Inflammation Meets Metabolism Roles: for the Receptor for Advanced Glycation End Products Axis in Cardiovascular Disease

Abstract

Fundamental modulation of energy metabolism in immune cells is increasingly being recognized for the ability to impart important changes in cellular properties. In homeostasis, cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs), are enabled to respond rapidly to various forms of acute cellular and environmental stress, such as pathogens. In chronic stress milieus, these cells may undergo a re-programming, thereby triggering processes that may instigate tissue damage and failure of resolution. In settings of metabolic dysfunction, moieties such as excess sugars (glucose, fructose and sucrose) accumulate in the tissues and may form advanced glycation end products (AGEs), which are signaling ligands for the receptor for advanced glycation end products (RAGE). In addition, cellular accumulation of cholesterol species such as that occurring upon macrophage engulfment of dead/dying cells, presents these cells with a major challenge to metabolize/efflux excess cholesterol. RAGE contributes to reduced expression and activities of molecules mediating cholesterol efflux. This Review chronicles examples of the roles that sugars and cholesterol, via RAGE, play in immune cells in instigation of maladaptive cellular signaling and the mediation of chronic cellular stress. At this time, emerging roles for the ligand-RAGE axis in metabolism-mediated modulation of inflammatory signaling in immune cells are being unearthed and add to the growing body of factors underlying pathological immunometabolism.

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

“…Patients with T2DM develop a variety of cardiac abnormalities, a phenomenon known as “diabetic cardiomyopathy” ( 39 ). Furthermore, the accumulation of AGEs due to hyperglycaemia can lead to microvascular remodeling and cardiac fibrosis ( 40 ). The primary mechanism for the progression of HF stems from the stimulation of the renin-angiotensin-aldosterone system (RAAS) ( 41 ), and excessive activation of the RAAS can interfere with insulin production, secretion, and metabolic pathways, leading to reduced insulin sensitivity and disturbed glucose metabolism ( 42 ).…”

The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease

“…AGEs can mediate cellular effects through activating RAGE (receptor for AGEs). 44 Although RAGE was first identified as a receptor for AGEs, it was later recognized to bind several other ligands, including members of the S100 family (S100A12 and S100B), high mobility group box protein 1, lysophosphatidic acid, and phosphatidylserine. It has, therefore, become apparent that RAGE plays a wider role in inflammatory states and that its actions are not limited to diabetes or hyperglycemia, although it does play an important role in diabetic atherosclerosis in mice.…”

“…It has, therefore, become apparent that RAGE plays a wider role in inflammatory states and that its actions are not limited to diabetes or hyperglycemia, although it does play an important role in diabetic atherosclerosis in mice. [44][45][46] Another possibility is that AGE-mediated stiffening of Human studies have shown that age and HbA1c (glycated hemoglobin A1; a marker of suboptimal glycemic control) are the strongest risk factors for incident cardiovascular disease (CVD) in people with T1D. Other risk factors that associate significantly with CVD risk are (in alphabetic order) APOC3 (apolipoprotein C3), blood pressure, low HDL (high-density lipoprotein) cholesterol and altered HDL composition, LDL (low-density lipoprotein) cholesterol, renal disease, smoking, triglycerides, and white blood cell (WBC) count.…”

The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications

“…The AGE receptors fall into two major groups, based on functional properties. In the first group, receptors such as RAGE, oligosaccharyl-transferase complex protein 48 (AGER1), 80 K-H protein (AGER2), and galectin-3 (AGER3) have been shown to bind AGEs and, through this binding, modulation of cellular properties ensues through various molecular modes [16][17][18][19][20]. In contrast, a distinct functional group of molecules serve as scavenger receptors (SR); among these are molecules such as class A type I and II (SR-AI/II), class B type I (SR-BI), CD36 and toll-like receptors (TLRs) [21][22][23][24].…”