TY - JOUR
T1 - Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia
AU - Bakr, Adel
AU - Pak, Oleg
AU - Taye, Ashraf
AU - Hamada, Farid
AU - Hemeida, Ramadan
AU - Janssen, Wiebke
AU - Gierhardt, Mareike
AU - Ghofrani, Hossein A.
AU - Seeger, Werner
AU - Grimminger, Friedrich
AU - Schermuly, Ralph T.
AU - Witzenrath, Martin
AU - Brandes, Ralf P.
AU - Huang, Ngan
AU - Cooke, John P.
AU - Weissmann, Norbert
AU - Sommer, Natascha
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
KW - Asymmetric dimethylarginine
KW - Cyclic guanosine monophosphate
KW - Hypoxia-induced pulmonary hypertension
KW - Hypoxic pulmonary vasoconstriction
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=84883469229&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883469229&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2012-0330OC
DO - 10.1165/rcmb.2012-0330OC
M3 - Article
C2 - 23642043
AN - SCOPUS:84883469229
SN - 1044-1549
VL - 49
SP - 491
EP - 500
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 3
ER -