Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia

Sanjana Dayal, Roman N. Rodionov, Erland Arning, Teodoro Bottiglieri, Masumi Kimoto, Daryl J. Murry, John P. Cooke, Frank M. Faraci, Steven R. Lentz

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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 dimethyl-arginine 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.

Original languageEnglish (US)
Pages (from-to)H816-H825
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number2
DOIs
StatePublished - Aug 1 2008

Keywords

  • Asymmetric dimethylarginine
  • Endothelium
  • Homocysteine
  • Vascular function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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