Endothelin-1 in Congenital Heart Disease

Abstract

Endothelin-1 (ET-1) is a 21-amino acid polypeptide produced primarily by vascular endothelial cells. First discovered in 1988 as a potent vasoconstrictor, it has subsequently been appreciated to participate in several biologic activities, including vascular smooth muscle proliferation, fibrosis, cardiac and vascular hypertrophy, and inflammation. Increasing data demonstrate alterations in ET-1 signaling in newborns, infants, and children with congenital heart defects that are associated with alterations in pulmonary blood flow. This review outlines the pathophysiologic role of the ET-1 cascade in the development of altered pulmonary vascular tone and reactivity that occurs with congenital heart disease and its repair, following the use of cardiopulmonary bypass. In addition, therapeutic implications for the use of novel ET receptor antagonists will be emphasized. Abbreviations CPB, cardiopulmonary bypass CHD, congenital heart defect ET-1, endothelin 1, PVR, pulmonary vascular resistance ET-1 was originally isolated in 1988 as a 21-amino acid polypeptide produced by pulmonary and systemic vascular endothelial cells, and was described as the most potent endogenous vasoconstrictor discovered to date (1). Subsequently it has been appreciated that ET-1 may be produced by a variety of cell types, and has numerous biologic properties within the cardiovascular, respiratory, renal, endocrine, gastrointestinal, and neurologic systems. These biologic properties include the regulation of vasomotor tone, vascular smooth muscle proliferation, fibrosis, cardiac and vascular hypertrophy, and inflammation (Fig. 1). In addition, alterations in the ET-1 cascade have been implicated in the pathophysiology of a variety of disease states, including congestive heart failure, bronchoconstriction, fibrotic disorders, and pulmonary hypertension (2-5). Increasing data demonstrate alterations in ET-1 signaling in newborns, infants, and children with congenital heart defects (CHD) that are associated with alterations in pulmonary blood flow (6 -10). This review outlines the pathophysiologic role of the ET-1 cascade in the development of altered pulmonary vascular tone and reactivity that occurs with congenital heart disease and its repair, following the use of cardiopulmonary bypass (CPB). In addition, therapeutic implications for the use of novel ET receptor antagonists will be emphasized. THE ENDOTHELIN CASCADEThe gene for human ET-1 is located on chromosome 6 and is translated to a 203-amino acid peptide precursor (preproET-1), which is then cleaved to form proendothelin-1. Proendothelin, big ET-1, is then cleaved by a membrane-bound metalloprotein converting enzyme (Endothelin Converting Enzyme-1, ECE-1) into its functional form (2,3,5,11). The biologic effects of ET-1 are mediated by at least two distinctive receptor populations, ET A and ET B , the densities of which are different depending on age, species, pathologic state, and vascular bed studied. The ET A receptors are located on vascular smooth muscle cells and mediate vasoconstr...

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

“…It is well known that stimulation of myocytes with hormones that activate IP 3 production, e.g. ET-1, can promote hypertrophy [150][151][152][153][154]. What is not fully understood, however, is how such hormones can affect subtle changes in Ca 2+ -dependent gene transcription inside cells that experience periodic surges of Ca 2+ during excitation-contraction coupling [155].…”

The acute effect of high intensity aerobic training on ANP and Endothelin-1 in obese women

“…It is shown in the surveys that Endothelin induce an increase of the ANP releasing [11], and inhibition of its receptors result in decrease of ANP responding in hypoxia condition [4]. Endothelin-1 that discovered in 1985 and is vasoconstrictor that releasing from the endothelium and its main synthesis, place is endothelial cells [12]. Types of endothelin consist of ET-1, ET-2, and ET-3 and was suggested that the order of secretagogue effect of ET family on ANP secretion was ET-1 ≥ ET-2 >> ET-3 > s6C [13].…”

“…Types of endothelin consist of ET-1, ET-2, and ET-3 and was suggested that the order of secretagogue effect of ET family on ANP secretion was ET-1 ≥ ET-2 >> ET-3 > s6C [13]. All of them contain 21 amino acids, and have difference in just some amino acids that among them endothelin-1 has a higher concentration compare to others [12].…”

Activation of Endothelin-1 Receptor Signaling Pathways Is Associated With Neointima Formation, Neoangiogenesis and Irreversible Pulmonary Artery Hypertension in Patients With Congenital Heart Disease

“…1,5, 6 It is mainly released from the basal surface of the endothelium and is partially synthesized in and released from smooth muscle cells (SMC). It acts on vascular SMC in a paracrine and autocrine fashion controlling basal vascular tone.…”