Endothelial Dysfunction in Dyslipidaemia: Molecular Mechanisms and Clinical Implications

Abstract

The endothelium consists of a monolayer of Endothelial Cells (ECs) which form the inner cellular lining of veins, arteries, capillaries and lymphatic vessels. ECs interact with the blood and lymph. The endothelium fulfils functions such as vasodilatation, regulation of adhesion, infiltration of leukocytes, inhibition of platelet adhesion, vessel remodeling and lipoprotein metabolism. ECs synthesize and release compounds such as Nitric Oxide (NO), metabolites of arachidonic acid, Reactive Oxygen Species (ROS) and enzymes that degrade the extracellular matrix. Endothelial dysfunction represents a phenotype prone to atherogenesis and may be used as a marker of atherosclerotic risk. Such dysfunction includes impaired synthesis and availability of NO and an imbalance in the relative contribution of endothelialderived relaxing factors and contracting factors such as endothelin-1 and angiotensin. This dysfunction appears before the earliest anatomic evidence of atherosclerosis and could be an important initial step in further development of atherosclerosis. Endothelial dysfunction was historically treated with vitamin C supplementation and L-arginine supplementation. Short term improvement of the expression of adhesion molecule and endothelial function during antioxidant therapy has been observed. Statins are used in the treatment of hyperlipidaemia, a risk factor for cardiovascular disease. Future studies should focus on identifying the mechanisms involved in the beneficial effects of statins on the endothelium. This may help develop drugs specifically aimed at endothelial dysfunction.

Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes

“…Endothelial dysfunction, a critical point in atherogenesis, is characterized by a disturbed nitric oxide (NO) metabolism and reduced bioactivity of NO ( 9 ). Such dysfunction includes impaired NO synthesis and availability and imbalances in endothelium-synthesized relaxing and contracting factors such as angiotensin (Ang) and endothelin-1 (ET-1) ( 10 ). Recently a new relationship was established between hydrogen peroxide and Ang, which demonstrates the existence of a quality control process as part of the redox homeostatic mechanisms that occur within the vascular endothelium ( 11 ).…”

“…This knowledge together with the World Health Organization (WHO) reporting 31% of global deaths are CVDrelated, of which 85% of deaths are due to heart attack and stroke (5), suggests atherosclerosis significantly impacts global mortality rates, but the full extent to which it contributes is not clear. factors such as angiotensin (Ang) and endothelin-1 (ET-1) (10). Recently a new relationship was established between hydrogen peroxide and Ang, which demonstrates the existence of a quality control process as part of the redox homeostatic mechanisms that occur within the vascular endothelium (11).…”

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

“…Increased oxidative stress at atherosclerotic site turn O 2 to ROS such as O2-which readily reacts with NO to form peroxynitrite (ONOO-) or nitrosothiols. ONOO−is a highly reactive, highly toxic, and pro-inflammatory agent that oxidizes and inactivates eNOS [74,75].…”

The Peroxisome Proliferator-Activated Receptor γ Agonist Pioglitazone Protects Vascular Endothelial Function in Hypercholesterolemic Rats by Inhibiting Myeloperoxidase

“…Vascular endothelial cells regulate vascular tone by secreting an endothelium-derived relaxing factor (EDRF, namely, NO) with a vasodilatory effect, and an endotheliumdependent vasodilatory function that is often used to reflect endothelial function [13]. Some studies have reported that hypercholesterolemia can lead to vascular endothelial dysfunction [14].…”