title: Dimethylarginine dimethylaminohydrolase1 is an organ-specific mediator of end organ damage in a murine model of hypertension.
abstract: BACKGROUND
  The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Moreover, elevated ADMA plasma concentrations are associated with the extent of hypertension. However, data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension.
  
  
  RESULTS
  Therefore, we investigated the role of ADMA and DDAH1 in hypertension-induced end organ damage using the uninephrectomized, deoxycorticosterone actetate salt, and angiotensin II-induced hypertension model in human DDAH1 (hDDAH1) overexpressing and wild-type (WT) mice. ADMA plasma concentrations differed significantly between hDDAH1 and WT mice at baseline, but did not significantly change during the induction of hypertension. hDDAH1 overexpression did not protect against hypertension-induced cardiac fibrosis and hypertrophy. In addition, the hypertension-induced impairment of the endothelium-dependent vasorelaxation of aortic segments ex vivo was not significantly attenuated by hDDAH1 overexpression. However, hDDAH1 mice displayed an attenuated hypertensive inflammatory response in renal tissue, resulting in less hypertensive renal injury.
  
  
  CONCLUSIONS
  Our data reveal that hDDAH1 organ-specifically modulates the inflammatory response in this murine model of hypertension. The lack of protection in cardiac and aortic tissues may be due to DDAH1 tissue selectivity and/or the extent of hypertension by the used combined model. However, our study underlines the potency of hDDAH1 overexpression in modulating inflammatory processes as a crucial step in the pathogenesis of hypertension, which needs further experimental and clinical investigation.
authors.affiliation: Department of Interventional Cardiology, Hamburg University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany. sydow@uke.uni-hamburg.de
authors.forename: Karsten
authors.initials: K
authors.lastname: Sydow
authors.forename: Christine
authors.initials: C
authors.lastname: Schmitz
authors.forename: Eike-Christin
authors.initials: EC
authors.lastname: von Leitner
authors.forename: Robin
authors.initials: R
authors.lastname: von Leitner
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
authors.forename: Dorothee
authors.initials: D
authors.lastname: Atzler
authors.forename: Christian
authors.initials: C
authors.lastname: Krebs
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wieboldt
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wenzel
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001794:Blood Pressure / Q000502:physiology; D006321:Heart / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000201:enzymology* / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase