Adesina 2015 Free Radic Biol Med
|Adesina SE, Kang BY, Bijli KM, Ma J, Cheng J, Murphy TC, Michael Hart C, Sutliff RL (2015) Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med 87:36-47.|
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 (O2•−) 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 O2•− (mtO2•−) and H2O2 (mtH2O2) increases Nox expression to promote PH pathogenesis and that mitochondria-targeted antioxidants can reduce mtROS, Nox expression, and hypoxia-induced PH.
Approach and Results
Exposure of human pulmonary artery endothelial cells to hypoxia for 72 hours increased mtO2•− and mtH2O2. To assess the contribution of mtO2•− and mtH2O2 to hypoxia-induced PH, mice that overexpress superoxide dismutase 2 (TghSOD2) or mitochondria-targeted catalase (MCAT) were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 weeks. Compared to hypoxic control mice, MCAT mice developed less hypoxia-induced increases in RVSP, α-SMA staining, extracellular H2O2 (Amplex Red), Nox2 and Nox4 (qRT-PCR and western blot), or cyclinD1 and PCNA (western blot). In contrast, TghSOD2 mice experienced exacerbated responses to hypoxia.
These studies demonstrate that hypoxia increases mtO2•− and mtH2O2. Targeting mtH2O2 attenuates PH pathogenesis, whereas, targeting mtO2•− 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 mtH2O2 generation may be particularly effective at preventing hypoxia-induced PH.
• Keywords: Mitochondria, ROS, Hydrogen Peroxide, Superoxide, Catalase, SOD2, NADPH Oxidase, Pulmonary Hypertension • Bioblast editor: Sobotka O
Stress:Oxidative stress;RONS, Hypoxia
Tissue;cell: Endothelial;epithelial;mesothelial cell Preparation: Intact cells