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(Circulation. 2006;114:II_160.)
© 2006 American Heart Association, Inc.

Growth Factors, Cytokines, Signal Transduction V

Abstract 893: Heme Oxygenase-1 and a Carbon Monoxide Releasing Compound, [Ru(CO)3Cl2]2,-induced ERK5 Activation Inhibits Inflammatory Responses via Peroxisome Proliferator-activated Receptor l Stimulation in Skeletal Muscle

Chang-Hoon Woo; Michael Massett; Tetsuro Shishido; Bo Ding; Chen Yan; Carolyn McClain; Jun-ichi Abe

Cardiovascular Rsch Institute, Univ of Rochester, Rochester, NY

Background: Peroxisome proliferator-activated receptors (PPAR) decrease the production of cytokine and iNOS expression, which are associated with aging-related inflammation and insulin resistance. Recently, the involvement of the induction of heme oxygenase-1 (HO-1) in regulating inflammation has been suggested, but the exact mechanisms for reducing inflammation by HO-1 remains unclear.

Methods and Results: We found that overexpression of HO-1 and [Ru(CO)3Cl2]2, a carbon monoxide (CO)-releasing compound, increased both ERK5 kinase and transcriptional activity (2.4±1.8 fold, p<0.01) in C2C12 cells. [Ru(CO)3Cl2]2 activated PPARd transcriptional activity was inhibited by dominant negative form of MEK5 and ERK5 (1.9±0.2 fold increase vs 0.8±0.2 (DN-MEK5) and 0.7±0.1 (DN-ERK5) , respectively, mean±SD, p<0.01). Overexpression of constitutive active form of MEK5 inhibits TNFa-induced NF-kB activity by 40±5% (p<0.01 vs TNFa alone: 100%). This inhibiton was reversed by a dominant negative form of PPARd (150±20%, p<0.01), suggesting that ERK5/PPARd activation is required for the anti-inflammatory effects of CO and HO-1. Based on a mammalian hybrid assay, we found that ERK5 associates with PPARd at the middle region (aa 411–577, Arg rich region) of ERK5. Finally, we found the concomitant reduction of HO-1 (1.0±0.2 vs 0.3±0.1, p<0.01) and ERK5 (1.0±0.1 vs 0.6±0.2, p<0.05), and induction of iNOS (1.0±0.1 vs 4.2±0.9, p<0.01) in skeletal muscle from 19 month old mice compared to 5 month old mice, which showed insulin resistance (mean glycemic levels: 260±50mg/dl vs 175±10mg/ dl, n=5). Interestingly, the ability of PPARd binding to iNOS promoter was also significantly decreased in old mice compared to young mice (1.6±0.5 vs 0.2±0.2 respectively, n=5, p<0.01) using chromatin immunoprecipitation assay in vivo.

Conclusion: We propose a new mechanism by which CO and HO-1 mediate anti-inflammatory effects via activating ERK5/ PPARd, and ERK5 mediates CO and HO-1-induced PPARd activation via its interaction with PPARd.

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Woo, C.-H. Articles by Abe, J.-i. PubMed Articles by Woo, C.-H. Articles by Abe, J.-i.