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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/H816    most recent 01348.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Dayal, S. Articles by Lentz, S. R. Search for Related Content PubMed PubMed Citation Articles by Dayal, S. Articles by Lentz, S. R.

Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia

Departments of ¹Internal Medicine and ²Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa; ³Baylor Institute of Metabolic Disease, Dallas, Texas; ⁴Department of Nutritional Science, Okayama Prefectural University, Okayama, Japan; ⁵University of Iowa College of Pharmacy, Iowa City, Iowa; ⁶Stanford University, Palo Alto, California; and ⁷Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 17 November 2007 ; accepted in final form 17 June 2008

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, has been proposed to be a mediator of vascular dysfunction during hyperhomocysteinemia. Levels of ADMA are regulated by dimethylarginine dimethylaminohydrolase (DDAH). Using both in vitro and in vivo approaches, we tested the hypothesis that hyperhomocysteinemia causes downregulation of the two genes encoding DDAH (Ddah1 and Ddah2). In the MS-1 murine endothelial cell line, the addition of homocysteine decreased NO production but did not elevate ADMA or alter levels of Ddah1 or Ddah2 mRNA. Mice heterozygous for cystathionine β-synthase (Cbs) and their wild-type littermates were fed either a control diet or a high-methionine/low-folate (HM/LF) diet to produce varying degrees of hyperhomocysteinemia. Maximal relaxation of the carotid artery to the endothelium-dependent dilator acetylcholine was decreased by 50% in Cbs^+/– mice fed the HM/LF diet compared with Cbs^+/+ mice fed the control diet (P < 0.001). Compared with control mice, hyperhomocysteinemic mice had lower levels of Ddah1 mRNA in the liver (P < 0.001) and lower levels of Ddah2 mRNA in the liver, lung, and kidney (P < 0.05). Downregulation of DDAH expression in hyperhomocysteinemic mice did not result in an increase in plasma ADMA, possibly due to a large decrease in hepatic methylation capacity (S-adenosylmethionine-to-S-adenosylhomocysteine ratio). Our findings demonstrate that hyperhomocysteinemia causes tissue-specific decreases in DDAH expression without altering plasma ADMA levels in mice with endothelial dysfunction.

asymmetric dimethylarginine; endothelium; homocysteine; vascular function