Constitutive activation of peroxisome proliferator-activated receptor-γ suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells

Peroidsome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated nuclear receptor that has an essential role in adipogenesis and glucose homeostasis. PPAR-γ is expressed in vascular tissues including endothelial cells (ECs). PPAR-γ activity can be regulated by many pathophysiological and pharmacological agonists. However, the role of PPAR-γ activation in ECs remains unclear. In this study, we examined the effect of the constitutive activation of PPAR-γ on the phenotypic modulation of ECs. Adenovirus-mediated expression of a constitutively active mutant of PPAR-γ resulted in significant ligand-independent activation of PPAR-γ and specific induction of the PPAR-γ target genes. However, PPAR-γ activation significantly suppressed the expression of vascular adhesion molecules in ECs and the ensuing leukocyte recruitment. Furthermore, constitutive activation of PPAR-γ resulted in simultaneous repression of AP-1 and NF-κB activity, which suggests that PPAR-γ may reduce pro-inflammatory phenotypes via, at least in part, suppression of the AP-1 and NF-κB pathways. Therefore, using a gain-of-function approach, our study provides novel evidence showing that constitutive activation of PPAR-γ is sufficient to prevent ECs from converting into a pro-inflammatory phenotype. These results also suggest that, in addition to pharmacological agonists, the genetic modification of the PPAR-γ activity in ECs may be a potential approach for therapeutic intervention in various inflammatory disorders.