The Elastin Receptor Complex: An Emerging Therapeutic Target Against Age-Related Vascular Diseases.

Dignê Tembely,Laetitia Vanalderwiert,Laurent Martiny,Stéphane Jaisson,Pascal Maurice,Hervé Sartelet,Céline Galés,Sébastien Blaise,Laurent Duca,Kevin Toussaint,Aubéri Henry,Amar Bennasroune,Béatrice Romier-Crouzet

doi:10.3389/fendo.2022.815356

Abstract

The incidence of cardiovascular diseases is increasing worldwide with the growing aging of the population. Biological aging has major influence on the vascular tree and is associated with critical changes in the morphology and function of the arterial wall together with an extensive remodeling of the vascular extracellular matrix. Elastic fibers fragmentation and release of elastin degradation products, also known as elastin-derived peptides (EDPs), are typical hallmarks of aged conduit arteries. Along with the direct consequences of elastin fragmentation on the mechanical properties of arteries, the release of EDPs has been shown to modulate the development and/or progression of diverse vascular and metabolic diseases including atherosclerosis, thrombosis, type 2 diabetes and nonalcoholic steatohepatitis. Most of the biological effects mediated by these bioactive peptides are due to a peculiar membrane receptor called elastin receptor complex (ERC). This heterotrimeric receptor contains a peripheral protein called elastin-binding protein, the protective protein/cathepsin A, and a transmembrane sialidase, the neuraminidase-1 (NEU1). In this review, after an introductive part on the consequences of aging on the vasculature and the release of EDPs, we describe the composition of the ERC, the signaling pathways triggered by this receptor, and the current pharmacological strategies targeting ERC activation. Finally, we present and discuss new regulatory functions that have emerged over the last few years for the ERC through desialylation of membrane glycoproteins by NEU1, and its potential implication in receptor transactivation.

Highlights

Over the last century, progress in living conditions, public health and medicine have led to a drastic increase in life expectancy worldwide
Interesting findings from the last decade came from the group of Szewczuk that describes a novel organizational signaling platform wherein NEU1 is placed at the center of tripartite molecular complexes involving G-protein coupled receptors (GPCRs), the matrix metalloproteinase 9 (MMP-9) and receptor tyrosine kinases (RTKs) or Toll-like receptors (TLRs) [43, 101,102,103,104,105], opening new roles for NEU1, and potentially for the elastin receptor complex (ERC), in receptor crosstalk and transactivation
Elastic fibers fragmentation and release of elastin-derived peptides (EDPs) have emerged as major contributors of vascular extracellular matrix (ECM) remodeling and associated diseases occurring with aging

Summary

Introduction

Progress in living conditions, public health and medicine have led to a drastic increase in life expectancy worldwide. In addition to its involvement in sialic acid generation, and as described below, NEU1 plays a pivotal role in ERC-mediated signaling pathways and biological effects through desialylation of membrane glycoproteins.

Results

Conclusion