Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital and The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Sex Med. 2011 Dec;8(12):3325-34. doi: 10.1111/j.1743-6109.2011.02500.x. Epub 2011 Oct 13.
Immunophilin ligands such as FK506 (FK) preserve erectile function (EF) following cavernous nerve injury (CNI), although the precise mechanisms are unclear. We examined whether the thioredoxin (Trx) and glutathione (GSH) redox systems mediate this effect after CNI.
To investigate the roles of Trx reductase 2 (TrxR2) and S-Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI.
Adult male rats, wild-type (WT) mice, and GSNOR deficient (GSNOR -/-) mice were divided into four groups: sham surgery (CN [cavernous nerves] exposure only) + vehicle; sham surgery + FK (5 mg/kg/day/rat or 2 mg/kg/day/mouse, for 2 days, subcutaneous); CNI + vehicle; and CNI + FK. At day 4 after injury, electrically stimulated changes in intracavernosal pressure (ICP) were measured. Penises were collected for Western blot analysis of TrxR2, GSNOR, and Bcl-2, and for immunolocalization of TrxR2 and GSNOR.
EF assessment represented by maximal ICP and total ICP in response to electrical stimulation. Evaluation of protein expression levels and distribution patterns of antioxidative/nitrosative and antiapoptotic factors in penile tissue.
EF decreased after CNI compared with sham surgery values in both rats (P < 0.01) and WT and GSNOR -/- mice (P < 0.05). FK treatment preserved EF after CNI compared with vehicle treatment in rats (P < 0.01) and WT mice (P < 0.05) but not in GSNOR -/- mice. In rats, GSNOR (P < 0.01) and Bcl-2 (P < 0.05) expressions were significantly decreased after CNI. FK treatment in CN-injured rats restored expression of GSNOR and upregulated TrxR2 (P < 0.001) and Bcl-2 (P < 0.001) expressions compared with vehicle treatment. Localizations of proteins in the penis were observed for TrxR2 (endothelium, smooth muscle) and for GSNOR (nerves, endothelium, smooth muscle).
The neuroprotective effect of FK in preserving EF after CNI involves antioxidative/nitrosative and antiapoptotic mechanisms mediated, to some extent, by Trx and GSH systems.
免疫亲和素配体，如 FK506（FK），在海绵体神经损伤（CNI）后可保持勃起功能（EF），尽管确切机制尚不清楚。我们研究了硫氧还蛋白（Trx）和谷胱甘肽（GSH）氧化还原系统在 CNI 后是否介导了这种作用。
研究 Trx 还原酶 2（TrxR2）和 S-亚硝基谷胱甘肽还原酶（GSNOR）作为 FK 在 CNI 后阴茎神经保护作用的抗氧化/亚硝化和抗凋亡介质的作用。
成年雄性大鼠、野生型（WT）小鼠和 GSNOR 缺陷（GSNOR-/-）小鼠分为四组：假手术（仅暴露 CN）+载体；假手术+FK（5mg/kg/天/大鼠或 2mg/kg/天/小鼠，皮下，连续 2 天）；CNI+载体；CNI+FK。在损伤后第 4 天，测量电刺激引起的海绵体内压（ICP）变化。收集阴茎进行 Western blot 分析 TrxR2、GSNOR 和 Bcl-2，以及 TrxR2 和 GSNOR 的免疫定位。
EF 评估表示为对电刺激的最大 ICP 和总 ICP。评估阴茎组织中抗氧化/亚硝化和抗凋亡因子的蛋白表达水平和分布模式。
与假手术相比，大鼠（P<0.01）和 WT 和 GSNOR-/-小鼠（P<0.05）的 CNI 后 EF 降低。与载体处理相比，FK 治疗在大鼠（P<0.01）和 WT 小鼠（P<0.05）中保留了 CNI 后的 EF，但在 GSNOR-/-小鼠中没有。在大鼠中，CNI 后 GSNOR（P<0.01）和 Bcl-2（P<0.05）的表达明显下降。与载体处理相比，FK 治疗在 CN 损伤的大鼠中恢复了 GSNOR 的表达，并上调了 TrxR2（P<0.001）和 Bcl-2（P<0.001）的表达。在阴茎中观察到 TrxR2（内皮、平滑肌）和 GSNOR（神经、内皮、平滑肌）的蛋白定位。
FK 在 CNI 后保护 EF 的神经保护作用涉及抗氧化/亚硝化和抗凋亡机制，在某种程度上由 Trx 和 GSH 系统介导。
