PPARσ and PGC1α act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress

Abstract

AimsPeroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARσ has an established role in metabolism, wound healing, and angiogenesis. However, little is known about its function in endothelial homeostasis. We investigated the role of PPAR and its co-activator, PPARγ co-activator 1α (PGC1α), in vasculoprotection against oxidant-induced injury via induction of haem oxygenase-1.Methods and resultsEn face confocal microscopy of murine aortas demonstrated that the PPARσ-selective ligand GW501516 induced endothelial haem oxygenase-1 expression. In vitro PPARσ ligands induced a significant increase in haem oxygenase-1 mRNA, protein, and enzyme activity, resulting in enhanced human endothelial cell protection against cellular stress induced by hydrogen peroxide or leptin. Moreover, adenoviral-mediated overexpression of haem oxygenase-1 increased PPARσ promoter activity and mRNA levels, amplifying the effect of PPARσ ligands through a positive feedback loop. Mutation of PPARσ response element binding sites in the haem oxygenase-1 promoter/enhancer region revealed haem oxygenase-1 to be a direct PPARσ target gene. Inhibition of either haem oxygenase-1 or PPARσ abrogated PPARσ ligand-induced endothelial cytoprotection. Furthermore, siRNA depletion of PGC1 demonstrated that this co-regulator acts as an essential PPARσ transcriptional co-activator for haem oxygenase-1 induction by PPARσ ligands and its subsequent cytoprotective actions.ConclusionWe have identified an important relationship between PPARσ, PGC1, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARσ ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARσ represents a potentially important therapeutic target in the vasculature.