Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine.

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a novel biomarker in cardiovascular disease. To date, it remains unclear whether elevated ADMA levels are merely associated with cardiovascular risk or whether this molecule is of functional relevance in the pathogenesis of atherosclerotic vascular disease. To clarify this issue, we crossed dimethylarginine dimethylaminohydrolase (DDAH) transgenic mice that overexpress the human isoform 1 of the ADMA degrading enzyme DDAH into ApoE-deficient mice to generate ApoE(-/-)/hDDAH1(+/-) mice. In these mice, as well as ApoE(-/-) wild-type littermates, atherosclerosis within the aorta as well as vascular function of aortic ring preparations was assessed. We report here that overexpression of hDDAH1 reduces plaque formation in ApoE(-/-) mice by lowering ADMA. The extent of atherosclerosis closely correlated with plasma ADMA levels in male but not female mice fed either a standard rodent chow or an atherogenic diet. Functional analysis of aortic ring preparations revealed improved endothelial function in mice overexpressing hDDAH1. Our findings provide proof-of-principle that ADMA plays a causal role as a culprit molecule in atherosclerosis and support recent evidence indicating a functional relevance of DDAH enzymes in genetic mouse models. Together, these results demonstrate that pharmacological interventions targeting the ADMA/DDAH pathway may represent a novel approach in the prevention and management of cardiovascular diseases.

• Authors: Johannes Jacobi, Renke Maas, Arturo J Cardounel, Michaela Arend, Arthur J Pope, Nada Cordasic, Juliane Heusinger-Ribeiro, Dorothee Atzler, Joachim Strobel, Edzard Schwedhelm, Rainer H Böger, Karl F Hilgers
• Journal: The American journal of pathology (Am J Pathol) Vol. 176 Issue 5 Pg. 2559-70 (May 2010) ISSN: 1525-2191 [Electronic] United States
• PMID: 20348244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Nitric Oxide
• N,N-dimethylarginine
• Arginine
• Amidohydrolases
• dimethylargininase

Topics

• Amidohydrolases (blood)
• Animals
• Aorta (pathology)
• Apolipoproteins E (metabolism)
• Arginine (analogs & derivatives, blood)
• Atherosclerosis (enzymology)
• Blood Pressure
• Cardiovascular Diseases (metabolism)
• Humans
• Male
• Mice
• Mice, Transgenic
• Models, Genetic
• Nitric Oxide (metabolism)
• Risk