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Endothelins as cardiovascular peptides
1Department of Medicine and Pharmacology, University of California, Irvine, USA.
Insights
Endothelin-1 (ET-1) is a potent vasoconstrictor involved in vascular diseases like hypertension and arteriosclerosis. Understanding ET-1
Area of Science:
- Vascular Biology and Medicine
- Endocrinology
- Cardiovascular Physiology
Background:
- Vasoactive substances modulate vascular health, influencing hypertension and arteriosclerosis.
- Three endothelins (ETs) identified; ET-1 is the most potent vasoconstrictor.
- ET-1 has a short plasma half-life, enabling rapid blood pressure regulation.
Purpose of the Study:
- To elucidate the role of endothelin-1 (ET-1) in normal and pathological vascular functions.
- To explore ET-1's involvement in conditions like hypertension, arteriosclerosis, and diabetes.
- To investigate potential therapeutic strategies targeting ET-1 pathways.
Main Methods:
- Characterization of ET-1 production and receptor binding.
- Analysis of ET-1's postreceptor signaling pathways, including MAPK cascade.
- Investigation of factors stimulating or inhibiting ET-1 secretion (e.g., prostaglandins, hypoxia, insulin).
Main Results:
- ET-1 is produced by various cell types and acts as a potent vasoconstrictor.
- ET-1 signaling involves the mitogen-activated protein kinase cascade, contributing to cell growth.
- ET-1 secretion is influenced by diverse stimuli and plays a role in nitric oxide and hormone regulation.
Conclusions:
- ET-1 significantly impacts vascular resistance, blood pressure, and hormonal balance.
- ET-1 is implicated in accelerated vascular disease in diabetes, asthma, pulmonary hypertension, and kidney disease.
- Further understanding of ET-1 functions may lead to novel therapies for vascular disorders.
Abstract:
The normal functional state of the vasculature and the events leading to the development of significant arterial disease involve the interaction of important vasoactive substances, which play important modulating or initiating roles in the development of hypertension and arteriosclerosis. Three endothelins have now been identified, of which ET-1 is the best characterized. ET-1 is produced by epithelial, mesangial, neuronal and glial, and liver cells, and is the most potent vasoconstrictor yet found. Each endothelin is derived from a different gene on separate chromosomes, and each binds to at least 2 types of receptor. The plasma half-life of ET-1 is about 7 min, and this provides a rapid mechanism for adjusting vascular resistance or blood pressure. The actions of endothelin are mediated through several pathways of postreceptor signaling, including activation of the mitogen-activated protein kinase cascade, which give rise to its growth-stimulating properties. Secretion of ET-1 from cultured endothelial cells is stimulated by a wide range of substances, and is inhibited by some prostaglandins. Endothelin in turn stimulates secretion of nitric oxide, arginine vasopressin and atrial natriuretic peptide, and participates in the hormonal control of salt and water balance. Hypoxia and ischemia augment ET-1 secretion, as does insulin, and this could play a role in the accelerated vascular disease of diabetes. ET-1 also causes bronchoconstriction and has been implicated in the development of acute asthma, primary pulmonary hypertension and pulmonary fibrosis. Its role in hypertension is still debatable, though most of the manifestations of congestive heart failure can theoretically be explained by the actions of ET-1. Endothelin also has extensive renovascular and parenchymal effects in the kidney. It is hoped that a fuller understanding of the role of endothelins in normal or pathologic vasculature will lead to effective therapy based on antagonism or augmentation of specific functions.