ERRα attenuates vascular inflammation via enhanced NFκB degradation pathway.

We have previously reported that β-aminoisobutyric acid (BAIBA), a muscle-derived exercise mimetic, had anti-inflammatory and reactive oxygen species (ROS) scavenging effects in vascular endothelial cells through the enhanced expression of peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β). Although BAIBA also increased the expression of estrogen-related receptor α (ERRα), the roles of ERRα in vascular endothelial cells have yet to be fully elucidated. Here, we found that human aortic endothelial cells (HAEC)-infected with ERRα-expressing adenovirus had significantly decreased mRNA levels of TNFα-stimulated pro-inflammatory molecules. However, ERRα overexpression had little effects on the mRNA levels of PGC-1β, peroxisome proliferator-activated receptors (PPAR), and almost all ROS scavenging molecules, except for superoxide dismutase 2 (SOD2). ERRα expression significantly decreased NFκB reporter activities in a dose-dependent manner with unaltered IκBα phosphorylation levels but with a significant increase in the mRNA levels of PDZ and LIM domain protein 2 (PDLIM2) and copper metabolism gene MURR1 domain-containing protein (COMMD1), which enhance the ubiquitination and degradation of NFκB. Also, PDLIM2 and COMMD1 mRNA levels were upregulated in BAIBA-treated HAEC. Finally, we identified the ERRα-response element in the COMMD1 promoter region (-283 to -29 bp). These results indicated that ERRα exerted anti-inflammatory effects in vascular endothelial cells through COMMD1-mediated attenuation of NFκB activity, which could be one of the atheroprotective mechanisms of physical exercise.