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Inflammatory Pathways Are Activated during Cardiomyocyte Hypertrophy and Attenuated by Peroxisome Proliferator-activated Receptors PPARα and PPARδ*S⃞

By Pascal J. H. Smeets, Birgit E. J. Teunissen, Anna Planavila, Heleen de Vogel-van den Bosch, Peter H. M. Willemsen, Ger J. van der Vusse and Marc van Bilsen

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 PPARα and PPARδ are able to inhibit NF-κB 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-α. 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-κB as both PE and TNF-α increased NF-κB binding activity as measured by electrophoretic mobility shift assay. Following transient transfection, the p65-induced transcriptional activation of a NF-κB reporter construct was significantly blunted after co-transfection of PPARα or PPARδ in the presence of their respective ligands. Finally, adenoviral overexpression of PPARα and PPARδ 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 PPARα and PPARδ are able to mitigate cardiomyocyte hypertrophy in vitro by inhibiting NF-κB activation

Topics: Mechanisms of Signal Transduction
Publisher: American Society for Biochemistry and Molecular Biology
OAI identifier: oai:pubmedcentral.nih.gov:2662011
Provided by: PubMed Central
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