In contrast to findings in the mice, H2O2 and Nox4 were upregulated in PAH cells as previously described.47,48 Differences in Nox4/H2O2 between mouse and human PH models may indicate the role of endothelial cells in our whole lung approach, where H2O2 is normally abundant and protective, whereas our human studies examined isolated VSMCs, in which Nox4-derived H2O2 is injurious.49 A potential switch from low-level H2O2 as a signaling molecule to a damaging ROS at higher levels is also suggested. This evidence concerns the gene NOX4 and pulmonary arterial hypertension.