Endothelins and Related Peptides

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Introduction

Endothelin is a vasoactive peptide secreted by endothelial cells. There are three types of endothelin in the human body: ET-1, ET-2, and ET-3, and their biological activities are different. It is mainly caused by autocrine or paracrine release of endothelial cells, which is of great significance for the stability of cardiovascular hemodynamics. Endothelin binds to its receptor and exerts its corresponding biological activity. Three endothelin receptors have been identified: ETA, ETB, and ETC. Endothelin is closely related to hypertension. The level of endothelin in plasma is higher than that in healthy people, and its level is positively correlated with the severity of hypertension. Endothelin is the strongest endogenous vasoconstrictor peptide ever discovered.

Mechanism of action

In humans, the receptors for endothelin are mainly ETA and ETB, all of which are G protein-coupled receptors. Endothelin, by binding to the corresponding receptor, stimulates its chemical activity and thus manifests its function in the human body. ETA is mainly expressed in muscle cells and binds to ET-1 and ET-2. ETB is mainly expressed in endothelial cells, endocrine cells, and nerve cells and can be combined with ET-1, 2, and 3. ETA activation promotes vascular smooth muscle contraction and proliferation, and ETB-1 promotes the release of vasodilating substances such as nitric oxide (NO). The relationship between blood pressure and elevated endothelin is a causal relationship: plasma ET-1 may be directly or indirectly involved in the development and progression of hypertension; elevated blood pressure and blood pressure variability are important risk factors for elevated plasma ET-1 levels.

Application of Endothelins and Related Peptides

ETA receptor antagonists can alleviate vascular inflammation, reduce vascular smooth muscle cell differentiation, calcification and sclerosing, suggesting that endothelin receptor antagonists will be a promising new drug that is expected to play a special role in the treatment of hypertension. In addition, endothelin receptor antagonists can play a good role in reducing mortality in patients with heart failure. The expression of vasoactive substances released by endothelial cells has been shown to be closely related to pulmonary hypertension (PAH), and endothelin-1 (ET-1) is particularly effective for pulmonary hypertension. Most endothelin receptor antagonists on the market are currently designed and developed around ETA, for example, Bosentan, macitentan, ambrisentan, and sitaxsentan.

References

1. Davenport, A. P., Kuc, R. E., Southan, C., & Maguire, J. J. (2018). New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiological Research, 67(Supplementum 1), S37.
2. Mcmahon, T. J. , & Bryan, N. S. . (2017). Biomarkers in pulmonary vascular disease: gauging response to therapy. The American Journal of Cardiology, 120(8), S89-S95.