**6. Possible role of endothelin in endothelial dysfunction**

It is generally accepted that generation of reactive oxygen species (ROS) and an increased level of oxidative low-density lipoprotein (oxLDL) induces endothelial dysfunction. The receptor for oxidative low-density lipoprotein (oxLDL) is the lectin-like oxidized LDL receptor (LOX-1) found on endothelial cells (**Figure 2**). Under normal conditions, LOX-1 is expressed at a low level on endothelial cells, but it is induced by pro-inflammatory cytokines and under proatherogenic conditions such as hypertension, diabetes, and hyperlipidemia [6]. Angiotensin II and homocysteine that induce oxidative stress also induce LOX-1 expression. Also, LDL is oxidized by oxidative stress, leading to generation of ox-LDL. Binding of oxLDL to its receptor LOX-1 reduces NO production from endothelial cells via generation of reactive oxygen. It also induces the production of superoxide anion and activation of redox-sensitive transcription factor NFkB [48], which in turn upregulates ET-1 as well as adhesive molecules and chemokines promoting endothelial dysfunction**.**

#### **Figure 2.**

*The role of endothelin in endothelial dysfunction: In a healthy cell (left), the protective role of nitric oxide (NO) signaling pathway predominates. The formation of NO from L-arginine is catalyzed by endothelial NO synthase (eNOS). NO is released from endothelial cells and acts on smooth muscle cells to exert vasodilator and proliferative effects. In a dysfunctional endothelial cell (right), the vascular homeostasis is disrupted via the engagement of endothelial LOX-1 with oxidized LDL (OxLDL) resulting in downregulation of NO and upregulation of NFkB and the endothelin (ET)-1 signaling pathway. ET-1 is released from endothelial cells and acts on smooth muscle cells through the interaction of two types of receptors (ET-1 receptor type A [ETR-A] and ET-1 receptor type B [ETR-B]), both of which mediate vasoconstriction and proliferation. Figure created using Servier Medical Art.*
