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

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.

The Matrix Reloaded—The Role of the Extracellular Matrix in Cancer

“…Aberrant expression of elastases and degradation of elastin trigger the release of elastokines (fragments of matrix proteins with cytokine-like properties) that promote angiogenesis and regulate cell adhesion, chemotaxis, migration, and proliferation. Much of the elastokine effects are mediated by membrane elastin receptor complexes [ 23 ] that trigger signalling pathways involving the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and serine/threonine-protein kinase (AKT) activation [ 25 ]. Elastases belong to the enzyme classes of MMP, aspartic proteases, serine proteases, and cysteine proteases.…”

Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond

“…Further, cardiomyocyte-specific NEU1 overexpression in vivo was associated with cardiac hypertrophy, but no changes in cardiac inflammation, following I/R injury compared with wild type littermates. Binding of pro-atherogenic elastin-derived peptides (EDP) to the elastin receptor complex (ERC), a heterotrimeric association of NEU1, PPCA, and the elastin binding protein, a splice variant of β-galactosidase ( 312 ), led to NEU1-mediated desialylation of the CD36 scavenger receptor and augmented uptake of oxidized LDL by human macrophages in vitro ( 22 ). In a subsequent report, EDP binding to the ERC also promoted NEU1-β2-integrin association and NEU1-driven β2-integrin desialylation in human monocytes, as well as NEU1-ICAM-1 association and NEU1-mediated ICAM-1 desialylation in human umbilical vein endothelial cells ( 23 ).…”

NEU1—A Unique Therapeutic Target for Alzheimer’s Disease

“…Another mechanism that potentially links NEU1 to AD is via G protein-coupled receptor (GPCR) kinases (GRKs) ( Tembely et al, 2022 ). G protein-coupled receptor (GPCR) kinases (GRKs) are essentially a family involving seven serine/threonine kinases (GRKs 1–7) that are involved in the phosphorylation and desensitization of GPCRs.…”

“…Furthermore, it has been suggested that these kinases may have direct or indirect involvement in the altered tau solubility, tau phosphorylation, as well as tau aggregation. Interestingly, there is a line of evidence that elaborates cross-talk between GPCR and the matrix metalloproteinase 9 (MMP-9) and Tyrosine kinase receptors (RTK) or TLRs signaling pathways where NEU1 plays a critical role ( Cattaneo et al, 2014 ; Tembely et al, 2022 ). This provides a unique role for NEU1 in receptor transactivation processes.…”