Journal Article

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Schriewer, Jacqueline M., Schumacker, Paul T., Guzy, Robert D., Mungai, Paul T., Dokic, Danijela, Marks, Jeremy D., Waypa, Gregory B., Ball, Molly K.

2013

Overview

The role of reactive oxygen species (ROS) signaling in the O(2) sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses. We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA). A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC). In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in [Ca(2+)](i). In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca(2+)](i) of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice. Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca(2+)](i) that cause acute hypoxic pulmonary vasoconstriction.

• Publisher: American Thoracic Society
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Biological and medical sciences / Cytosol - metabolism / Disease Models, Animal / Electron Transport Complex III - genetics / Electron Transport Complex III - metabolism / Hypotheses / Hypoxia / Hypoxia - genetics / Hypoxia - metabolism / Intensive care medicine / Iron-sulfur proteins / Lung - blood supply / Lung - metabolism / Lungs / Medical sciences / Mice / Mice, Transgenic / Mitochondria / Mitochondria - metabolism / Myocytes, Smooth Muscle - metabolism / Oxidation / Pneumology / Pulmonary arteries / Pulmonary Artery - metabolism / Pulmonary Circulation / Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases / Reactive Oxygen Species - metabolism / Signal transduction / Smooth muscle / Superoxides - metabolism / Variance analysis / Veins & arteries