Constitutive Activation of Peroxisome Proliferator-activated Receptor-γ Suppresses Pro-inflammatory Adhesion Molecules in Human Vascular Endothelial Cells

Abstract

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

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

“…We therefore evaluated whether PPARg insufficiency promotes thyroid carcinogenesis in TRb PV/PV PPARg þ /À mice via the activation of the NF-kB signaling pathway. Consistent with the findings by others (Setoguchi et al, 2001;Wang et al, 2002;Fan et al, 2005), PPARg insufficiency owing to the lack of one PPARg allele resulted in the significantly increased protein abundance of NF-kB in the thyroid of TRb PV/PV PPARg þ /À mice (lanes 10-12 versus lanes 7-9 and lanes 1-3; Figure 5a). The functional consequence of the increased expression of NF-kB at the protein level is evident by the significantly increased cyclin D1 protein levels (lanes 10-12 versus 7-9 and 1-3; Figure 5b).…”

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

“…This is consistent with evidence from other laboratories showing that PPARs can inhibit NF-B signaling by protein-protein interactions. [38][39][40][41] The current findings strongly suggest that PPAR␤/␦ can modulate NF-B signaling and by doing so, attenuate chemically induced liver toxicity. Because this was not examined in response to AOM or other chemicals, whether this occurs in response to all hepatotoxicants remains to be determined.…”

Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation

“…This notion was further bolstered by the observation of reduced NFkB activity (and suppressed adhesion molecule expression) in cells that were engineered to express a constitutively active form of PPARg. 20 Potential connections between PPAR activation, anti-inflammatory activity, and insulin sensitization Insulin resistance, obesity, and type II diabetes (ie 'metabolic syndrome') are known to be associated with a proinflammatory state and a high risk of accelerated atherosclerosis. Markers of inflammation that are increased in these disease states include acute-phase reactants (fibrinogen, C-reactive protein, a1 acid glycoprotein, and serum amyloid A3) and cytokines such as IL-6 and TNFa.…”