Ihrig Colin M, Montgomery McLane M, Nomura Yohei, Nakano Mitsunori, Pandey Deepesh, La Favor Justin D
Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL 32306, United States.
Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8507, Japan.
Sex Med. 2025 Jan 9;12(6):qfae096. doi: 10.1093/sexmed/qfae096. eCollection 2024 Dec.
Erectile dysfunction is a condition with a rapidly increasing prevalence globally with a strong correlation to the increase in obesity and cardiovascular disease rates.
The aim of the current study is to investigate the potential role of tubacin, a histone deacetylase 6 (HDAC6) inhibitor, in restoring erectile function in a hypercholesterolemia-induced endothelial dysfunction model.
Thirty-nine male C57Bl/6 J mice were divided into 3 groups. Two groups were administered an adeno-associated virus encoding for the gain of function of proprotein convertase subtilisin/kexin type 9 (PCSK9) and placed on a high-fat diet (HFD) with 1.25% cholesterol added for 18 weeks in order to induce a prolonged state of hypercholesterolemia. One of the PCSK9 groups received daily intraperitoneal injections of the HDAC6 inhibitor tubacin, while the other 2 groups received daily vehicle injections. Erectile function was assessed through measurement of intracavernosal pressure and mean arterial pressure during cavernous nerve stimulation, as well as assessment of agonist-stimulated ex vivo relaxation of the corpus cavernosum (CC). Western blotting was performed from CC tissue samples.
Erectile and endothelial functions were assessed, as well as protein markers of mitochondrial dynamics, mitophagy, and autophagy.
Erectile function was impaired in the HFD + PCSK9 group throughout the entire voltage range of stimulation. However, the HFD + PCSK9 mice that were treated with tubacin experienced significant restoration of erectile function at the medium and high voltages of nerve stimulation. Similarly, ex vivo CC relaxation responses to acetylcholine and the cystathionine γ-lyase (CSE) substrate L-cysteine were reduced in the vehicle-treated HFD + PCSK9 mice, both of which were restored in the HFD + PCSK9 mice treated with tubacin. Corpus-cavernosum protein expression of CSE was significantly elevated in the tubacin-treated HFD + PCSK9 mice relative to both other groups. There were no significant differences observed in any of the protein markers of mitochondrial dynamics, mitophagy, or autophagy investigated.
Histone deacetylase 6 inhibition may protect against erectile and endothelial dysfunction associated with hypercholesterolemia.
This was the first study to investigate HDAC6-specific inhibition for treatment of erectile dysfunction. A study limitation was the exclusive focus on the CC, rather than structure and function of the pre-penile arteries that may develop a substantial atherosclerotic plaque burden under hypercholesterolemic conditions.
Tubacin may prevent hypercholesterolemia-induced erectile dysfunction through a hydrogen sulfide-related mechanism unrelated to regulation of mitophagy or autophagy.
勃起功能障碍在全球的患病率迅速上升，与肥胖率和心血管疾病发病率的增加密切相关。
本研究旨在探讨组蛋白去乙酰化酶6（HDAC6）抑制剂tubacin在高胆固醇血症诱导的内皮功能障碍模型中恢复勃起功能的潜在作用。
将39只雄性C57Bl/6 J小鼠分为3组。两组给予编码前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）功能增强的腺相关病毒，并置于添加1.25%胆固醇的高脂饮食（HFD）中18周，以诱导长期高胆固醇血症状态。其中一组PCSK9组每日腹腔注射HDAC6抑制剂tubacin，而另外两组每日注射溶剂。通过测量海绵体神经刺激期间的海绵体内压和平均动脉压，以及评估海绵体（CC）激动剂刺激的离体舒张来评估勃起功能。对CC组织样本进行蛋白质免疫印迹分析。
评估勃起和内皮功能，以及线粒体动力学、线粒体自噬和自噬的蛋白质标志物。
在整个刺激电压范围内，HFD + PCSK9组的勃起功能均受损。然而，用tubacin治疗的HFD + PCSK9小鼠在神经刺激的中高电压下勃起功能有显著恢复。同样，在溶剂处理的HFD + PCSK9小鼠中，CC对乙酰胆碱和胱硫醚γ-裂解酶（CSE）底物L-半胱氨酸的离体舒张反应降低，而在用tubacin治疗的HFD + PCSK9小鼠中两者均恢复。与其他两组相比，tubacin治疗的HFD + PCSK9小鼠CC中CSE的蛋白表达显著升高。在所研究的线粒体动力学、线粒体自噬或自噬的任何蛋白质标志物中均未观察到显著差异。
组蛋白去乙酰化酶6抑制可能预防与高胆固醇血症相关的勃起和内皮功能障碍。
这是第一项研究HDAC6特异性抑制治疗勃起功能障碍的研究。研究的局限性是仅关注CC，而不是阴茎前动脉的结构和功能，在高胆固醇血症条件下阴茎前动脉可能会形成大量动脉粥样硬化斑块负担。
Tubacin可能通过与线粒体自噬或自噬调节无关的硫化氢相关机制预防高胆固醇血症诱导的勃起功能障碍。
