What is Endothelin-1 (ET-1)?

From the Guidelines

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that plays a crucial role in regulating vascular tone and blood pressure, and its dysregulation is implicated in various cardiovascular disorders, including pulmonary arterial hypertension. ET-1 is primarily produced by vascular endothelial cells and consists of 21 amino acids. It acts through two receptor subtypes, ETA and ETB, with ETA receptors mediating vasoconstriction and cell proliferation, while ETB receptors can cause both vasoconstriction and vasodilation depending on their location 1. Some key points about ET-1 include:

• ET-1 promotes inflammation, cell growth, and fibrosis in various tissues
• Dysregulation of ET-1 is implicated in several cardiovascular disorders including hypertension, heart failure, pulmonary arterial hypertension, and atherosclerosis
• ET-1 levels can be measured in plasma as a biomarker in certain clinical conditions, though such testing is primarily used in research settings rather than routine clinical practice
• The development of endothelin receptor antagonists like bosentan and ambrisentan has been led by the understanding of ET-1's role in pulmonary arterial hypertension, as evidenced by studies such as those reported in 1 and 1 The most recent and highest quality study, 1, provides further insight into the role of ET-1 and the use of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension.

From the Research

Definition of ET-1

• Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow 2
• It is a vasoconstrictor secreted by endothelial cells, which acts as the natural counterpart of the vasodilator nitric oxide (NO) 3
• ET-1 is an extremely potent vasoconstrictor peptide originally isolated from endothelial cells 4

Role of ET-1 in Vascular Tone

• ET-1 contributes to vascular tone and regulates cell proliferation through activation of ETA and ETB receptors 3
• It induces an increase in intracellular Ca(2+), mainly from the extracellular space through voltage-independent mechanisms, the receptor-operated channels and store-operated channels 4
• Arterial vasoconstriction is mediated mainly by the ETA receptor 4

Biosynthesis and Signaling of ET-1

• The synthesis of ET-1 involves processing of a precursor by a furin-type proprotein convertase to an inactive intermediate, big ET-1 4
• ET-1 signals through two G protein-coupled receptors, endothelin receptor A (ETA) and endothelin receptor B (ETB) 4
• ET-1 also induces signaling through epidermal growth factor receptor transactivation, oxidative stress induction, rho-kinase, and the activation (ETA) or inhibition (ETB) of the adenylate cyclase/cyclic adenosine monophosphate pathway 4

Pathophysiological Roles of ET-1

• ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke 2
• It may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis 2
• ET-1 has a wide range of biological actions apart from its direct effects on vascular tone, including constriction of non-vascular smooth muscle, cardiac effects, mitogenesis and stimulation of the release of hormones such as atrial natriuretic peptide and prostacyclin 5