The PPARβ/δ agonist GW0742 modulates signaling pathways associated with cardiac myocyte growth via a non-genomic redox mechanism

Abstract

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.

Regulatory mechanisms mediated by peroxisome proliferator‐activated receptor‐β/δ in skin cancer

“…Moreover, bioinformatic analyses of microarray and chromatin immunoprecipitation sequencing (ChIP‐seq) data revealed that ligand activation of PPARβ/δ with GW0742 did not cause changes in PTEN/ILK1/PDPK1 expression or promoter occupancy of PPARβ/δ on any of these genes in primary keratinocytes after ligand activation of PPARβ/δ as suggested by a previous study . These studies are also consistent with other experiments showing that ligand activation of PPARβ/δ with GW0742 or GW501516 in other cell types may actually increase PTEN expression and inhibit phosphorylation of AKT1 . Combined, the evidence that ligand activation of PPARβ/δ inhibits apoptosis in keratinocytes via modulation of PTEN/ILK1/PDPK1/AKT1 is inconsistent with many other studies, including those that have shown there is a unique form of programmed cell death associated with keratinocyte differentiation that differs substantially from apoptosis …”

Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview

“…They dimerize with retinoid X receptor (RXR) and bind to PPAR-responsive DNA regulatory elements controlling the expression of genes involved in adipogenesis, glucose, lipid, and cholesterol metabolism ( 9 , 10 ). Similarly to the membrane Estrogen receptorα (ERα), recently it has been demonstrated that PPARs can activate a non-genomic, rapid signaling pathway ( 11 , 12 ), but while several studies so far described the activation of the ER non-genomic, rapid pathway in response to potential EDCs ( 13 – 16 ), information regarding ability of pollutants to activate the PPAR-non genomic signaling is still lacking.…”

Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

“…PPARb/d agonists have been shown to hold therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases through activation of PI3K/Akt pathway [146], whereas they also inhibit platelet aggregation and activation [147] via unidentified nongenomic mechanisms. A recent study provided the first evidence that the PPARb/d agonist GW0742 inhibits the phosphorylation of growth-related protein kinases in cardiac myocytes by modulating the activity of phosphatases through a nongenomic, PPARb/d-independent, redox mechanism [148].…”