Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia.
BACKGROUND
Nitric oxide (NO) plays an important part in lowering pulmonary vascular resistance after birth, and in persistent pulmonary hypertension of the newborn (PPHN), NO-mediated dilation is dysfunctional. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) circulates in plasma, and its concentrations are elevated in certain cardiovascular diseases, including pulmonary hypertension. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the activity of which regulates ADMA concentrations and provides a mechanism for modulating NO synthase in vivo. We investigated the changes in expression and activity of the 2 isoforms of DDAH in lungs from newborn piglets both during normal development and in PPHN.


RESULTS
Using Western blotting, we showed that DDAHI expression did not change in the normal developing lung; however, DDAHII increased after birth and reached a peak at 1 day. This was reflected in an increase in total DDAH activity according to an L-citrulline assay. With pulmonary hypertension, no changes in DDAHI expression were observed, but DDAHII expression was markedly decreased compared with age-matched controls. Total DDAH activity was similarly reduced.


CONCLUSIONS
These results indicate that each DDAH isoform is differentially regulated during both lung development and PPHN. Suppression of DDAHII isoform expression may be a mechanism underlying PPHN.
Arrigoni
Francesca I
FI
Centre for Clinical Pharmacology, The BHF Laboratories, The Rayne Institute, Developmental Vascular Biology and Pharmacology Unit, The Institute of Child Health, London, UK.
Vallance
Patrick
P
Haworth
Sheila G
SG
Leiper
James M
JM
D000581:Amidohydrolases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D000860:Hypoxia / Q000150:complications; D007150:Immunohistochemistry; D008168:Lung / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D011312:Pressure; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D020033:Protein Isoforms; D012333:RNA, Messenger; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase