preproendothelin

Preproendothelin-1 is the initial translation product of the EDN1 gene and serves as the precursor to endothelin-1, a potent vasoconstrictor peptide produced by endothelial cells. As its name implies, it contains an N-terminal signal peptide that directs the polypeptide into the secretory pathway, where the signal sequence is removed.

After signal peptide cleavage, preproendothelin-1 is converted to proendothelin-1 (proET-1), an inactive intermediate. Proteolytic processing by furin-like convertases then produces big endothelin-1 (big ET-1), another precursor that circulates in the bloodstream. Endothelin-converting enzymes (ECE-1 and ECE-2) cleave big ET-1 to yield active endothelin-1 (ET-1), a 21-amino-acid peptide that exerts its biological effects.

ET-1 acts through two receptor subtypes, ET_A and ET_B. ET_A receptors, primarily on vascular smooth muscle, mediate vasoconstriction and proliferative responses. ET_B receptors are found on endothelial cells, where their activation can stimulate nitric oxide and prostacyclin release leading to vasodilation, while ET_B located on other cells can contribute to vasoconstriction and ET-1 clearance. The net vascular effect of ET-1 depends on the balance of receptor activation in a given tissue.

Regulation of EDN1 expression and preproendothelin-1 processing is influenced by factors such as shear stress, hypoxia, angiotensin II, and inflammatory mediators. Dysregulation of endothelin signaling is associated with cardiovascular and renal diseases, including pulmonary arterial hypertension and systemic hypertension. Therapeutic strategies commonly target downstream components, such as endothelin receptors or endothelin-converting enzymes, to modulate ET-1 activity.