xanthine oxidase-derived ros upregulate egr-1 via erk12 in pa smooth muscle cells; model to test impact of extracellular ros in chronic hypoxia黄嘌呤oxidase-derived ros上调egr-1通过erk12 pa平滑肌细胞;.pdf

Xanthine Oxidase-Derived ROS Upregulate Egr-1 via ERK1/2 in PA Smooth Muscle Cells; Model to Test Impact of Extracellular ROS in Chronic Hypoxia 1. 1. 1 1,2 1 Tanya Hartney , Rahul Birari , Sujatha Venkataraman , Leah Villegas , Maylyn Martinez , Stephen M. Black3, Kurt R. Stenmark1,2, Eva Nozik-Grayck1,2* 1 Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, United States of America, 2 Cardiovascular Pulmonary Research Laboratory, University of Colorado Denver, Aurora, Colorado, United States of America, 3 Georgia Health Sciences University, Augusta, Georgia, United States of America Abstract Exposure of newborn calves to chronic hypoxia causes pulmonary artery (PA) hypertension and remodeling. Previous studies showed that the redox-sensitive transcription factor, early growth response-1 (Egr-1), is upregulated in the PA of chronically hypoxic calves and regulates cell proliferation. Furthermore, we established in mice a correlation between hypoxic induction of Egr-1 and reduced activity of extracellular superoxide dismutase (EC-SOD), an antioxidant that scavenges extracellular superoxide. We now hypothesize that loss of EC-SOD in chronically hypoxic calves leads to extracellular superoxide-mediated upregulation of Egr-1. To validate our hypothesis and identify the signaling pathways involved, we utilized PA tissue from normoxic and chronically hypoxic calves and cultured calf and human PA smooth muscle cells (PASMC). Total SOD activity was low in the PA tissue, and only the extracellular SOD component decreased with hypoxia. PA tissue of hypoxic calves showed increased oxidative stress and