The endogenous methylated derivative of ʟ-arginine, Nω,Nω′-dimethyl-ʟ-arginine (asymmetric dimethylarginine, ADMA), an independent risk factor in many diseases, inhibits the activity of nitric oxide synthases and, consequently, modulates the availability of nitric oxide. While most studies on the biological role of ADMA have focused on endothelial and inducible nitric oxide synthases modulation and its contribution to cardiovascular, metabolic, and renal diseases, a role in regulating neuronal nitric oxide synthases and pathologies of the central nervous system is less understood. The two isoforms of dimethylarginine dimethylaminohydrolase (DDAH), DDAH1 and DDAH2, are thought to be the main enzymes responsible for ADMA catabolism. A current impediment is limited knowledge on specific tissue and cellular distribution of DDAH enzymes within the brain. In this study, we provide a detailed characterization of the regional and cellular distribution of DDAH1 and DDAH2 proteins in the adult murine and human brain. Immunohistochemical analysis showed a wide distribution of DDAH1, mapping to multiple cell types, while DDAH2 was detected in a limited number of brain regions and exclusively in neurons. Our results provide key information for the investigation of the pathophysiological roles of the ADMA/DDAH system in neuropsychiatric diseases and pave the way for the development of novel selective therapeutic approaches.

Background: Cardiovascular complications are the leading cause of death and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from Ang II-induced end organ damage. Methods and Results: Angiotensin II (ANGII) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (TG) and wild type (WT) littermates for two or four weeks. Echocardiography was performed in the first and fourth week of the infusion, systolic blood pressure (SBP) was measured weekly and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after one week of ANGII infusion was not different between the groups, while TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 weeks of ANGII infusion in the high dose and after 4 weeks in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross sectional area and less interstitial fibrosis as compared to WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2 and showed better endothelium-dependent relaxation. Conclusions: We demonstrated that overexpression of DDAH1 protects from ANGII-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.