Aims: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARdelta 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 PPARdelta and its co-activator, PPARgamma co-activator 1alpha (PGC1alpha), 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 PPARdelta-selective ligand GW501516 induced endothelial haem oxygenase-1 expression. In vitro PPARdelta 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 PPARdelta promoter activity and mRNA levels, amplifying the effect of PPARdelta 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 PPARdelta target gene. Inhibition of either haem oxygenase-1 or PPARdelta abrogated PPARdelta ligand-induced endothelial cytoprotection. Furthermore, siRNA depletion of PGC1alpha demonstrated that this co-regulator acts as an essential PPARdelta transcriptional co-activator for haem oxygenase-1 induction by PPARdelta ligands and its subsequent cytoprotective actions.
Conclusion: We have identified an important relationship between PPARdelta, PGC1alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARdelta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARdelta represents a potentially important therapeutic target in the vasculature.