Agonism of adiponectin Receptor Prevents 7‐ketocholesterol‐induced Endothelial Inflammation through Suppressing Endoplasmic Reticulum and Oxidative Stresses

Abstract

Endoplasmic reticulum (ER) stress is involved in endothelial inflammation and injury by various cardiovascular risk factors including oxysterols. AdipoRon is a selective small‐molecule agonist of adiponectin receptor, which has been shown to mimics many beneficial effects of adiponectin on the cardiovascular system including endothelial cells. However, the molecular mechanisms that mediate adipoRon‐induced endothelial protection are not well understood. Here, we studied whether adipoRon treatment interferes with the induction of ER stress to protect the endothelial cells from oxysterol‐induced inflammation and injury in vitro and to inhibit vascular inflammation from acute hypercholesterolemia in vivo. In cultured murine endothelial cells, adipoRon prevented 7‐ketocholesterol‐induced increases in endothelial cell death, inflammatory gene expression, monocyte adhesion, and Nlrp3 inflammasome activation. In parallel, adipoRon inhibited 7‐ketocholesterol‐induced ER stress and reactive oxygen species (ROS) production. In mice with acute hypercholesterolemia, adipoRon pre‐treatment could inhibit ROS production and ER stress in the coronary arterial wall without alterations in the plasma cholesterol concentration. Moreover, adipoRon reduced expression of ICAM1 in the coronary arterial intima and decreased numbers of CD45+ immune cells that adhere to or accumulate around the coronary arteries. Together, our results indicate that the cardiovascular protective action of adipoRon is associated with its inhibitory effects on ROS production and ER stress and consequent inflammatory responses in endothelial cells.Support or Funding InformationNational Institutes of Health (HL122769 and HL122937)