HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nozik-Grayck, E. Articles by Stenmark, K. R. PubMed Articles by Nozik-Grayck, E. Articles by Stenmark, K. R.

Extracellular Superoxide Induces Egr-1 and Promotes Hypoxic Pulmonary Vascular Remodeling

¹ Cardiovascular Physiology Laboratory and Developmental Lung Biology Group, University of Colorado, Denver, Colorado; and ² Department of Anesthesiology, Duke University, Durham, North Carolina

Correspondence and requests for reprints should be addressed to Eva Nozik-Grayck, M.D., Associate Professor, University of Colorado, Denver, 4200 E. 9th Ave., B131, Denver, CO 80262. E-mail: Eva.Grayck{at}uchsc.edu

Egr-1 is a redox-sensitive transcription factor that regulates multiple genes relevant to the pathogenesis of cardiopulmonary diseases, including hypoxic pulmonary hypertension (PH). Chronic hypoxia induces Egr-1 and tissue factor in mouse lung to promote fibrin deposition. Emerging evidence supports a role for extracellular O₂^– in chronic hypoxia–induced PH. We hypothesize that extracellular O₂^– generated in hypoxia up-regulates Egr-1 and tissue factor in the mouse lung, contributing to chronic hypoxia–induced pulmonary vascular remodeling. We exposed four strains of mice to 0, 1, 14, and 35 days of hypobaric hypoxia (18,000 ft): wild-type C57/Bl6 mice (WT), mice lacking extracellular superoxide dismutase (EC-SOD KO), mice overexpressing EC-SOD (EC-SOD TG), and mice lacking gp91phox subunit of NADPH oxidase (Nox2 KO). Hypoxic induction of Egr-1 and tissue factor mRNA and protein in WT mouse lung increased further in EC-SOD KO mice. In contrast, hypoxia did not increase Egr-1 and tissue factor mRNA or protein in the two strains with decreased extracellular O₂^–, EC-SOD TG and Nox2 mice. By 14 days, hypoxic pulmonary vascular remodeling was evident in WT and EC-SOD KO mice, as shown by -smooth muscle actin immunostaining in newly muscularized distal PA, and picrosirius red staining in mid-sized PA. EC-SOD TG and Nox2 KO mice did not exhibit either feature of hypoxic pulmonary vascular remodeling. At 35 days, the hypoxia-induced increase in right ventricular systolic pressures in WT mice (from 25 ± 0.7 to 41 ± 1 mm Hg) was attenuated in EC-SOD TG mice (23 ± 0.7 to 30 ± 0.3 mm Hg, n = 3–7, P < 0.05 by ANOVA). These data suggest that extracellular O₂^– regulates hypoxia-induced expression of Egr-1 and its downstream gene, tissue factor, to promote pulmonary vascular remodeling and contribute to chronic hypoxic PH.

FOOTNOTES

Supported by March of Dimes #6-FY06–316 (E.N.-G.) and NIH/NHLBI HL084923–01 (K.R.S.).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 1, 2007; accepted in final form October 16, 2007)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nozik-Grayck, E. Articles by Stenmark, K. R. PubMed Articles by Nozik-Grayck, E. Articles by Stenmark, K. R.