. How to improve the efficacy of ED treatment is the focus of current research.
To explore whether icariin can improve the erectile function of spontaneously hypertensive rats (SHR) by affecting post-translational protein-protein interactions to regulate endothelial nitric oxide synthetase (eNOS) activity.
Twelve-week-old healthy male SHR rats and Wistar-Kyoto rats (WKY) were randomly divided into four groups: SHR control group, SHR + icariin (10 mg/kg·d gavage) treatment group, WKY control group, and WKY + icariin (10 mg/kg·d gavage) treatment group (n = 5). After 4 weeks, the maximum penile intracavernous pressure/mean arterial pressure (ICPmax/MAP), the expression of heat-shock protein 90 (Hsp90), caveolin-1, calmodulin, p-eNOS, and eNOS in penile cavernous tissue and the content of nitric oxide (NO) and cGMP were measured. The interaction between eNOS and Hsp90, caveolin-1, and calmodulin were detected by immunoprecipitation.
The ICPmax/MAP in the SHR + icariin treatment group (0.08 ± 0.01, 0.23 ± 0.07, 0.40 ± 0.05) was significantly higher than the SHR group (0.03 ± 0.01, 0.13 ± 0.03, 0.21 ± 0.02) under 3V and 5V electrical stimulations (P < .05). Compared with the SHR group, the expression of HSP90, calmodulin, P-eNOS, eNOS, and P-eNOS/eNOS in the penile cavernous tissue of rats in the WKY group and the SHR + icariin treatment group were significantly increased (P < .05), and the expression of caveolin-1 was significantly decreased (P < .05). The NO content (2.16 ± 0.22 μmol/g) and cGMP concentration (3.69 ± 0.12 pmol/mg) in the SHR + icariin treatment group were significantly higher than those in the SHR group (1.01 ± 0.14 μmol/g, 2.31 ± 0.22 pmol/mg) (P < .05). Compared with the SHR group, the interaction between eNOS and HSP90 in the cavernosa of the rats in the SHR + icariin treatment group was significantly increased (P < .05), the interaction between eNOS and caveolin-1 was significantly decreased (P < .01), and the interaction between eNOS and calmodulin did not significantly change.
Up-regulating the expression of HSP90 and calmodulin and inhibiting caveolin-1 in SHR corpus cavernosum, promoting the interaction between eNOS and HSP90, inhibiting the interaction between eNOS and caveolin-1, increasing p-eNOS/eNOS, may be the mechanism of icariin that improves SHR erectile function.