Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going

Abstract

Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.

Cryo-EM structure of the endothelin-1-ETB-Gicomplex

“…ET-1 transmits signals through two receptor subtypes, the ET A and ET B receptors, which belong to the class A G-protein-coupled receptors (GPCRs) 4,5 . ET-1 has a strong vasoconstrictor effect through the activation of ET A , while ET B activation has different functions 3,6,7 . The ET B receptor couples to both of G i and G q 8 .and is reported to be a promiscuous GPCR, which can activate all G-protein subtypes 9 .…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…At the meantime, Ang II causes CMs hypertrophy, CFs hyperplasia ( Leancă et al, 2022 ), and the secretion of molecular mediators (e.g., norepinephrine and endothelin) to promote cardiac remodeling ( Williams, 2001 ; Gajarsa and Kloner, 2011 ). For example, endothelin 1 (ET-1), a potent vasoconstrictor peptide, promotes inflammatory and CMs hypertrophy to cause adverse remodeling ( Zhang et al, 2019a ; Haryono et al, 2022 ). Interestingly, alamandine, a substance with only one amino acid residue difference from Ang II, alleviates cardiac dysfunction and fibrosis via inhibiting oxidative stress in vivo and vitro models ( Zhao et al, 2022a ).…”

Novel Dual Endothelin Inhibitors in the Management of Resistant Hypertension

“…However, the central role of ET B receptors on endothelial cells is in the clearance of circulating ET-1. The effect of ET-1 is determined by the distribution of its receptors on different vessels [ 36 ].…”