Cys(11)-Cys(15)-endothelin-1 (11-21)

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide composed of 21 amino acids, including two disulfide bonds formed by its cysteine residues. It plays a crucial role in the cardiovascular system and is involved in various pathophysiological conditions. ET-1 is synthesized by endothelial cells and is implicated in the regulation of vascular tone and cell proliferation. It acts through two G-protein-coupled receptors, ETA and ETB, which mediate its diverse biological effects56. The synthesis and release of ET-1 are influenced by factors such as cytokines, and its activity is tightly regulated by endothelin-converting enzymes (ECE)12. Understanding the mechanism of action and the applications of ET-1 in various fields is essential for developing therapeutic strategies for cardiovascular diseases and other conditions where ET-1 plays a significant role.

ET-1 is produced by vascular endothelial cells and is converted from its precursor, big ET-1, by ECE-1. The enzyme ECE-1 forms a disulfide-linked dimer, which is essential for the effective conversion of big ETs into ETs3. ET-1 acts through ETA and ETB receptors, which are present on vascular smooth muscle cells and endothelial cells. The activation of these receptors leads to an increase in intracellular calcium and vasoconstriction. Additionally, ET-1 can stimulate the release of relaxing factors such as nitric oxide and prostacyclin from endothelial cells6. In the context of cardiovascular diseases, ET-1 contributes to the functional and structural changes observed in conditions such as arterial and pulmonary hypertension, atherosclerosis, and heart failure2. Moreover, ET-1 can inhibit cardiac delayed rectifier K+ currents via a pertussis toxin-sensitive mechanism, indicating its role in cardiac electrophysiology4.

Cardiovascular Medicine

ET-1 is a key player in cardiovascular homeostasis and disease. It is involved in the pathogenesis of hypertension, heart failure, and atherosclerosis. The development of ET receptor antagonists has provided new therapeutic options for treating pulmonary arterial hypertension and has shown potential in renal failure and diabetic nephropathy25. Additionally, ET-1's role in microvascular dysfunction has implications for conditions such as cyclosporin A-induced vasculopathy, suggesting that targeting ET-1 could prevent endothelial dysfunction9.

Inflammatory Conditions

ET-1 is also implicated in inflammatory processes, as it can stimulate the production of proinflammatory cytokines in human periodontal ligament cells via the mitogen-activated protein kinase (MAPK) pathway7. This suggests that ET-1 may contribute to the inflammation observed in periodontitis and potentially other inflammatory diseases.

Vascular Smooth Muscle Cell Proliferation

ET-1 induces vascular smooth muscle cell (VSMC) proliferation, which is mediated by cytochrome P-450 arachidonic acid metabolites. This mechanism is relevant to the development and maintenance of hypertension and provides a target for therapeutic intervention10.

Endocrine System

The ET system, including ET-1, plays a role in the endocrine system's homeostatic and compensatory actions. It is involved in the regulation of blood pressure and has been linked to vasospasm, suggesting its importance in the circulatory system8.