Intracellular Signaling of LOX-1 in Endothelial Cell Apoptosis

A therosclerosis in the coronary artery is a major culprit in unstable coronary syndromes and sudden cardiac death.Rupture of the cap covering the atherosclerotic plaque is thought to lead to platelet deposition and formation of an occlusive thrombus resulting in cessation of blood flow.Oxidatively modified LDL (ox-LDL) has been implicated in the pathogenesis of atherosclerosis and plaque rupture by promoting lipid accumulation, proinflammatory response, release of metalloproteinases, and apoptotic cell death.1,2 Ox-LDL leads to endothelial activation, characterized by expression of adhesion molecules, contributing to adherence and migration of inflammatory cells across the endothelial barrier.Endothelial activation is followed by endothelial dysfunction and injury characterized by loss of expression and activity of constitutive endothelial nitric oxide synthase and a state of oxidative stress.Ox-LDL, particularly in large concentrations, induces apoptosis in endothelial cells, macrophages, and smooth muscle cells.[3][4][5] Ox-LDL is taken up by monocytes/macrophages and smooth muscle cells through a variety of scavenger receptors (SRs), such as SR-AI/II, CD36, SR-BI, macrosialin/CD68, SREC, and LOX-1, and exerts its proatherogenic effects on the vessel wall.1,6,7 Several studies have demonstrated that SRs other than LOX-1 are absent or expressed in minimal amounts in endothelial cells.6 -8 LOX-1 plays a crucial role in ox-LDL-induced pathological transformation of the vessel wall components.The importance of LOX-1 became evident in studies that showed significant limitation of atherosclerotic lesion formation in the LDL receptor knockout mice with LOX-1 deletion.9 In these studies, there was clear evidence of preservation of endothelial function and reduction in oxidative stress and inflammatory response.