title: p53 protects against LPS-induced lung endothelial barrier dysfunction.
abstract: New therapies toward heart and blood vessel disorders may emerge from the development of Hsp90 inhibitors. Several independent studies suggest potent anti-inflammatory activities of those agents in human tissues. The molecular mechanisms responsible for their protective effects in the vasculature remain unclear. The present study demonstrates that the transcription factor p53, an Hsp90 client protein, is crucial for the maintenance of vascular integrity, protects again LPS-induced endothelial barrier dysfunction, and is involved in the mediation of the anti-inflammatory activity of Hsp90 inhibitors in lung tissues. p53 silencing by siRNA decreased transendothelial resistance (a measure of endothelial barrier function). A similar effect was induced by the p53 inhibitor pifithrin, which also potentiated the LPS-induced hyperpermeability in human lung microvascular endothelial cells (HLMVEC). On the other hand, p53 induction by nutlin suppressed the LPS-induced vascular barrier dysfunction. LPS decreased p53 expression in lung tissues and that effect was blocked by pretreatment with Hsp90 inhibitors both in vivo and in vitro. Furthermore, the Hsp90 inhibitor 17-allyl-amino-demethoxy-geldanamycin suppressed the LPS-induced overexpression of the p53 negative regulator MDMX as well as p53 and MDM2 (another p53 negative regulator) phosphorylation in HLMVEC. Both negative p53 regulators were downregulated by LPS in vivo. Chemically induced p53 overexpression resulted in the suppression of LPS-induced RhoA activation and MLC2 phosphorylation, whereas p53 suppression caused the opposite effects. These observations reveal new mechanisms for the anti-inflammatory actions of Hsp90 inhibitors, i.e., the induction of the transcription factor p53, which in turn can orchestrate robust vascular anti-inflammatory responses both in vivo and in vitro.
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Norfolk, Virginia; and nbarabutis@gmail.com.
authors.forename: Nektarios
authors.initials: N
authors.lastname: Barabutis
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Norfolk, Virginia; and.
authors.forename: Christiana
authors.initials: C
authors.lastname: Dimitropoulou
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Norfolk, Virginia; and.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Birmpas
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Norfolk, Virginia; and.
authors.forename: Atul
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Norfolk, Virginia; and.
authors.forename: Gagan
authors.initials: G
authors.lastname: Thangjam
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Norfolk, Virginia; and School of Medical Diagnostic and Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, Virginia.
authors.forename: John D
authors.initials: JD
authors.lastname: Catravas
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C066737:RHOA protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020742:rhoA GTP-Binding Protein
keywords: acute lung injury; hsp90; human pulmonary endothelium; lung barrier function; p53