HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: 292/2/E453    most recent 00267.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Buroker, N. E. Articles by Portman, M. A. Search for Related Content PubMed PubMed Citation Articles by Buroker, N. E. Articles by Portman, M. A.

The dominant negative thyroid hormone receptor -mutant 337T alters PPAR signaling in heart

¹Division of Cardiology, Department of Pediatrics, Children's Hospital and Regional Medical Center, and University of Washington School of Medicine, Seattle, Washington; ²United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Department of Pediatrics; ³Department of Biostatistics and Applied Mathematics, University of Texas M. D.Anderson Cancer Center, Houston, Texas; and ⁴Center for Expression Arrays, Department of Microbiology, University of Washington, School of Medicine, Seattle, Washington

Submitted 5 June 2006 ; accepted in final form 12 September 2006

PPAR and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs interact with PPAR regulation of target genes and used mice exhibiting a cardioselective 337T TR1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TR and TR. We used UCP3 and MTE-1 as principal reporters and analyzed gene expression from hearts of transgenic (MUT) and nontransgenic (WT) littermates 6 h after receiving either specific PPAR ligand (WY-14643) or vehicle. Interactions were determined through qRT-PCR analyses, and the extent of these interactions across multiple genes was determined using expression arrays. In the basal state, we detected no differences between groups for protein content for UCP3, PPAR, TR2, RXR, or PGC-1. However, protein content for TR1 and the PPAR heterodimeric partner RXR was diminished in MUT, whereas PPAR increased. We demonstrated cross-talk between PPAR and TR for multiple genes, including the reporters UCP3 and MTE1. WY-14643 induced a twofold increase in UCP3 gene expression that was totally abrogated in MUT. We demonstrated variable cross-talk patterns, indicating that multiple mechanisms operate according to individual target genes. The non-ligand-binding TR1 mutation alters expression for multiple nuclear receptors, providing a novel mechanism for interaction that has not been previously demonstrated. These results indicate that therapeutic response to PPAR ligands may be determined by thyroid hormone state and TR function.

cardiac metabolism; nuclear receptors; microarrays