Low Soluble Receptor for Advanced Glycation End Products Precedes and Predicts Cardiometabolic Events in Women With Rheumatoid Arthritis

Abstract

Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients.Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed.Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years.Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD.Trial registration:ClinicalTrials.gov with ID NCT03449589. Registered 28, February 2018.

The Potential Influence of Advanced Glycation End Products and (s)RAGE in Rheumatic Diseases

“…The increased CVD rate in RA patients appears to be related to sRAGE levels as well [16,65,75]. In female RA patients, low serum sRAGE levels were significantly associated with previous history and new imminent cardiometabolic events.…”

“…Binding AGEs, on the other hand, blocks AGE-RAGE signaling, reduces the positive feedback loop for RAGE upregulation, and thus potentially limits RAGE enzymatic cleavage. Based on these findings, sRAGE could be used to monitor cardiometabolic health in RA patients [16]. Further, in a cohort of early RA patients, a prospective study investigated the relationship between serum levels of sRAGE and the progression of carotid atherosclerosis and arterial stiffness measures.…”

“…The higher the expected density of the cell-bound receptor, RAGE, the greater the likelihood of increased production of soluble (s)RAGE by cleavage [16]. sRAGE is a positively charged 48-kDa cleavage product that keeps the ligand binding site but loses the transmembrane and signaling domains [17,18].…”

AGE/Non-AGE Glycation: An Important Event in Rheumatoid Arthritis Pathophysiology

“…Proteolytic cleavage of RAGE is mediated by A-disintegrin and metalloprotease-10 (ADAM 10) which is a membrane metalloproteinase, forming sRAGE [43]. Recently low levels of sRAGE receptor have been demonstrated as a biomarker of metabolic failure developed during chronic inflammation, indicating an increased risk factor of CVD in RA patients [44].…”

Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy‐mediated macrophage alternative activation

“…The receptor for advanced glycation end products (RAGE), a multi-ligand cell surface molecule of the immunoglobulin superfamily, 34 is closely related to diabetes, 35 cancer, 36 atherosclerosis, 37,38 Alzheimer's diseases, 39 vascular damage, 40 and rheumatoid arthritis. 41 RAGE is found on the surface of multiple cells, including monocytes/macrophages, lymphocytes, endothelial cells, smooth muscles, and neurons. Under homeostatic conditions, RAGE expression is very low in normal cells but enhanced in chronic inflammation or oxidative stress.…”