title: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets.
abstract: The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor whose activation regulates metabolism and inflammation. Recent data indicate that the zinc finger transcription factor early growth response gene-1 (Egr-1) acts as a master switch for the inflammatory response in ischemic vessels. Experiments tested the hypothesis that activation of endogenous PPAR-gamma inhibits induction of Egr-1. Egr-1 is rapidly induced in murine lungs after ischemia-reperfusion, as well as in alveolar mononuclear phagocytes deprived of oxygen as an ischemic model. In vitro, the natural PPAR-gamma ligand (15-deoxy-Delta12,14-prostaglandin J2) and a PPAR-gamma activator (troglitazone), but not a PPAR-alpha activator (bezafibrate), strikingly diminished Egr-1 mRNA and protein expression and nuclear DNA binding activity corresponding to Egr-1. In vivo, treatment with troglitazone before ischemia prevented induction of Egr-1 and its target genes such as interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-2. As a consequence of PPAR-gamma activation, pulmonary leukostasis was decreased and oxygenation and overall survival were improved. Activation of PPAR-gamma suppresses activation of Egr-1 and its inflammatory gene targets and provides potent protection against ischemic pulmonary injury. These data reveal a new mechanism whereby PPAR-gamma activation may decrease tissue inflammation in response to an ischemic insult.
authors.affiliation: College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.forename: Shi Fang
authors.initials: SF
authors.lastname: Yan
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins; D007249:Inflammation / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010586:Phagocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016019:Survival Analysis; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D016207:Cytokines; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone