Novel mechanism for endothelial dysfunction: Dysregulation of dimethylarginine dimethylaminohydrolase

Akira Ito, Philip S. Tsao, Shanthi Adimoolam, Masumi Kimoto, Tadashi Ogawa, John P. Cooke

Research output: Contribution to journalArticle

603 Scopus citations

Abstract

Background - Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Plasma levels of ADMA are elevated in individuals with hypercholesterolemia or atherosclerosis. We postulated that reduced degradation of ADMA may play a role in the accumulation of ADMA in these individuals. Accordingly, we studied the effects of oxidized LDL (oxLDL) or tumor necrosis factor-α (TNF-α) on the accumulation of ADMA by transformed human umbilical vein endothelial cells (ECV304) and on the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which degrades ADMA. Methods and Results - ECV304 were incubated with or without native LDL (100 μg/mL), oxLDL (100 μg/mL), or TNF-α (250 U/mL) for 48 hours. The concentration of ADMA in the conditioned medium was determined by high-performance liquid chromatography. Western blotting was performed to evaluate DDAH expression. We assayed DDAH activity by determining L-citrulline formation from ADMA. The addition of oxLDL or TNF-α to ECV304 significantly increased the level of ADMA in the conditioned medium. The effect of oxLDL or TNF-α was not due to a change in DDAH expression but rather to the reduction of DDAH activity. To determine whether dysregulation of DDAH also occurred in vivo, New Zealand White rabbits were fed normal chow or a high-cholesterol diet. Hypercholesterolemia significantly reduced aortic, renal, and hepatic DDAH activity. Conclusions - These results suggest that the endothelial vasodilator dysfunction observed in hypercholesterolemia may be due to reduced degradation of ADMA, the endogenous inhibitor of NOS.

Original languageEnglish (US)
Pages (from-to)3092-3095
Number of pages4
JournalCirculation
Volume99
Issue number24
DOIs
StatePublished - Jun 22 1999

Keywords

  • Amino acids
  • Asymmetric dimethylarginine
  • Endothelium
  • Lipoproteins
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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