School of Kinesiology, Shanghai University of Sport, Shanghai, China.
Department of Exercise Rehabilitation, Shanghai University of Sport, Shanghai, China.
Biosci Trends. 2020 May 21;14(2):115-122. doi: 10.5582/bst.2019.01351. Epub 2020 Apr 1.
Dimethylarginine dimethylaminohydrolase-1 (DDAH1) maintains nitric oxide (NO) bioavailability by degrading asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS). It has been well established that DDAH1 and exercise play crucial roles in promoting cardiac angiogenesis under pathological conditions. However, the role of DDAH1 in exercise-induced cardiac angiogenesis remains unclear. In this study, we focused on the change in DDAH1 in response to moderate exercise and the underlying mechanism of exercise-induced cardiac angiogenesis. Eight-week-old male DDAH1 global knockout (KO) mice and DDAH1 mice (wild-type) were randomly divided into sedentary groups (control) and swimming groups (exercise). After eight weeks of swimming at five days per week, all the mice were anesthetized and sacrificed. Histological examination and Western blot analysis were performed. There were low levels of myocardial capillaries in DDAH1 KO mice under control and exercise conditions. Notably, exercise elevated DDAH1 protein expression, as observed by Western blot analysis. The common cardiac angiogenesis biomarkers vascular endothelial growth factor (VEGF) and Caveolin-1 were increased during exercise. A significant difference in VEGF was observed between the DDAH1 KO and wild-type groups. Similarly, increased Caveolin-1 expression was abrogated in DDAH1 KO mice. Furthermore, we tested the R-Ras/AKT/GSK3β signaling pathway to study the underlying molecular mechanism. DDAH1 may regulate the R-Ras/AKT/GSK3β pathway due to distinct protein changes in this pathway in the DDAH1 KO and wild-type groups. Our findings suggest that DDAH1 plays an important role in exercise-induced cardiac angiogenesis by regulating the R-Ras/AKT/GSK3βsignaling pathway.
二甲基精氨酸二甲胺水解酶-1（DDAH1）通过降解内源性一氧化氮合酶（NOS）抑制剂不对称二甲基精氨酸（ADMA）来维持一氧化氮（NO）的生物利用度。已经证实，DDAH1 和运动在病理条件下促进心脏血管生成中起着至关重要的作用。然而，DDAH1 在运动诱导的心脏血管生成中的作用尚不清楚。在这项研究中，我们专注于 DDAH1 对适度运动的反应变化以及运动诱导的心脏血管生成的潜在机制。将 8 周龄的雄性 DDAH1 全局敲除（KO）小鼠和 DDAH1 小鼠（野生型）随机分为安静组（对照）和游泳组（运动）。经过 8 周的每周 5 天游泳后，所有小鼠均进行麻醉并处死。进行组织学检查和 Western blot 分析。在对照和运动条件下，DDAH1 KO 小鼠的心肌毛细血管水平较低。值得注意的是，运动通过 Western blot 分析观察到 DDAH1 蛋白表达增加。运动期间，血管内皮生长因子（VEGF）和小窝蛋白-1 等常见的心脏血管生成生物标志物增加。DDAH1 KO 组和野生型组之间 VEGF 存在显著差异。同样，在 DDAH1 KO 小鼠中，Caveolin-1 的表达增加也被阻断。此外，我们还测试了 R-Ras/AKT/GSK3β 信号通路，以研究潜在的分子机制。由于 DDAH1 KO 和野生型组中该通路的蛋白变化不同，DDAH1 可能通过调节 R-Ras/AKT/GSK3β 通路来调节 R-Ras/AKT/GSK3β 通路。我们的研究结果表明，DDAH1 通过调节 R-Ras/AKT/GSK3β 信号通路在运动诱导的心脏血管生成中发挥重要作用。
