Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension

Pulmonary hypertension (PH) is characterized by increased pulmonary vascular remodeling, resistance, and pressures. Reactive oxygen species (ROS) contribute to PH-associated vascular dysfunction. NADPH oxidases (Nox) and mitochondria are major sources of superoxide (O-2(center dot-)) and hydrogen peroxide (H2O2) in pulmonary vascular cells. Hypoxia, a common stimulus of PH, increases Nox expression and mitochondrial ROS (mtROS) production. The interactions between these two sources of ROS generation continue to be defined. We hypothesized that mitochondria-derived O-2(center dot-) and H2O2 (mtH(2)O(2)) increase Nox expression to promote PH pathogenesis and that mitochondria-targeted antioxidants can reduce mtROS, Nox expression, and hypoxia-induced PH. Exposure of human pulmonary artery endothelial cells to hypoxia for 72 h increased mtO(2)(center dot-) and mtH(2)O(2) To assess the contribution of mtO(2)(center dot-) and mtH(2)O(2) to hypoxia-induced PH, mice that overexpress superoxide dismutase 2 (Tg(hSOD2)) or mitochondria-targeted catalase (MCAT) were exposed to normoxia (21% O-2) or hypoxia (10% O-2) for three weeks. Compared with hypoxic control mice, MCAT mice developed smaller hypoxia-induced increases in RVSP, alpha-SMA staining, extracellular H2O2 (Amplex Red), Nox2 and Nox4 (c[RT-PCR and Western blot), or cyclinD1 and PCNA (Western blot). In contrast, Tghs D2 mice experienced exacerbated responses to hypoxia. These studies demonstrate that hypoxia increases mtO(2)(center dot-) and mtH(2)O(2). Targeting natH(2)O(2) attenuates PH pathogenesis, whereas targeting mtO(2)(center dot-) exacerbates PH. These differences in PH pathogenesis were mirrored by RVSP, vessel muscularization, levels of Nox2 and Nox4, proliferation, and H2O2 release. These studies suggest that targeted reductions in H2O2H2O2 generation may be particularly effective in preventing hypoxia-induced PH. (C) 2015 Elsevier Inc All rights reserved,