Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
J Sex Med. 2019 Nov;16(11):1708-1720. doi: 10.1016/j.jsxm.2019.08.014. Epub 2019 Sep 26.
Oxidative stress is a significant contributor to the poor treatment efficacy on erectile dysfunction induced by diabetes mellitus (DMED). Thus, understanding the mechanism underlying oxidative stress will aid in the identification of novel therapeutic targets.
To define the role of Janus kinase 2 (JAK2) in mediating oxidative stress in the corpus cavernosum smooth muscle cells (CCSMCs) and to investigate the therapeutic effect of monomeric berberine (BB), which inhibits JAK2, in the pathogenesis of DMED.
Streptozotocin was used to establish type I diabetic rat models and apomorphine tests were conducted to determine DMED rats. Eighteen DMED rats were divided into the DMED group and the DMED+BB group, whereas another 10 age-matched rats formed the control group. CCSMCs were isolated from the corpus cavernosum of rats and were treated with the JAK2 inhibitor alpha cyanano-(3,4-hydroxyl)N-benzophenylamine (AG490) and/or BB.
Metabolic parameters; erectile function; histologic and molecular alterations.
Erectile function was impaired and excessive oxidative stress was found in the DMED group. Excessive oxidative stress led to decreased expression level of phosphorylated endothelial nitric oxide synthase at serine 1177/endothelial nitric oxide synthase and increased expression level of Ras homolog gene family and Rho kinase 1/2. Meanwhile, the relative expression ratio of phosphorylated JAK2/JAK2 was significantly greater in the DMED group than that in the other groups. In vitro, oxidative stress was significantly reduced along with reduced intracellular calcium upon treatment with the JAK2 inhibitor, AG490. Moreover, the CCSMCs treated with BB showed changes similar to those upon treatment with AG490. In vivo experiments also confirmed that the erectile function of the DMED+BB group was improved, accompanied by decreased phosphorylated JAK2/JAK2 and decreased oxidative stress.
JAK2 can be used as a therapeutic target and BB can be used as a potential drug for the clinical treatment of DMED.
This study examines the promoting effect of JAK2 on oxidative stress occurrence in the corpus cavernosum and on the development of DMED in both animal experiments and cell experiments, as well evaluates the inhibitory effect of BB on JAK2 and its therapeutic effect on DMED. The main limitation of our current study is the lack of an appropriate means for activating JAK2.
JAK2 can induce DMED by enhancing oxidative stress and BB can play a role in treating DMED by inhibiting JAK2 and reducing oxidative stress. Our study provides an option and an idea for further studies on the pathogenesis and treatment of DMED. Song J, Tang Z, Li H, et al. Role of JAK2 in the Pathogenesis of Diabetic Erectile Dysfunction and an Intervention With Berberine. J Sex Med 2019;16:1708-1720.
氧化应激是导致糖尿病性勃起功能障碍（DMED）治疗效果不佳的重要因素。因此，了解氧化应激的机制将有助于确定新的治疗靶点。
定义 Janus 激酶 2（JAK2）在介导海绵体平滑肌细胞（CCSMCs）氧化应激中的作用，并研究抑制 JAK2 的单体小檗碱（BB）在 DMED 发病机制中的治疗作用。
使用链脲佐菌素建立 1 型糖尿病大鼠模型，并进行阿扑吗啡试验以确定 DMED 大鼠。将 18 只 DMED 大鼠分为 DMED 组和 DMED+BB 组，另将 10 只年龄匹配的大鼠分为对照组。从大鼠海绵体中分离 CCSMCs，并使用 JAK2 抑制剂 alpha cyanano-(3,4-hydroxyl)N-benzophenylamine（AG490）和/或 BB 进行处理。
代谢参数；勃起功能；组织学和分子改变。
JAK2 可作为治疗靶点，BB 可作为治疗 DMED 的潜在药物。
本研究在动物实验和细胞实验中研究了 JAK2 对海绵体氧化应激发生和 DMED 发展的促进作用，并评估了 BB 对 JAK2 的抑制作用及其对 DMED 的治疗作用。我们目前研究的主要局限性是缺乏激活 JAK2 的适当手段。
JAK2 可通过增强氧化应激诱导 DMED，BB 可通过抑制 JAK2 减少氧化应激在治疗 DMED 中发挥作用。我们的研究为进一步研究 DMED 的发病机制和治疗提供了一种选择和思路。
