TY - JOUR T1 - Superoxide dismutase: Master and Commander? JF - European Respiratory Journal JO - Eur Respir J SP - 234 LP - 236 DO - 10.1183/09031936.00062510 VL - 36 IS - 2 AU - Weir, E.K. AU - Hong, Z. AU - Chen, Y. Y1 - 2010/08/01 UR - http://erj.ersjournals.com/content/36/2/234.abstract N2 - Inhaled nitric oxide (NO) has long been known to be an effective pulmonary vasodilator in the normal pulmonary vasculature. In the classical NO signalling pathway, it activates soluble guanylate cyclase in the cytoplasm of pulmonary artery smooth muscle cells, leading to the production of cyclic guanosine monophosphate (cGMP), which then activates protein kinase G (PKG). PKG, acting through several downstream targets, causes vasodilatation. In addition, NO acts through induction of post-translational changes, such as S-nitrosylation of proteins with reactive thiols. NO levels are decreased in idiopathic pulmonary arterial hypertension (IPAH) 1, 2, in patients with PAH secondary to anorectic agents 3 and in infants with persistent pulmonary hypertension of the newborn (PPHN) 4. In part, NO is decreased because of the reduced endothelial NO synthase (eNOS) that has been reported in PAH and in PPHN 5, 6. More recently, an additional mechanism has been described. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and IPAH patients have increased levels of ADMA in their blood and lungs 7. ADMA is metabolised by dimethylarginine dimethylaminohydrolase (DDAH) 1 or DDAH2, two enzymes encoded by different genes. Although solid evidence supporting a role for DDAH2 in the degradation of lung ADMA is not available, DDAH1 gene deletion in vascular endothelial cells causes accumulation of ADMA in the lung tissue of mice 8. Similarly, monocrotaline injection causes a decrease in lung DDAH1 expression and DDAH activity, leading to the accumulation of ADMA in rats, which may then contribute to the development of pulmonary hypertension 9. The increased ADMA levels provide another mechanism to explain the decreased NO levels in PAH. It is also worth noting that in IPAH patients, higher ADMA plasma levels correlate with … ER -