Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II-induced cardiac hypertrophy and vascular remodeling

• Published in: American journal of physiology. Heart and circulatory physiology 2021-11, Vol.321 (5), p.H825-H838
• Main Authors: Kopaliani, Irakli, Jarzebska, Natalia, Billoff, Silke, Kolouschek, Anne, Martens-Lobenhoffer, Jens, Bornstein, Stefan R, Bode-Böger, Stefanie M, Ragavan, Vinitha N, Weiss, Norbert, Mangoni, Arduino A, Deussen, Andreas, Rodionov, Roman N
• Format: Article
• Language: English
• Subjects: Amidohydrolases - biosynthesis; Amidohydrolases - genetics; Angiotensin; Angiotensin II; Animals; Aorta; Aorta - enzymology; Aorta - pathology; Aorta - physiopathology; Blood Pressure; Cardiomyocytes; Complications; Dimethylargininase; Disease Models, Animal; Echocardiography; Elastin; Endothelium; Enzyme Induction; Fibrosis; Heart; Heart Ventricles - enzymology; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Histology; Hypertension; Hypertension - chemically induced; Hypertension - enzymology; Hypertension - pathology; Hypertension - physiopathology; Hypertrophy; Hypertrophy, Left Ventricular - chemically induced; Hypertrophy, Left Ventricular - enzymology; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - physiopathology; Inflammation; Inflammation Mediators - metabolism; Male; Matrix metalloproteinase; Matrix metalloproteinases; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nitric oxide; Nitric-oxide synthase; Time Factors; Transgenic mice; Vascular Remodeling; Vasodilation; Ventricle; Ventricular Function, Left; Ventricular Remodeling
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00064.2021

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 dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with 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. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation. We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.