Increased (E)-4-hydroxy-2-nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression

J Affect Disord. 2004 Jun;80(2-3):249-56. doi: 10.1016/S0165-0327(03)00135-6.


Background: (E)-4-Hydroxy-2-nonenal (HNE) is a highly electrophilic end-product of lipid peroxidation. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (NOS). ADMA is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). DDAH contains a nucleophilic cysteine residue in its active site. There is an increase in lipid peroxidation in major depression. Major depression is associated with the development of coronary heart disease (CHD) and greatly increases morbidity and mortality. There is an increase in circulating ADMA in CHD and vascular risk factors.

Objectives: To determine plasma HNE, ADME and nitric oxide (NO) concentrations in patients with major depression compared to normal volunteers and to examine the effect of HNE on ADMA formation and DDAH activity in cultured endothelial cells.

Methods: The study was conducted in 25 patients with major depression (DSM-IV criteria) and 25 healthy control subjects. Plasma concentrations of HNE were determined as the O-pentafluorylbenzyl oxime using capillary column GC-MS and deuterated HNE as the internal standard; ADME by LC-MS-MS using 13C6-L-arginine as the internal standard; and NO by GC-MS following reduction to nitrate and nitrite and derivatisation to the pentafluorobenzyl derivative using [15N]nitrate and [15N]nitrite as the internal standards. Human umbilical vein endothelial cells were incubated in serum-free medium in the presence of HNE. The concentration of ADMA in the medium was determined by LC-MS-MS. DDAH activity was determined by measuring L-citrulline in endothelial cell lysates using LC-MS.

Results: There was a significant increase in the plasma concentration of HNE (P<0.0001) and ADMA (P<0.0002) in patients with major depression. There was a significant decrease in the plasma concentration of NO (P<0.0001). A significant positive correlation was found between the plasma concentrations of HNE and ADMA (r=0.63, P<0.0001). A significant negative correlation was detected between the plasma concentrations of ADMA and NO (r=-0.595, P<0.0001). HNE significantly increased ADMA formation (P<0.0001) and significantly decreased DDAH activity (P<0.0001) in cultured endothelial cells. The effects of HNE on DDAH activity were significantly attenuated by the addition of glutathione (P<0.0001).

Limitations: No allowance was made for the phase of the menstrual cycle which could influence plasma nitric oxide concentrations.

Conclusions: There is an increase in circulating HNE in major depression. HNE inactivates the cysteine residue in the active site of endothelial DDAH leading to the accumulation of ADMA in the circulation. The ADMA then decreases the production of eNOS. This could reduce the amount of NO diffusing from cerebral blood vessels to nearby neurons and influence the release of neurotransmitters. ADMA also constricts cerebral blood vessels and may contribute to the decreased regional perfusion in major depression. The accumulation of ADMA could explain the increased risk of CHD in major depression. The preservation of DDAH activity and the reduction of ADMA accumulation may represent a novel therapeutic approach to the treatment of major depression.

MeSH terms

  • Aldehydes / blood*
  • Arginine / analogs & derivatives
  • Arginine / blood*
  • Arginine / metabolism
  • Citrulline / metabolism
  • Coronary Disease / epidemiology
  • Depressive Disorder, Major / blood*
  • Depressive Disorder, Major / epidemiology
  • Female
  • Glutathione / metabolism
  • Humans
  • Lipid Peroxidation / physiology
  • Male
  • Middle Aged
  • Nitrates / metabolism
  • Nitric Oxide / blood*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitrites / metabolism


  • Aldehydes
  • Nitrates
  • Nitrites
  • dimethylarginine
  • tert-4-hydroxy-2-nonenal
  • Citrulline
  • Nitric Oxide
  • Arginine
  • Nitric Oxide Synthase
  • Glutathione