Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
J Sex Med. 2014 Jun;11(6):1442-51. doi: 10.1111/jsm.12522. Epub 2014 Mar 18.
Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases.
This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis.
Five groups of rats (8-10 weeks, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-β1 (TGF-β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α-SMA) antibodies.
We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-β1 protein expression; penile fibrosis; penile α-SMA content.
There was a voltage-dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF-β1 protein expression after BCNI. Histological analysis showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α-SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (P < 0.05).
HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.
双侧海绵体神经损伤（BCNI）导致阴茎发生凋亡和纤维化等深刻变化，进而引发勃起功能障碍（ED）。组蛋白去乙酰化酶（HDAC）已被牵连到慢性纤维化疾病中。
本研究将描述 BCNI 后阴茎 HDAC 的分子变化，并确定 HDAC 抑制是否可预防 BCNI 诱导的 ED 和阴茎纤维化。
利用五组大鼠（8-10 周龄，每组 n=10）：（i）假手术组；（ii 和 iii）损伤后 14 天和 30 天的 BCNI 组；（iv 和 v）BCNI 联合组氨酸去乙酰化酶抑制剂丙戊酸钠（VPA 250mg/kg；14 天和 30 天）。所有组均接受海绵体神经刺激（CNS）以测定阴茎内压（ICP）。通过 Western blot 检测阴茎 HDAC3、HDAC4、纤维连接蛋白和转化生长因子-β1（TGF-β1）蛋白表达。各组阴茎进行三色染色和纤维化面积分数测定。用抗α-平滑肌肌动蛋白（α-SMA）抗体进行免疫荧光染色检测海绵体平滑肌含量。
我们测量了 ICP；HDAC3、HDAC4、纤维连接蛋白和 TGF-β1 蛋白表达；阴茎纤维化；阴茎α-SMA 含量。
BCNI 后 14 天和 30 天，CNS 引起的 ICP 呈电压依赖性下降（P<0.05）。BCNI 后 14 天，阴茎 HDAC3、HDAC4 和纤维连接蛋白明显增加（P<0.05）。BCNI 后 TGF-β1 蛋白表达略有增加。组织学分析显示，BCNI 后两个时间点均出现 corporal 纤维化增加（P<0.05）。VPA 治疗降低了（P<0.05）阴茎 HDAC3、HDAC4 和纤维连接蛋白蛋白表达以及 corporal 纤维化。各组之间阴茎α-SMA 无变化。此外，VPA 治疗的 BCNI 大鼠对 CNS 的勃起反应得到改善（P<0.05）。
BCNI 后 HDAC 诱导的病理性信号传导导致阴茎血管功能障碍。HDAC 的药物抑制可预防阴茎纤维化、使纤维连接蛋白表达正常化，并保持勃起功能。HDAC 途径可能是预防根治性前列腺切除术后发生 ED 的合适靶点。
