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The role of mitochondrial reactive oxygen species in hypoxia‐induced pulmonary hypertension (1089.16)
Author(s) -
Adesina Sherry,
Hart C.,
Sutliff Roy
Publication year - 2014
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.28.1_supplement.1089.16
Subject(s) - sod2 , oxidative stress , nox4 , reactive oxygen species , hypoxia (environmental) , mitochondrial ros , pathogenesis , mitochondrion , catalase , pulmonary hypertension , chemistry , microbiology and biotechnology , superoxide dismutase , endocrinology , biology , medicine , oxygen , biochemistry , nadph oxidase , organic chemistry
Oxidative stress plays a critical role in pulmonary hypertension (PH) pathogenesis. The specific reactive oxygen species (ROS) responsible have not been defined, though mitochondrial ROS likely contribute. We hypothesize that mitochondrial O 2 • − and H 2 O 2 promote PH pathogenesis. Hypoxia effects on mitochondrial O 2 • − and H 2 O 2 were measured using mitoPY1 and mitoSOX in human pulmonary arterial endothelial cells (HPAECs) exposed to normoxia (21% O 2 ) or hypoxia (1% O 2 ) for 72 hours. Mouse models with mitochondria‐targeted SOD2 (Tg hSOD2 ) or catalase (mCAT) expression were used to modulate mitochondrial ROS. Control and transgenic mice were exposed to normoxia (21% O 2 ) or hypoxia (10% O 2 ) for 3 weeks. ROS levels (confocal microscopy and Amplex red assay), Nox mRNA levels (qRT‐PCR), and proliferation and remodeling (α‐smooth muscle actin, α‐SMA, staining) were measured at the conclusion of the study. Hypoxia exposed HPAECs had increased mitochondria‐derived O 2 •− and H 2 O 2 (p 蠄 0.5). Compared to control, mCAT expression prevented hypoxia‐induced increases in lung H 2 O 2 , Nox2, Nox4, and PCNA mRNA, and α‐SMA staining (p 蠄 0.5). Hypoxia‐induced alterations in these markers were exacerbated in Tg hSOD2 lungs (p 蠄 0.5). These studies suggest that targeted attenuation of mitochondria‐derived H 2 O 2 attenuates pulmonary vascular derangements involved in PH pathogenesis. Grant Funding Source : VA Merit Review 1I01BX001910. NIH grants DK074519/ HL102167 (CMH/RLS). NRSA 1F31HL114386 ‐ 01A1 SEA