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

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.

Automated summary

The incidence of cardiovascular diseases is increasing due to the aging population, which has a major influence on the vascular tree. Aging leads to changes in the morphology and function of the arterial wall, as well as remodeling of the vascular extracellular matrix. The release of elastin-derived peptides (EDPs) from elastin degradation products is a characteristic feature of aged conduit arteries. These EDPs not only affect the mechanical properties of arteries but also modulate the development and progression of various vascular and metabolic diseases. The elastin receptor complex (ERC), which contains elastin-binding protein, protective protein/cathepsin A, and neuraminidase-1 (NEU1), plays a crucial role in mediating the biological effects of these peptides. This review provides an overview of the consequences of aging on the vasculature and the release of EDPs, discusses the composition and signaling pathways of the ERC, and explores the pharmacological strategies targeting ERC activation. Additionally, it highlights the emerging regulatory functions of the ERC through desialylation of membrane glycoproteins by NEU1 and its potential implication in receptor transactivation.