Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling.
Although production of reactive oxygen species (ROS) such as superoxide (O(2)(.-)) has been implicated in chronic hypoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling, the transcription factors and gene targets through which ROS exert their effects have not been completely identified. We used mice overexpressing the extracellular antioxidant enzyme extracellular superoxide dismutase (EC-SOD TG) to test the hypothesis that O(2)(.-) generated in the extracellular compartment under hypoxic conditions contributes to PH through the induction of the transcription factor, early growth response-1 (Egr-1), and its downstream gene target, tissue factor (TF). We found that chronic hypoxia decreased lung EC-SOD activity and protein expression in wild-type mice, but that EC-SOD activity remained five to seven times higher in EC-SOD TG mice under hypoxic conditions. EC-SOD overexpression attenuated chronic hypoxic PH, and vascular remodeling, measured by right ventricular systolic pressures, proliferation of cells in the vessel wall, muscularization of small pulmonary vessels, and collagen deposition. EC-SOD overexpression also prevented the early hypoxia-dependent upregulation of the redox-sensitive transcription factor Egr-1 and the procoagulant protein TF. These data provide the first evidence that EC-SOD activity is disrupted in chronic hypoxia, and increased EC-SOD activity can attenuate chronic hypoxic PH by limiting the hypoxic upregulation of redox-sensitive genes.
Nozik-Grayck
Eva
E
Department of Pediatrics, Univ. of Colorado, Denver, 4200 E. 9th Ave., B131, Denver, CO 80262, USA. eva.grayck@uchsc.edu
Suliman
Hagir B
HB
Majka
Susan
S
Albietz
Joseph
J
Van Rheen
Zachary
Z
Roush
Kevin
K
Stenmark
Kurt R
KR
D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000473:pathology; D002908:Chronic Disease; D017931:DNA Primers / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D015870:Gene Expression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; C441642:SOD3 protein, human; D013482:Superoxide Dismutase