Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid metabolism at the transcriptional level and modulates the expression of genes involved in inflammation, cell proliferation and differentiation. Although PPARalpha has been shown to mitigate cardiac hypertrophy, knowledge about underlying mechanisms and nature of signalling pathways involved is fragmentary and incomplete. The aim of this study was to identify the processes and signalling pathways regulated by PPARalpha in hearts challenged by a chronic pressure overload by means of whole genome transcriptomic analysis. Thereto, PPARalpha-/- and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days and left ventricular gene expression profile was determined using Affymetrix GeneChip Mouse Genome 430 2.0 arrays containing over 45,000 probe sets. In unchallenged hearts, the mere lack of PPARalpha resulted in 821 differentially expressed genes, many of which were related to lipid metabolism and immune response. TAC resulted in a more pronounced cardiac hypertrophy and more extensive changes in gene expression (1910 and 312 differentially expressed genes, respectively) in PPARalpha-/- mice than in wild-type mice. Many of the hypertrophy related genes were related to development, signal transduction, actin filament organization, and collagen synthesis. Compared to wild-type hypertrophied hearts, PPARalpha-/- hypertrophied hearts revealed enrichment of gene clusters related to extracellular matrix remodelling, immune response, oxidative stress, and inflammatory signalling pathways. The present study demonstrates therefore that, in addition to lipid metabolism, PPARalpha is an important modulator of the immune- and inflammatory response in the cardiac muscle. Key words: microarray, lipid metabolism, inflammation, immune response.
|Publication status||Published - 1 Jan 2008|