Cardiovascular diseases (CVDs) including peripheral artery disease, coronary artery disease, myocardial infarction, and stroke are the most important causes of mortality worldwide . In 2016, there were approximately 17.9 million deaths due to CVDs, that is 31%, of all-cause global deaths . This annual mortality has been expected to escalate to 23.6 million by 2030 . A variety of risk factors are involved in the morbidity and mortality of CVDs including but not limited to obesity, hypertension, dyslipidemia, and diabetes . Among these, type II diabetes (T2D) is the most important one and accounts for two-thirds of all CVD-caused mortalities .
Diabetes mellitus (DM) is defined by a hyperglycemic status. The occurrence of DM is increasing considerably worldwide. An estimate of 592 million people, worldwide, is expected to have DM by 2035, as predicted by the International Diabetes Federation [6, 7]. Diabetes mellitus is a metabolic disease that is recognized as an independent predisposing factor for CVDs. It shows microvascular manifestations such as retinopathy, nephropathy, neuropathy, and macrovascular manifestations such as myocardial infarction, stroke, and coronary artery disease. The chance of macrovascular complications is two to four times higher in patients with type 2 DM (T2DM), compared to patients without T2DM .
Endothelial cell (EC) dysfunction has an important role in the pathogenesis of both diabetes and CVDs . Endothelial damage is characterized by the incapability of endothelium to modulate vascular homeostasis, the physiological balance of vasoconstriction, pro-thrombotic and pro-inflammatory effects  that promote atherosclerosis and coronary heart disease. Several studies have demonstrated that high levels of reactive oxygen species (ROS), decreased bioavailability of nitric oxide (NO), and modification of endothelial permeability are associated with hyperglycemia in endothelial damage [10, 11].
Studies of diseased human coronary arteries showed that about 60% of total vascular ROS is produced by NADPH oxidase (NOX), and NOX4 has the most important role in ROS generation in HUVECs [12, 13].
Nitric oxide is a key determinant of vascular homeostasis, and it has an antiatherogenic role . NO has two distinct pathways to regulate cardiovascular function: stimulation of PKG by activating soluble guanylate cyclase, and direct S nitrosylation of proteins . Nitric oxide is produced from its precursor, L-arginine, by endothelial nitric oxide synthase (eNOS) .
Adropin is a peptide hormone with an endogenous biologically active substance encoded by the energy homeostasis associated (ENHO) gene that was discovered in 2008 . Kidney, pancreas, liver, brain, heart, coronary artery endothelial cells, and HUVECs express adropin . Adropin levels change in response to different physiological and pathophysiological stimuli. This protein is a key modulator in the homeostasis of glucose, fatty acid, and energy. It improves insulin sensitivity, and it may be involved in the pathogenesis of T2DM . Adropin has a beneficial effect on endothelial cells and has been recognized as a novel regulator for these cells . It is a key modulator of eNOS gene expression and regulates the bioavailability of NO in coronary arteries .
Therapeutic approaches that prevent high glucose (HG) induced oxidative stress may decrease the risk of cardiovascular-diabetic complications . Anti-oxidant therapies are the new approach to defeat endothelial dysfunction by decreasing ROS generation, improving oxidative balance , and increasing the production of endothelial NO. Recently, different antioxidants have been found to activate and increase the synthesis of endothelial NO . Flavonols have a wide range of biological activities, such as vasorelaxant, antioxidant, and anti-inflammatory effects in addition to inhibiting some kinases. As a result, there is a strong positive correlation between the dietary consumption of high levels of flavonols and reduced risk of cardiovascular diseases [22, 23]. Flavonols can readily enter the cells and show their biological activities due to their small, lipid-soluble molecules .
Ellagic acid (EA) is a phenolic compound that can be found in the form of ellagitannin in fruits such as pomegranate, blackberry, strawberry, and raspberry . Several studies have demonstrated that EA can suppress oxidative stress [12, 25]. It is capable of exerting protective effects against oxidative stress in the aorta of diabetic mice . Furthermore, many studies have shown anti-inflammatory, anti-cancer, and anti-atherosclerotic properties for EA [27, 28]. In this study, we verified the potential beneficial effect of ellagic acid on HG-induced endothelial dysfunction in HUVECs. We also investigated the possible role of some key mediators in this regard.