Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia

Adel Bakr, Oleg Pak, Ashraf Taye, Farid Hamada, Ramadan Hemeida, Wiebke Janssen, Mareike Gierhardt, Hossein A. Ghofrani, Werner Seeger, Friedrich Grimminger, Ralph T. Schermuly, Martin Witzenrath, Ralf P. Brandes, Ngan Huang, John P. Cooke, Norbert Weissmann, Natascha Sommer

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH), is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase-1 (DDAH1). We investigated the effects of DDAH1 overexpression (DDAH1tg) on HPV and chronic hypoxia-induced PH. HPV was measured during acute (10 min) and sustained (3 h) hypoxia in isolated mouse lungs. Chronic PH was induced by the exposure of mice to 4 weeks of hypoxia. ADMA and cyclic 3′,5′-guanosine monophosphate (cGMP) were determined by ELISA, and NO generation was determined by chemiluminescence. DDAH1 overexpression exerted no effects on acute HPV. However, DDAH1tg mice showed decreased sustained HPV compared with wild-type (WT) mice. Concomitantly, ADMA was decreased, and concentrations of NO and cGMP were significantly increased in DDAH1tg. The administration of either Nω-nitro-L-arginine or 1H-[1,2,4]oxadiazolo [4,3-a] quinoxalin-1-one potentiated sustained HPV and partly abolished the differences in sustained HPV between WT and DDAH1tg mice. The overexpression of DDAH1 exerted no effect on the development of chronic hypoxia-induced PH. DDAH1 overexpression selectively decreased the sustained phase of HPV, partly via activation of the NO-cGMP pathway. Thus, increased ADMA concentrations modulate sustained HPV, but not acute HPV or chronic hypoxia-induced PH.

Original languageEnglish (US)
Pages (from-to)491-500
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume49
Issue number3
DOIs
StatePublished - Sep 2013

Keywords

  • Asymmetric dimethylarginine
  • Cyclic guanosine monophosphate
  • Hypoxia-induced pulmonary hypertension
  • Hypoxic pulmonary vasoconstriction
  • Nitric oxide

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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