Liraglutide Ameliorates Erectile Dysfunction via Regulating Oxidative Stress, the RhoA/ROCK Pathway and Autophagy in Diabetes Mellitus
Liraglutide Ameliorates Erectile Dysfunction via Regulating Oxidative Stress, the RhoA/ROCK Pathway and Autophagy in Diabetes Mellitus
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DOI：
10.3389/fphar.2020.01257
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发表时间：
2020-08
影响因子：
5.6
通讯作者：
Penghui Yuan;Delin Ma;Xintao Gao;Jiaxin Wang;Rui Li;Zhuo Liu;Tao Wang;Shaogang Wang;Jihong Liu
中科院分区：
文献类型：
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作者：
Penghui Yuan;Delin Ma;Xintao Gao;Jiaxin Wang;Rui Li;Zhuo Liu;Tao Wang;Shaogang Wang;Jihong Liu
背景 与非糖尿病男性相比，糖尿病患者勃起功能障碍 (ED) 发生的频率更高，并且对一线治疗的反应更差。海绵体血管功能障碍在糖尿病ED（DMED）的发生中起着关键作用。本研究的目的是探讨胰高血糖素样肽-1 (GLP-1) 类似物利拉鲁肽对 ED 的保护作用，并探讨体内和体外的潜在机制。方法链脲佐菌素诱导大鼠1型糖尿病，阿朴吗啡试验筛选糖尿病大鼠DMED模型。然后随机皮下注射利拉鲁肽（0.3 mg/kg/12 h）治疗4周。通过海绵体神经电刺激评估勃起功能。海绵体用于进一步研究。在体外，通过暴露于含或不含利拉鲁肽和 GLP-1 受体 (GLP-1R) 抑制剂的低或高葡萄糖 (HG) 培养基的原代海绵体平滑肌细胞 (CCSMC) 评估利拉鲁肽的作用。采用蛋白质印迹、荧光探针、免疫组织化学和相关检测试剂盒来测量目标蛋白的水平。结果 服用利拉鲁肽对糖尿病大鼠的血糖和体重没有显着影响，但DMED组的勃起功能明显改善，NADPH氧化酶和ROS产生水平降低，Ras同源基因家族（RhoA）和Rho相关蛋白激酶（ROCK）2的表达显着下调。利拉鲁肽治疗进一步促进了DMED组的自噬并恢复了GLP-1R的表达。此外，与HG处理相比，用利拉鲁肽培养的CCSMC表现出较低水平的氧化应激并伴有RhoA/ROCK通路的抑制和较高水平的自噬。 GLP-1R 抑制剂可有效逆转利拉鲁肽的这些有益作用。结论 利拉鲁肽对 ED 具有保护作用，该作用与调节平滑肌功能障碍、氧化应激和自噬有关，与降糖作用无关。它为利拉鲁肽的胰外作用提供了新的见解，并为 DMED 的潜在治疗提供了临床前证据。
Background Erectile dysfunction (ED) occurs more frequently and causes a worse response to the first-line therapies in diabetics compared with nondiabetic men. Corpus cavernosum vascular dysfunction plays a pivotal role in the occurrence of diabetes mellitus ED (DMED). The aim of this study was to investigate the protective effects of glucagon-like peptide-1 (GLP-1) analog liraglutide on ED and explore the underlying mechanisms in vivo and in vitro. Methods Type 1 diabetes was induced in rats by streptozotocin, and the apomorphine test was for screening the DMED model in diabetic rats. Then they were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Erectile function was assessed by cavernous nerve electrostimulation. The corpus cavernosum was used for further study. In vitro, effects of liraglutide were evaluated by primary corpus cavernosum smooth muscle cells (CCSMCs) exposed to low or high glucose (HG)-containing medium with or without liraglutide and GLP-1 receptor (GLP-1R) inhibitor. Western blotting, fluorescent probe, immunohistochemistry, and relevant assay kits were performed to measure the levels of target proteins. Results Administration of liraglutide did not significantly affect plasma glucose and body weights in diabetic rats, but improved erectile function, reduced levels of NADPH oxidases and ROS production, downregulated expression of Ras homolog gene family (RhoA) and Rho-associated protein kinase (ROCK) 2 in the DMED group dramatically. The liraglutide treatment promoted autophagy further and restored expression of GLP-1R in the DMED group. Besides, cultured CCSMCs with liraglutide exhibited a lower level of oxidative stress accompanied by inhibition of the RhoA/ROCK pathway and a higher level of autophagy compared with HG treatment. These beneficial effects of liraglutide effectively reversed by GLP-1R inhibitor. Conclusion Liraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress and autophagy, independently of a glucose- lowering effect. It provides new insight into the extrapancreatic actions of liraglutide and preclinical evidence for a potential treatment for DMED.