Previous studies on atherosclerosis have provided some information on this topic. For example, increased expression of proteins such as VCAM-1, ICAM-1, E-selectin, CD40, lectin-like oxidized LDL receptor-1, production of matrix metalloproteinases and reactive oxygen species, and decreased secretion levels of NO contribute to both initiation and progression of atherosclerosis. Estrogen has protective effects against cardiovascular diseases, and its receptors ER a and ER b have been shown to mediate anti-atherogenic effects. Recently, a third membrane-bound ER has emerged, G protein-coupled estrogen receptor-1, that has beneficial effects on the cardiovascular system. GPER-1 is a seven transmembrane-domain G protein-coupled receptor that binds to 17b-estradiol with high affinity and mediates estrogenic signals. GPER-1 is widely expressed in human tissues, including the cardiovascular system. It was recently found that selective activation of GPER-1 potently inhibits the growth of human vascular smooth muscle cells. To find the role of GPER-1 on endothelial protection, G1 and G15 have been evaluated. These pharmacological agents are currently used most frequently as tools for investigating the role of GPER-1 in various systems. In this study, both agents were used to modulate GPER-1 in vitro and in vivo to investigate the protective role Oligomycin A protocatechuic aldehyde has in endothelial dysfunction through GPER-1. Protocatechuic aldehyde is a phenolic aldehyde found in the aqueous extract of Salvia Miltiorrhiza that has recently been reported for its anti-oxidative effects. It was recently reported that PCA reduces myocardial infarct size and the activities of creatine kinase-MB and cardiac troponin in serum. Also, it can inhibit migration and proliferation of vascular smooth muscle cells and intravascular thrombosis. However, the underlying mechanism of PCA on reducing inflammation and its effects on endothelial dysfunction remains to be determined. In this study, we investigated the protective effect of PCA on endothelial cells and injured vessels in vivo in association with GPER-1. PCA has exhibited various therapeutic effects in different cell types such as vascular smooth muscle cells, cancer cells, and a cardiac animal model. However, PCA has not been evaluated for its effect against endothelial dysfunction and has rarely been studied in HUVECs. Unlike PCA, GPER-1 has been consistently reported for its role in attenuating atherosclerosis because it regulates the activity of many vasoconstrictors and proliferation of vascular smooth muscle cells. Thus, it is becoming increasingly difficult to ignore the importance of endothelial cells and GPER-1 in developing therapeutic agents against endothelial dysfunction and atherosclerosis. The activation of GPER-1 by PCA protects endothelial cells in various ways from inflammation in vitro. One of them is the inhibition of ROS production, which is closely related to NF-kB. The reduction of ROS by PCA and GPER-1 agonist has shed light on the relationship between GPER-1 and NF-kB. Previous studies have pointed out the beneficial effects of GPER-1 on atherosclerosis, but they have failed to find connections with NFkB.