Superoxide generated at mitochondrial complex iii triggers acute responses to hypoxia in the pulmonary circulation

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

*Corresponding author for this work

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Rationale: The role of reactive oxygen species (ROS) signaling in the O2 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. Objectives:We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA). Methods: 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). Measurements and Main Results: 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 [Ca21]i. In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISPmice with transgenic mice expressing tamoxifen-activated Cre in smooth musclepermittedthe depletionofRISP in PASMCin vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca21]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. Conclusions: Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca21]i that cause acute hypoxic pulmonary vasoconstriction.

Original languageEnglish (US)
Pages (from-to)424-432
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume187
Issue number4
DOIs
StatePublished - Feb 15 2013

Keywords

  • Hypoxic pulmonary vasoconstriction
  • Oxygen sensing
  • Reactive oxygen species
  • Rieske iron-sulfur protein
  • RoGFP

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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