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.

METHODOLOGY/PRINCIPAL FINDINGS:

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.

CONCLUSION/SIGNIFICANCE:

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: Karsten Sydow, Christine Schmitz, Eike-Christin von Leitner, Robin von Leitner, Anna Klinke, Dorothee Atzler, Christian Krebs, Hartwig Wieboldt, Heimo Ehmke, Edzard Schwedhelm, Thomas Meinertz, Stefan Blankenberg, Rainer H Böger, Tim Magnus, Stephan Baldus, Ulrich Wenzel
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e48150 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23110194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• N,N-dimethylarginine
• Arginine
• Amidohydrolases
• dimethylargininase

Topics

• Amidohydrolases (genetics, metabolism)
• Animals
• Arginine (analogs & derivatives, blood)
• Blood Pressure (physiology)
• Heart (physiology)
• Humans
• Hypertension (blood, enzymology, genetics)
• Kidney (metabolism, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic