ERR alpha Attenuates Vascular Inflammation via Enhanced NF kappa B Degradation Pathway

We have previously reported that beta-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-1 beta (PGC-1 beta). Although BAIBA also increased the expression of estrogen-related receptor alpha (ERR alpha), the roles of ERR alpha in vascular endothelial cells have yet to be fully elucidated. Here, we found that human aortic endothelial cells (HAECs) infected with ERR alpha-expressing adenovirus had significantly decreased mRNA levels of tumor necrosis factor alpha-stimulated proinflammatory molecules. However, ERR alpha overexpression had little effect on the mRNA levels of PGC-1 beta, peroxisome proliferator-activated receptors, and almost all ROS scavenging molecules, except for superoxide dismutase 2. ERR alpha expression significantly decreased NF kappa B reporter activities in a dose-dependent manner with unaltered I kappa B alpha 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 NF kappa B. Also, PDLIM2 and COMMD1 mRNA levels were upregulated in BAIBA-treated HAECs. Finally, we identified the ERR alpha-response element in the COMMD1 promoter region (-283 to -29 bp). These results indicated that ERR alpha exerted anti-inflammatory effects in vascular endothelial cells through COMMD1-mediated attenuation of NF kappa B activity, which could be an atheroprotective mechanism of physical exercise.