title: Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension.
abstract: The development of pulmonary hypertension (PH) involves the uncontrolled proliferation of pulmonary smooth muscle cells via increased growth factor receptor signaling. However, the role of epidermal growth factor receptor (EGFR) signaling is controversial, as humans with advanced PH exhibit no changes in EGFR protein levels and purpose of the present study was to determine whether there are post-translational mechanisms that enhance EGFR signaling in PH. The EGFR inhibitor, gefinitib, significantly attenuated EGFR signaling and prevented the development of PH in monocrotaline (MCT)-exposed rats, confirming the contribution of EGFR activation in MCT induced PH. There was an early MCT-mediated increase in hydrogen peroxide, which correlated with the binding of the active metabolite of MCT, monocrotaline pyrrole, to catalase Cys377, disrupting its multimeric structure. This early oxidative stress was responsible for the oxidation of EGFR and the formation of sodium dodecyl sulfate (SDS) stable EGFR dimers through dityrosine cross-linking. These cross-linked dimers exhibited increased EGFR autophosphorylation and signaling. The activation of EGFR signaling did not correlate with pp60(src) dependent Y845 phosphorylation or EGFR ligand expression. Importantly, the analysis of patients with advanced PH revealed the same enhancement of EGFR autophosphorylation and covalent dimer formation in pulmonary arteries, while total EGFR protein levels were unchanged. As in the MCT exposed rat model, the activation of EGFR in human samples was independent of pp60(src) phosphorylation site and ligand expression. This study provides a novel molecular mechanism of oxidative stress stimulated covalent EGFR dimerization via tyrosine dimerization that contributes into development of PH.
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Rafikova
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: Archana
authors.initials: A
authors.lastname: Kangath
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Qu
authors.affiliation: Department of Anesthesiology, University of Alabama, Birmingham, AL, United States.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Center For Biotechnology & Genomic Medicine, Georgia Regents University, Augusta, GA, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, United States.
authors.forename: Julin
authors.initials: J
authors.lastname: Desai
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, United States.
authors.forename: Taylor
authors.initials: T
authors.lastname: Fields
authors.affiliation: Institute of Pathology, Hannover Medical School, Hanover, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Ludewig
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: Jason X-Y
authors.initials: JX
authors.lastname: Yuan
authors.affiliation: Institute of Pathology, Hannover Medical School, Hanover, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States. Electronic address: steveblack@email.arizona.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016686:Monocrotaline / Q000633:toxicity; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D010766:Phosphorylation; D055503:Protein Multimerization / Q000235:genetics; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism
chemical_list: D014443:Tyrosine; D016686:Monocrotaline; D066246:ErbB Receptors
keywords: Catalase; EGFR; Oxidative stress; Proliferation; Pulmonary hypertension