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

Irakli Kopaliani, Natalia Jarzebska, Silke Billoff, Anne Kolouschek, Jens Martens-Lobenhoffer, Stefan R. Bornstein, Stefanie M. Bode-Böger, Vinitha N. Ragavan, Norbert Weiss, Arduino A. Mangoni, Andreas Deussen, Roman N. Rodionov

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)H825-H838
Number of pages14
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume321
Issue number5
DOIs
Publication statusPublished - Nov 2021

Keywords

  • Angiotensin II
  • Cardiac remodeling
  • Dimethylarginine dimethylaminohydrolase 1
  • Hypertension
  • Vascular remodeling

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