NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling

Scott A Barman, Feng Chen, Yunchao Su, Christiana Dimitropoulou, Yusi Wang, John D. Catravas, Weihong Han, Laszlo Orfi, Csaba Szantai-Kis, Gyorgy Keri, Istvan Szabadkai, Nektarios Barabutis, Olga Rafikova, Ruslan Rafikov, Stephen Matthew Black, Danny Jonigk, Athanassios Giannis, Reto Asmis, David W Stepp, Ganesan RameshDavid J Fulton

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Objective - Pulmonary hypertension (PH) is a progressive disease arising from remodeling and narrowing of pulmonary arteries (PAs) resulting in high pulmonary blood pressure and ultimately right ventricular failure. Elevated production of reactive oxygen species by NADPH oxidase 4 (Nox4) is associated with increased pressure in PH. However, the cellular location of Nox4 and its contribution to aberrant vascular remodeling in PH remains poorly understood. Therefore, we sought to identify the vascular cells expressing Nox4 in PAs and determine the functional relevance of Nox4 in PH. Approach And Results - Elevated expression of Nox4 was detected in hypertensive PAs from 3 rat PH models and human PH using qualititative real-time reverse transcription polymerase chain reaction, Western blot, and immunofluorescence. In the vascular wall, Nox4 was detected in both endothelium and adventitia, and perivascular staining was prominently increased in hypertensive lung sections, colocalizing with cells expressing fibroblast and monocyte markers and matching the adventitial location of reactive oxygen species production. Small-molecule inhibitors of Nox4 reduced adventitial reactive oxygen species generation and vascular remodeling as well as ameliorating right ventricular hypertrophy and noninvasive indices of PA stiffness in monocrotaline-treated rats as determined by morphometric analysis and high-resolution digital ultrasound. Nox4 inhibitors improved PH in both prevention and reversal protocols and reduced the expression of fibroblast markers in isolated PAs. In fibroblasts, Nox4 overexpression stimulated migration and proliferation and was necessary for matrix gene expression. CONCLUSION - : These findings indicate that Nox4 is prominently expressed in the adventitia and contributes to altered fibroblast behavior, hypertensive vascular remodeling, and development of PH.

Original languageEnglish (US)
Pages (from-to)1704-1715
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • Adventitia
  • Fibroblast
  • NADPH oxidase
  • Pulmonary artery

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Barman, S. A., Chen, F., Su, Y., Dimitropoulou, C., Wang, Y., Catravas, J. D., Han, W., Orfi, L., Szantai-Kis, C., Keri, G., Szabadkai, I., Barabutis, N., Rafikova, O., Rafikov, R., Black, S. M., Jonigk, D., Giannis, A., Asmis, R., Stepp, D. W., ... Fulton, D. J. (2014). NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arteriosclerosis, thrombosis, and vascular biology, 34(8), 1704-1715. https://doi.org/10.1161/ATVBAHA.114.303848