title: Inflammatory pathways are activated during cardiomyocyte hypertrophy and attenuated by peroxisome proliferator-activated receptors PPARalpha and PPARdelta.
abstract: Accumulating evidence indicates an important role for inflammation in cardiac hypertrophy and failure. Peroxisome proliferator-activated receptors (PPARs) have been reported to attenuate inflammatory signaling pathways and, as such, may interfere with cardiac remodeling. Accordingly, the objectives of the present study were to explore the relationship between cardiomyocyte hypertrophy and inflammation and to investigate whether PPARalpha and PPARdelta are able to inhibit NF-kappaB activation and, consequently, the hypertrophic growth response of neonatal rat cardiomyocytes (NCM). mRNA levels of markers of both hypertrophy and inflammation were increased following treatment with the pro-hypertrophic factor phenylephrine (PE) or the chemokine TNF-alpha. Induction of inflammatory genes was found to be fast (within 2 h after stimulation) and transient, while induction of hypertrophic marker genes was more gradual (peaking at 24-48 h). Inflammatory and hypertrophic pathways appeared to converge on NF-kappaB as both PE and TNF-alpha increased NF-kappaB binding activity as measured by electrophoretic mobility shift assay. Following transient transfection, the p65-induced transcriptional activation of a NF-kappaB reporter construct was significantly blunted after co-transfection of PPARalpha or PPARdelta in the presence of their respective ligands. Finally, adenoviral overexpression of PPARalpha and PPARdelta markedly attenuated cell enlargement and the expression of hypertrophic marker genes in PE-stimulated NCM. The collective findings reveal a close relationship between hypertrophic and inflammatory signaling pathways in the cardiomyocyte. It was shown that both PPARalpha and PPARdelta are able to mitigate cardiomyocyte hypertrophy in vitro by inhibiting NF-kappaB activation.
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Pascal J H
authors.initials: PJ
authors.lastname: Smeets
authors.forename: Birgit E J
authors.initials: BE
authors.lastname: Teunissen
authors.forename: Anna
authors.initials: A
authors.lastname: Planavila
authors.forename: Heleen
authors.initials: H
authors.lastname: de Vogel-van den Bosch
authors.forename: Peter H M
authors.initials: PH
authors.lastname: Willemsen
authors.forename: Ger J
authors.initials: GJ
authors.lastname: van der Vusse
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D047493:PPAR alpha; D047494:PPAR delta; D014409:Tumor Necrosis Factor-alpha