Abstract 1248: Critical Role of Peroxisome Proliferator-Activated Receptor Binding Protein in the Heart
Myocardial energy metabolism is regulated at the transcriptional level by members of the nuclear receptor superfamily, particularly peroxisome proliferator-activated receptors (PPARs). Optimal nuclear receptor function requires the participation of various interacting coactivators that act either to modify chromatin structure or to facilitate the assembly of the basal transcriptional machinery. Among numerous coactivators, PPAR binding protein (PBP) specifically interacts with nuclear receptors as a subunit of the TRAP/DRIP/ARC/Mediator complex and creates the link to RNA polymerase II. To explore the role of PBP in the heart, we generated cardiomyocyte-restricted PBP knockout (CR-PBP KO) mice by crossing mice carrying a loxP-flanked allele of PBP with transgenic mice expressing Cre recombinase under the control of the α-myosin heavy chain gene promoter. CR-PBP KO mice are viable but exhibit profound eccentric cardiac hypertrophy by post-natal day 20 (HW/BW: 0.46% in controls vs. 0.59% in KO mice). Subsequently they all develop heart failure and die by post-natal day 23–33. Microarray analysis with RNA from hearts of 20 day old mice shows that deletion of PBP leads to a suppression of metabolic genes in the mitochondrial fatty acid β-oxidation pathway, including PPARα, retinoid X receptor α (RXRα), PPAR gamma coactivator-1, mitochondrial 3-oxoacyl-CoA thiolase, acyl-CoA synthetase, medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase Iβ (CPT Iβ) and CPTII (by 70%, 67%, 77%, 77%, 53%, 57%, 33% and 49%, respectively). The transcript level of calcium-handling proteins, including ryanodine receptor-2 (RyR2), phospholamban (PL), sarcoplasmic reticulum Ca2+-ATPase-2 (SERCA2) is also dramatically reduced in CR-PBP KO mice (by 66%, 82% and 60%, respectively). Western analysis confirmed reduced protein levels of RXRα, RyR2, PL and SERCA2. Interestingly, CR-PBP KO mice do not show inflammation or fibrosis, suggesting a pure metabolic cardiomyopathy. Together, our data show that PBP is crucial to maintain the expression of genes related to cardiac fatty acid metabolism and disruption of this pathway leads to rapidly lethal postnatal heart failure, a unique model of metabolic cardiomyopathy.