HO-1, a new target of PPARδ with ‘anti-atherogenic’ properties: is it the one?

Extract

While synthetic peroxisome proliferator-activated receptor PPARα (fibrates) and PPARγ (thiazolinediones) agonists are used clinically in the treatment of hyperlipidaemia and diabetes, respectively, the function of PPARδ has not clearly been defined, although fatty acids and prostacyclin have been proposed to be endogenous PPARδ ligands.¹ PPARs can exert positive and negative regulatory control over a range of genes involved in metabolism and inflammation,^2–5 and thus their impact on cardiovascular physiology and pathophysiology is potentially enormous. Using synthetic PPARα and PPARγ ligands, Kronke et al.⁵ were the first to demonstrate in vitro that the anti-proliferative and anti-inflammatory properties of PPARs could be related to the up-regulation of one of the PPAR target genes, the haem oxygenase-1 (HO-1), an inducible stress-response protein known for its cytoprotective functions.^6,7

In the current issue, Ali et al.⁸ use an in vivo approach with the ‘en face’ measurement of aortic HO-1 expression from PPARδ ligand-treated mice to extend this concept by demonstrating that HO-1 is also up-regulated by PPARδ ligands. In addition, the authors demonstrate the essential role of the co-activator PGC1α⁹ in PPARδ-induced HO-1 cytoprotective properties in human endothelial cells (HUVEC) exposed to an exogenous oxidative stress. The extrapolation from the in vitro anti-oxidative and anti-apoptotic functions of PGC1α-PPARδ-HO-1 in HUVEC exposed to mild H₂O₂ or leptin concentrations to anti-atherosclerotic properties of this pathway, however, may be premature. This study needs to be confirmed in animal models of atherosclerosis: in an endogenous pro-oxidative and pro-inflammatory context, are PPARδ ligands and HO-1 induction still effective in counterbalancing the vascular detrimental effects of atherosclerosis? The animal studies suggest that PPARδ exerts beneficial actions in different models of atherosclerosis and metabolic syndromes,^1,10 but the link with HO-1 remains to be elucidated.