Impaired nitric oxide synthase pathway in diabetes mellitus: Role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase

Ken Y. Lin, Akira Ito, Tomoko Asagami, Philip S. Tsao, Shanthi Adimoolam, Masumi Kimoto, Hideaki Tsuji, Gerald M. Reaven, John P. Cooke

Research output: Contribution to journalArticle

598 Scopus citations

Abstract

Background - An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM. Methods and Results - Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33 ± 0.31 versus 0.48 ± 0.08 μmol/L; P<0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P<0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glycol- conjugated superoxide dismutase (22 U/mL) reversed the effects of the high-glucose condition on DDAH activity, ADMA accumulation, and cGMP synthesis. Conclusions - A glucose-induced impairment of DDAH causes ADMA accumulation and may contribute to endothelial vasodilator dysfunction in DM.

Original languageEnglish (US)
Pages (from-to)987-992
Number of pages6
JournalCirculation
Volume106
Issue number8
DOIs
StatePublished - Aug 20 2002

Keywords

  • Endothelium
  • Nitric oxide
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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