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Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts

YingJie Chen1, Yunfang Li, Ping Zhang

  • 1Department of Medicine, Univ. of Minnesota Medical School, Minneapolis, MN 55455, USA. chenx106@umn.edu

American Journal of Physiology. Heart and Circulatory Physiology
|July 19, 2005
PubMed

Insights

Congestive heart failure (CHF) impairs blood vessel function due to reduced dimethylarginine dimethylaminohydrolase (DDAH) activity. This decrease contributes to endothelial dysfunction in failing hearts.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Biology
  • Biochemistry

Background:

  • Congestive heart failure (CHF) is linked to impaired nitric oxide (NO)-mediated vasodilation, a condition known as endothelial dysfunction.
  • Endothelial dysfunction in CHF may stem from reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme crucial for degrading NO synthase (NOS) inhibitors like asymmetric dimethylarginine.

Purpose of the Study:

  • To investigate the role of DDAH in coronary endothelial dysfunction observed in canine models of CHF.
  • To determine if decreased DDAH activity and expression contribute to the impaired vasodilation in CHF.

Main Methods:

  • CHF was induced in dogs via rapid ventricular pacing over 4 weeks.
  • Coronary blood flow and vasodilator responses to acetylcholine were measured.
  • DDAH activity, DDAH isoform protein levels (DDAH-1 and DDAH-2), endothelial NOS, and other related proteins were quantified in heart tissue.
  • Immunohistochemistry and cell culture studies were used to localize DDAH isoforms.

Main Results:

  • CHF led to a significant decrease in coronary blood flow and myocardial oxygen consumption.
  • The vasodilator response to acetylcholine was reduced by 39% in CHF dogs.
  • DDAH activity and DDAH-2 protein content were significantly reduced (53% and 58%, respectively) in CHF hearts.
  • Endothelial NOS and DDAH-1 expression were increased in CHF hearts, while Caveolin-1 and protein arginine N-methyltransferase 1 remained unchanged.

Conclusions:

  • Decreased DDAH activity and DDAH-2 protein expression are implicated in the endothelial dysfunction associated with congestive heart failure.
  • The accumulation of endogenous NOS inhibitors due to reduced DDAH function likely contributes to impaired vasodilation in the failing heart.

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