Soluble Receptor for Advanced Glycation End-products regulates age-associated Cardiac Fibrosis

Abstract

Myocardial aging increases the cardiovascular risk in the elderly. The Receptor for Advanced Glycation End-products (RAGE) is involved in age-related disorders. The soluble isoform (sRAGE) acts as a scavenger blocking the membrane-bound receptor activation. This study aims at investigating RAGE contribution to age-related cardiac remodeling. We analyzed the cardiac function of three different age groups of female Rage-/-and C57BL/6N (WT) mice: 2.5-(Young), 12-(Middle-age, MA) and 21-months (Old) old. While aging, Rage-/-mice displayed an increase in left ventricle (LV) dimensions compared to age-matched WT animals, with the main differences observed in the MA groups. Rage-/-mice showed higher fibrosis and a larger number of α-Smooth Muscle Actin (SMA)+ cells with age, along with increased expression of pro-fibrotic Transforming Growth Factor (TGF)-β1 pathway components. RAGE isoforms were undetectable in LV of WT mice, nevertheless, circulating sRAGE declined with aging and inversely associated with LV diastolic dimensions. Human cardiac fibroblasts stimulated with sRAGE exhibited a reduction in proliferation, pro-fibrotic proteins and TGF-beta Receptor 1 (TGFbR1) expression and Smad2-3 activation. Finally, sRAGE administration to MA WT animals reduced cardiac fibrosis. Hence, our work shows that RAGE associates with age-dependent myocardial changes and indicates sRAGE as an inhibitor of cardiac fibroblasts differentiation and age-dependent cardiac fibrosis.

Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study

“…The membrane-bound RAGE (FL-RAGE) is a pattern recognition receptor that recognizes AGEs and several other ligands, some of which act as damage-associated molecular patterns (DAMPS) and pathogen-associated molecular patterns (PAMPs) [ 9 – 11 ]. Under physiological conditions, RAGE is expressed in the lungs while is almost undetectable in other tissues [ 12 , 13 ]; however, its levels are induced by ligand accumulation [ 14 – 16 ]. The cytoplasmic domain of RAGE binds to the formin DIAPH1 that is essential for RAGE/ligand-mediated activation and production of reactive oxygen species (ROS) eventually promoting inflammatory processes in ARDs [ 17 , 18 ].…”

“…sRAGE does not transduce signal upon ligand binding, acting as a decoy molecule to restrain the RAGE/ligand induced cell activation [ 20 ]. Accordingly, sRAGE administration reduces diabetes and atherosclerosis tissue remodeling, age-associated cardiac fibrosis and neointima expansion after vessel injury [ 13 , 21 – 23 ].…”

Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors

“…However, N‐RAGE can exhibit its V‐domain‐independent pathological functions and signal transduction (Yonekura et al, 2003). Further, the cleavage of the extracellular domain from the cell surface via metalloproteinases produce soluble form of RAGE (sRAGE; residues 23–342) which is the dominant form counteracting the RAGE‐mediated functions by acting as its decoy receptor (Emanuele et al, 2005; Falcone et al, 2005; Kalea et al, 2009; Scavello et al, 2021). The direct administration of sRAGE in vivo has been shown to reverse the RAGE‐mediated pathological conditions (Cho et al, 2009; Geroldi et al, 2006; Kalea et al, 2009; Scavello et al, 2021).…”

Effects of RAGE Deletion on the Cardiac Transcriptome during Aging

“…The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor (PRR) expressed at a very low level in most tissues during homeostasis, except the lung [ 4 , 5 , 6 , 7 ]. The membrane-bound full-length RAGE (FL-RAGE) recognizes several inflammatory molecules, including advanced glycation end-products (AGEs), S100/calgranulins proteins, and high mobility group box one (HMGB1) [ 8 , 9 , 10 , 11 ], is rapidly up-regulated at the site of injury where its ligands accumulate and promotes the development of numerous inflammatory diseases [ 10 , 11 , 12 , 13 , 14 ].…”

“…FL-RAGE/ligands binding regulates cell migration, adhesion, and inflammation through the activation of various signaling pathways [ 9 , 15 , 16 , 17 ]. Soluble forms of RAGE, collectively named sRAGE, have been identified in the bloodstream and tissues of humans and rodents; they act as protective anti-inflammatory decoy receptors by preventing FL-RAGE activation [ 4 , 7 , 18 , 19 , 20 , 21 ]. Consistently, animals treated with sRAGE or RAGE knockout ( Rage−/− ) mice exhibit reduced tissue damage in various diseases, such as diabetes, atherosclerosis, arterial injury, and ischemic cardiac damage [ 7 , 10 , 11 , 22 , 23 , 24 ].…”