Disruption of methylarginine metabolism impairs vascular homeostasis

Research output: Contribution to journalArticle

Authors

  • James Leiper
  • Manasi Nandi
  • Belen Torondel
  • Judith Murray-Rust
  • Mohammed Malaki
  • Bernard O'Hara
  • Sharon Rossiter
  • Shelagh Anthony
  • David Selwood
  • Caroline Smith
  • Beata Wojciak-Stothard
  • Alain Rudiger
  • Ray Stidwill
  • Neil Q McDonald
  • Patrick Vallance

Abstract

Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.

Details

Original languageEnglish
Pages (from-to)198-203
Number of pages6
JournalNature Medicine
Volume13
Issue number2
Publication statusPublished - Feb 2007

Keywords

  • Acetylcholine, Amidohydrolases, Animals, Arginine, Blood Pressure, Blood Vessels, Blotting, Northern, Blotting, Western, Calcimycin, Cardiovascular Physiological Phenomena, Chromatography, High Pressure Liquid, Crystallography, Dose-Response Relationship, Drug, Echocardiography, Endothelium, Gene Deletion, Homeostasis, Humans, Mice, Models, Molecular, Muscle Contraction, Nitric Oxide, Nitroprusside, Phenylephrine, Rats, Rats, Sprague-Dawley, Signal Transduction, Vascular Resistance, omega-N-Methylarginine