Endothelin-1

Endothelin-1 (ET-1) is a 21-amino acid peptide identified in 1988 by Masashi Yanagisawa and colleagues from the culture medium of porcine aortic endothelial cells. It is the most potent endogenous vasoconstrictor known, approximately 10 times more potent than angiotensin II on a molar basis. ET-1 is one of three endothelin isoforms (ET-1, ET-2, ET-3), with ET-1 being the predominant form produced by vascular endothelial cells and the most relevant to cardiovascular disease.

ET-1 is produced from a large precursor (preproendothelin-1) through a two-step proteolytic process. First, furin-like proteases cleave it to big endothelin-1, then endothelin-converting enzymes (ECE-1 and ECE-2) produce the mature, biologically active ET-1. The peptide acts on two receptor subtypes: ETA receptors (primarily on vascular smooth muscle cells, mediating vasoconstriction and cell proliferation) and ETB receptors (on endothelial cells, mediating vasodilation through nitric oxide release, and also involved in ET-1 clearance and sodium/water excretion in the kidney).

Under normal physiological conditions, ET-1 is produced in small amounts and contributes to basal vascular tone. However, in pathological states, ET-1 production is markedly increased, contributing to vasoconstriction, vascular remodeling, inflammation, and fibrosis. Elevated ET-1 levels are found in pulmonary arterial hypertension (PAH), systemic hypertension, heart failure, atherosclerosis, and chronic kidney disease.

The therapeutic targeting of the endothelin system has been most successful in pulmonary arterial hypertension. Endothelin receptor antagonists (ERAs) including bosentan, ambrisentan, and macitentan are FDA-approved treatments for PAH. These drugs block ET-1's vasoconstrictive and proliferative effects on pulmonary vasculature, improving exercise capacity, hemodynamics, and outcomes in PAH patients. Attempts to use ERAs for systemic hypertension and heart failure have been less successful, partly due to fluid retention effects.