Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α

Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE). A substantial proportion of patients with SLE display accelerated endothelial dysfunction, which precedes cardiovascular disease. Melatonin and its nuclear receptor retinoid-related orphan receptor alpha (ROR alpha) have been reported to have some protective effects on the development of atherosclerosis. However, the function of melatonin in SLE-induced endothelial dysfunction and the role that ROR alpha plays are still unknown. In this study, we found that ROR alpha protein expression was decreased in aortas of lupusprone mice and in human umbilical vein endothelial cells (HUVECs) cultured with medium containing sera of patients with SLE. Melatonin-treated HUVECs showed a decrease of pro-inflammatory mRNAs [interleukin-1beta (IL-1 beta), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha)] under the stimulation of SLE medium. Melatonin increased nitric oxide and antioxidant mRNAs (SOD1, GPX1, and CAT) and downregulated reactive oxygen species (ROS) level in HUVECs, which may subsequently delay endothelial senescence and promote HUVEC proliferation and repair after injury. Melatonin inhibited SLE medium-induced RAW264.7 macrophage migration. HUVECs pretreated with melatonin expressed less adhesion-related proteins (ICAM-1 and VCAM-1); as a result, these cells adhered to fewer peripheral blood monocytes. In addition, we also showed that the protective effects of melatonin on endothelial cells were largely diminished when ROR alpha was knockdown in HUVECs. In conclusion, by targeting the nuclear receptor ROR alpha, melatonin preserves normal functions of endothelium in SLE by its anti-inflammatory, antioxidant, and anti-senescence effects. ROR alpha may have the potential to become a prophylactic or therapeutic target in preventing endothelial dysfunction and atherosclerotic cardiovascular disease in patients with SLE.