Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches

Abstract

Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events in the development and pathophysiology of atherosclerosis and are associated with an elevated risk of cardiovascular events. There is great interest to further understand the pathophysiologic mechanisms underlying endothelial dysfunction and atherosclerosis progression, and to identify novel biomarkers and therapeutic strategies to prevent endothelial dysfunction, atherosclerosis and to reduce the risk of developing CAD and its complications. The use of liquid biopsies and new molecular biology techniques have allowed the identification of a growing list of molecular and cellular markers of endothelial dysfunction, which have provided insight on the molecular basis of atherosclerosis and are potential biomarkers and therapeutic targets for the prevention and or treatment of atherosclerosis and CAD. This review describes recent information on normal vascular endothelium function, as well as traditional and novel potential biomarkers of endothelial dysfunction and inflammation, and pharmacological and non-pharmacological therapeutic strategies aimed to protect the endothelium or reverse endothelial damage, as a preventive treatment for CAD and related complications.

Keywords: atherosclerosis; coronary artery disease (CAD); endothelial cells (EC); endothelial dysfunction; endothelium; inflammation; novel biomarkers; therapeutics.

Figure 1

Structure of the arterial wall. Because arteries are supplying blood to tissues and are exposed to high pressure, their walls are thicker than those of other blood vessels. Arterial walls are composed of three layers: the tunica intima is the innermost layer and is made up of endothelial cells anchored to the basal lamina (connective tissue); the tunica media contains vascular smooth muscle cells and regulates vascular tone; and the tunica adventitia is the outermost and contains nerve endings, perivascular adipose tissue, and connective tissue [27,28,29].

Figure 2

Key structures for epithelium permeability. The arterial endothelium is a semipermeable barrier that prevents passage of blood cells and large molecules from circulating blood to subendothelial space. The glycocalyx and junction complexes are the main structures that help to maintain this function. The glycocalyx, covering the luminal surface of endothelium, comprises proteoglycans, glycosaminoglycans and glycoproteins. Proteoglycans are syndecanes 1, 2 and 4, glypican and perlecan; the main glycosaminoglycans are heparan sulfate, chondritin sulfate, and hyaluronic acid; glycoproteins, involve three families of adhesion molecules, selectin family, the integrin family, and the immunoglobulin superfamily, and their expression depends on the surrounding microenvironment. There are three subtypes of junction complexes connecting adjacent EC. Tight junctions are formed by claudins, junction adhesion molecules (JAM), and occludins. Tight junctions bind to zonule occludens-1 (ZO-1), allowing interaction with cytoskeleton components. Second, adherens junctions are formed by nectin, poncin, afadin, and vascular endothelial cadherin (VE-cadherin) complexes. VE-cadherin binds to filamentous actin (F-actin) via intracellular proteins such as pacoglobin, β-catenin, α-catenin, and α-actin. Third, gap junctions consist of two connexons that form an intercellular channel that physically communicates adjacent endothelial cells (EC) and allows passive diffusion of ions and small molecules [30,40].

Figure 3

Endothelial inflammation. Endothelial dysfunction is triggered by different cardiovascular risk factors such as hypertension, hyperglycemia, and hyperlipidemia. These events increased production of interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and C reactive protein (CRP). Proinflammatory cytokines bind to their receptors and culminate in the activation of the nuclear transcription factor κB (NF-κB) that stimulate the transcription of selectin-E, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). CRP down-regulates endothelial nitric oxide synthase (eNOS) transcription and destabilizes eNOS mRNA, resulting in decreased nitric oxide (NO). Furthermore, the reorganization of actin filaments allows the opening of intercellular junctions through other signaling pathways [63,64].