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

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 (DDAH1(tg)) 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, DDAH1(tg) 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 DDAH1(tg). 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 DDAH1(tg) 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.

• Authors: 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
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 49 Issue 3 Pg. 491-500 (Sep 2013) ISSN: 1535-4989 [Electronic] United States
• PMID: 23642043 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one
• Oxadiazoles
• Nitroarginine
• Nitric Oxide
• N,N-dimethylarginine
• Arginine
• Amidohydrolases
• dimethylargininase
• Cyclic GMP

Topics

• Amidohydrolases (genetics, metabolism)
• Animals
• Arginine (analogs & derivatives, metabolism)
• Blood Vessels (drug effects, physiopathology)
• Cyclic GMP (metabolism)
• Gene Expression
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (etiology, genetics, metabolism, physiopathology)
• Hypoxia (complications, genetics, metabolism, physiopathology)
• Lung (drug effects, metabolism, physiopathology)
• Mice
• Nitric Oxide (metabolism)
• Nitroarginine (pharmacology)
• Organ Culture Techniques
• Oxadiazoles (pharmacology)
• Signal Transduction
• Vasoconstriction (drug effects)