The PPARβ/δ agonist GW0742 modulates signaling pathways associated with cardiac myocyte growth via a non-genomic redox mechanism
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and appear to have beneficial effects in the cardiovascular system. PPARβ/δ has been shown previously to exert an inhibitory effect on cardiac myocyte hypertrophy in vivo and in vitro although the exact mechanism is not fully clear yet. The principal signaling pathways that have been involved in triggering cardiac hypertrophic response are mitogen-activated protein kinases (MAPKs) and PI3K/Akt cascades. In this study, we sought to evaluate the potential effects evoked by PPARβ/δ activation on signaling pathways that are implicated in cardiac myocyte growth responses. The selective PPARβ/δ agonist GW0742 attenuated ERK1/2 and Akt phosphorylation that was stimulated by growth promoting agonists (phenylephrine, insulin or IGF-1). This effect was not reversed by the specific PPARβ/δ antagonist, GSK0660, but was inhibited by vanadate, a potent protein tyrosine phosphatase inhibitor. In addition, GW0742 prevented the oxidation and inactivation of PTEN supporting further the notion that its inhibitory action on the agonist-induced kinase phosphorylation is mediated by the modulation of phosphatase activity. Furthermore, GW0742 abolished the agonist-induced intracellular generation of reactive oxygen species, independently of PPARβ/δ activation. Our data reveals a new non-genomic mechanism of GW0742, which ameliorates the generation of reactive oxygen species and attenuates ERK1/2 and PI3K/Akt signaling, with implications in the regulation of cardiac hypertrophic response.
KeywordsCardiac hypertrophy PI3K/Akt ERK1/2 PTEN Protein tyrosine phosphatases Superoxide dismutase Reactive oxygen species
This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund.
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