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

Aims Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARδ 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 PPARδ and its co-activator, PPARγ co-activator 1α (PGC1α), in vasculoprotection against oxidant-induced injury via induction of haem oxygenase-1. Methods and results En face confocal microscopy of murine aortas demonstrated that the PPARδ-selective ligand GW501516 induced endothelial haem oxygenase-1 expression. In vitro PPARδ 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 PPARδ promoter activity and mRNA levels, amplifying the effect of PPARδ ligands through a positive feedback loop. Mutation of PPAR response element binding sites in the haem oxygenase-1 promoter/enhancer region revealed haem oxygenase-1 to be a direct PPARδ target gene. Inhibition of either haem oxygenase-1 or PPARδ abrogated PPARδ ligand-induced endothelial cytoprotection. Furthermore, siRNA depletion of PGC1α demonstrated that this co-regulator acts as an essential PPARδ transcriptional co-activator for haem oxygenase-1 induction by PPARδ ligands and its subsequent cytoprotective actions. Conclusion We have identified an important relationship between PPARδ, PGC1α, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARδ ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARδ represents a potentially important therapeutic target in the vasculature.