BioScience Trends. 2020;14(2):115-122. (DOI: 10.5582/bst.2019.01351)

Dimethylarginine dimethylaminohydrolase-1 contributes to exercise-induced cardiac angiogenesis in mice

Shi XW, Luo XT, Xu X


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 DDAH1flox/flox 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/GSK3β signaling pathway.

KEYWORDS: swim, cardiac capillary density, eNOS, VEGF, Caveolin-1, R-Ras

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