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Contribution of Mitochondria‐Derived Reactive Oxygen Species to Augmented Pulmonary Vasoconstriction Following Chronic Hypoxia
Author(s) -
Yan Simin,
Sheak Joshua R.,
Jernigan Nikki L.,
Walker Benjimen R.,
Resta Thomas C.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.845.9
Subject(s) - hypoxic pulmonary vasoconstriction , vasoconstriction , nitric oxide , hypoxia (environmental) , medicine , chemistry , endocrinology , reactive oxygen species , rho associated protein kinase , vasodilation , pharmacology , oxygen , biochemistry , signal transduction , organic chemistry
Chronic hypoxia (CH) augments pulmonary arterial tone through O 2 − ‐dependent stimulation of RhoA, a response that may contribute to the vasoconstrictor component of pulmonary hypertension. Although mitochondria are an important source of reactive oxygen species (ROS) in the pulmonary vasculature, the role of mitochondria‐derived ROS (mitoROS) in enhanced vasoconstrictor reactivity following CH is unknown. We hypothesized that mitoROS contribute to elevated basal pulmonary arterial tone and endothelin‐1 (ET‐1) induced vasoconstriction following CH. To test our hypothesis, we measured basal tone by videomicroscopy in isolated, pressurized small pulmonary arteries [~150 μm inner diameter (i.d.)] from normoxic and CH (4 wk, 0.5 atm) rats following administration of the mitochondria‐targeted antioxidants, MitoQ (1 μM) or MitoTEMPO (200 μM), or their respective vehicles. Parallel studies evaluated effects of mitoROS inhibition on vasoconstrictor responses to increasing concentrations of ET‐1. Experiments were performed either in the presence of the nitric oxide (NO) synthase inhibitor N ω ‐nitro‐L‐arginine (300 μM) or after endothelial disruption to limit the influence of endogenous NO. Pulmonary arterial tone was calculated as the percent difference in i.d. between Ca 2+ ‐free and Ca 2+ ‐containing conditions, whereas vasoconstriction to ET‐1 was expressed as a percentage of baseline i.d. Exposure to CH significantly (P < 0.05) increased basal pulmonary arterial tone and vasoconstrictor responsiveness to ET‐1 in both NOS‐inhibited and endothelium‐disrupted arteries. Treatment with either MitoQ or MitoTEMPO prevented these responses to CH and normalized values between groups. We conclude that mitoROS provide a major contribution to CH‐induced increases in pulmonary vasoconstrictor reactivity. Support or Funding Information This work was supported by NIH grant R01 HL132883 (to T.C. Resta). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .