Things We “kNOw” and Do Not “kNOw” about Pulmonary Hypertension

Things We "kNOw" and Do Not "kNOw" about Pulmonary Hypertension Pulmonary hypertension (PH) is a devastating disease affecting .100 million people worldwide and defined by increased pulmonary artery pressure (.25 mm Hg) and pulmonary vascular resistance, which often results in right ventricular failure and premature death (1, 2).The World Health Organization classifies patients with PH into five groups on the basis of etiology (3).Multiple phenotypes such as vasoconstriction, dysregulated pulmonary vascular cell proliferation and remodeling, and inflammation contribute to the PH disease process (4-6) making therapeutic design complicated (7,8).Nitric oxide (NO) regulates pulmonary vascular tone and remodeling, inflammation, and coagulation.Three different nitric oxide synthase (NOS) isoforms control enzymatic formation of NO that differ in catalytic activity, location, and regulation.These are neuronal NOS (nNOS; NOS I), inducible NOS (iNOS; NOS II), and endothelial NOS (eNOS; NOS III) (9, 10).Several studies have shown that loss of eNOS-derived NO contributes to PH.This can occur by lower eNOS levels or lower NO bioavailability as a result of eNOS uncoupling despite no changes, or even increased eNOS expression (11,12).Mice genetically deficient in eNOS spontaneously develop PH and right ventricular failure (13, 14), and NO metabolite levels are lower in patients with pulmonary arterial hypertension (PAH) compared with control patients (15, 16), with the levels inversely correlating with the severity of disease.Moreover, therapies that increase NO in the pulmonary vasculature (e.g., inhaled NO or nitrite), or those that enhance downstream cyclic guanosine monophosphate-dependent signaling, are among the few available therapies to counter vasoconstriction in group 1 PAH (1,(17)(18)(19)(20).Treatment options for the other PH groups, however, are currently limited or lacking.In this issue of the Journal, Ogoshi and colleagues (pp.232-244) confirmed a critical role for eNOS in PH, using a mouse model of hypoxia-induced PH (21).Indices of PH including elevated right systolic pressure and hypertrophy, pulmonary vascular remodeling, and decreased survival were more prominent in eNOS-deficient mice compared with wild-type mice or mice lacking either nNOS or iNOS.These data further support a functional role for eNOS in protection against PH (13,14,22).The most intriguing findings by Ogoshi and colleagues were that mice devoid of all three NOS isoforms (triple NOS knockouts) had a greater degree of PH compared with mice lacking only eNOS; mortality was approximately twofold higher in triple NOS knockouts.This result reveals an unexpected interaction between NO produced by eNOS and either nNOS and/or iNOS.Although this aspect was not investigated in detail in the current study, it is notable that iNOS expression was increased in hypoxia-exposed eNOS-deficient mice, suggesting iNOS may offer compensatory