Faculty of Pharmacy, Department of Biochemistry, Ankara University, Ankara, Turkey.
Faculty of Pharmacy, Department of Pharmacology, Cukurova University, Adana, Turkey.
Andrology. 2022 Oct;10(7):1441-1453. doi: 10.1111/andr.13231. Epub 2022 Jul 29.
In different animal models, a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) reduced inflammation, oxidative stress and fibrosis which were involved in the pathogenesis of erectile dysfunction (ED), but whether NaBu could improve ED in an experimental animal model of benign prostate hyperplasia (BPH) was not known.
To investigate the preventive effect of NaBu on ED in a partial bladder outlet obstruction (PBOO) rat model.
PBOO was induced by partial urethral obstruction. NaBu (20 mg/kg/day) was administered orally to rats for 6 weeks after creation of PBOO. In vivo erectile responses, in vitro relaxation and contraction responses in cavernosal tissue were measured. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to determine the gene and protein expression. Inflammation, fibrosis, and localization of proteins were evaluated using histological techniques. HDAC activity and tumor necrosis factor (TNF)-α levels were measured in penile tissues.
NaBu improved decreased intracavernosal pressure/mean arterial pressure, nitrergic and endothelium-dependent relaxation responses, and contractile responses to phenylephrine and electrical field stimulation in the PBOO group without affecting increased bladder weight. Increased endothelial nitric oxide synthase (eNOS), transforming growth factor (TGF)-β1, and nuclear factor kappa B (NF-κB) gene levels in PBOO group were ameliorated by NaBu treatment. The administration of NaBu to PBOO rats significantly increased neuronal NOS (nNOS) and decreased TGF-β1 protein expression. The nuclear/cytosolic ratio of NF-κB demonstrated a decrease in PBOO and all treatment groups compared to control. A significant increase in the nuclear-to-cytoplasmic ratio of nuclear factor erythroid 2-related factor 2 (Nrf2) after PBOO was reduced by the treatment. Both eNOS and inducible NOS (iNOS) protein expression, together with TNF-α levels did not differ in the penile tissue of all groups. In histological analysis, increased TGF-β1 protein expression and fibrosis, as well as decreased nNOS protein in PBOO, were reversed by the treatment. NaBu did not normalize moderate inflammation in obstructed rats. An increase in the HDAC activity in PBOO was significantly suppressed by NaBu.
Inhibition of the HDAC activity by NaBu in penile tissue could ameliorate fibrosis-associated changes induced by PBOO.
NaBu promotes recovery of erectile function, and also significantly prevents penile fibrosis and normalizes TGF-β1 and nNOS protein expression in a rat model of PBOO. The HDAC pathway may present a promising target to prevent ED in patients with BPH.
在不同的动物模型中，组蛋白去乙酰化酶（HDAC）抑制剂丁酸钠（NaBu）可减轻与勃起功能障碍（ED）发病机制相关的炎症、氧化应激和纤维化，但是否 NaBu 可改善良性前列腺增生（BPH）的实验动物模型中的 ED 尚不清楚。
研究丁酸钠（NaBu）对部分尿道梗阻（PBOO）大鼠模型中 ED 的预防作用。
通过部分尿道梗阻诱导 PBOO。在创建 PBOO 后，将 NaBu（20mg/kg/天）经口给予大鼠 6 周。测量体内勃起反应、海绵体组织的体外松弛和收缩反应。通过实时聚合酶链反应（RT-PCR）和 Western blot 确定基因和蛋白表达。使用组织学技术评估炎症、纤维化和蛋白定位。测量阴茎组织中的 HDAC 活性和肿瘤坏死因子（TNF）-α水平。
NaBu 改善了 PBOO 组降低的海绵体内压/平均动脉压、硝普盐诱导的和内皮依赖性的松弛反应以及对苯肾上腺素和电刺激的收缩反应，而不影响增加的膀胱重量。NaBu 治疗可改善 PBOO 组中内皮型一氧化氮合酶（eNOS）、转化生长因子（TGF）-β1 和核因子 kappa B（NF-κB）基因水平的增加。NaBu 给药可显著增加神经元型一氧化氮合酶（nNOS）并降低 TGF-β1 蛋白表达。与对照组相比，PBOO 和所有治疗组的核质比 NF-κB 降低。PBOO 后核红细胞 2 相关因子 2（Nrf2）的核质比显著增加，经治疗后减少。所有组的阴茎组织中，eNOS 和诱导型一氧化氮合酶（iNOS）蛋白表达以及 TNF-α 水平均无差异。在组织学分析中，PBOO 中 TGF-β1 蛋白表达和纤维化的增加以及 nNOS 蛋白的减少被治疗所逆转。NaBu 并未使梗阻大鼠的中度炎症正常化。PBOO 中 HDAC 活性的增加被 NaBu 显著抑制。
在阴茎组织中抑制 HDAC 活性可改善 PBOO 引起的纤维化相关变化。
NaBu 促进了勃起功能的恢复，并且在 PBOO 大鼠模型中还可显著预防阴茎纤维化并使 TGF-β1 和 nNOS 蛋白表达正常化。HDAC 途径可能为预防 BPH 患者的 ED 提供有希望的靶点。
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