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: Morihito Okada, Shi Fang Yan, David J Pinsky
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 16 Issue 14 Pg. 1861-8 (Dec 2002) ISSN: 1530-6860 [Electronic] United States
• PMID: 12468449 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chromans
• Cytokines
• DNA-Binding Proteins
• Early Growth Response Protein 1
• Egr1 protein, mouse
• Egr1 protein, rat
• Immediate-Early Proteins
• Ligands
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• Thiazolidinediones
• Transcription Factors
• Troglitazone

Topics

• Animals
• Cell Line
• Cell Movement (drug effects)
• Chromans (pharmacology)
• Cytokines (biosynthesis, genetics)
• DNA-Binding Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Early Growth Response Protein 1
• Gene Expression Regulation
• Immediate-Early Proteins
• Inflammation (immunology)
• Leukocytes (drug effects, immunology)
• Ligands
• Lung (drug effects, immunology, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Phagocytes (metabolism)
• RNA, Messenger (biosynthesis)
• Rats
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Reperfusion Injury (genetics, immunology, metabolism)
• Survival Analysis
• Thiazoles (pharmacology)
• Thiazolidinediones
• Transcription Factors (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Troglitazone