The importance of endothelin-1 for vascular dysfunction in cardiovascular disease

Abstract

Endothelin (ET)-1 is a potent vasoconstrictor peptide originally isolated from endothelial cells. Its production is stimulated in a variety of different cell types under the influence of risk factors for cardiovascular disease and during the development of cardiovascular disease. Based on these observations and the biological effects induced by ET-1, including profound vasoconstriction, pro-inflammatory actions, mitogenic and proliferative effects, stimulation of free radical formation and platelet activation, ET-1 has been implicated as an important factor in the development of vascular dysfunction and cardiovascular disease. In the following the pathogenic role of ET-1, the mechanisms underlying the involvement of ET-1 for the development of vascular dysfunction and the potentially beneficial therapeutic effects of selective ET A and dual ET A /ET B receptor antagonists will be discussed. In particular the changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed. These changes may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists.

Agonist-promoted Ubiquitination Differentially Regulates Receptor Trafficking of Endothelin Type A and Type B Receptors

“…The mechanisms for desensitization remain to be determined. The ET B R expression level is reported to be elevated in several pathologic conditions, such as atherosclerosis, chronic heart failure, and pulmonary hypertension (42)(43)(44)(45), and it is probable that the elevated ET B R levels play a critical role in the genesis and/or development of these pathological conditions. In this context, it is important to investigate the molecular mechanism for the elevated receptor levels, especially in terms of disturbed ubiquitination or enhanced deubiquitination in those pathological conditions.…”

The Relationship between Vascular Function and the Autonomic Nervous System

“…The effect of endothelin is powerful and long lasting, in contrast to short-lived prostacyclin and NO. 7) The target of factors that regulate vascular tone is smooth muscle cells adjacent to the endothelium. Other than regulation of vascular tone, the endothelium affects other biological functions via interactions with different cell populations, such as immune cells and blood cells.…”

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

“…[10] However, in pathological conditions such as diabetes mellitus, dysregulation of the endothelin system, characterized by enhanced expression, activity or responsiveness of different constituents contributes to dysfunction of the vascular cells. [11,12] Hyperglycemia-induced vascular deleterious effects are partially mediated by the endothelin-1 (ET-1). Increased synthesis of ET-1, the main effector of the endothelin system, induces vasoconstriction, dysfunction of endothelial cells (EC), phenotypic alteration of smooth muscle cells, vascular remodeling, inflammation and oxidative stress.…”