Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension

Eva Nozik-Grayck*, Crystal Woods, Joann M. Taylor, Richard K.P. Benninger, Richard D. Johnson, Leah R. Villegas, Kurt R. Stenmark, David G. Harrison, Susan M. Majka, David Irwin, Kathryn N. Farrow

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SODloxp/loxp X Tgcre/SMMHCmice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inacti-vation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.

Original languageEnglish (US)
Pages (from-to)L868-L876
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume307
Issue number11
DOIs
StatePublished - Nov 1 2014

Keywords

  • Endothelial nitric oxide synthase
  • Extracellular superoxide dismutase
  • Guanosine 3' 5'-cyclic monophosphate
  • Guanylate cyclase
  • Hypoxia
  • Nitric oxide synthase
  • Phosphodiesterase
  • Pulmonary vascular remodeling

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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