Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice

Abstract

Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE -/-mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.

Angiotensin II stimulates MCP-1 production in rat glomerular endothelial cells via NAD(P)H oxidase-dependent nuclear factor-kappa B signaling

“…cytes (16). Our results suggest that Ang II can induce MCP-1 formation in rat GECs and promote monocyte adhesion to endothelial cells.…”

Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study

“…The current view is that the activation of RAGE, a 55 kDa protein and member of the immunoglobulin superfamily of cell-surface receptors, through ligand binding activates the endothelial cell and triggers multiple signalling cascades [8,9]. This results in activation and translocation of nuclear transcription factors and transcription of the target genes, including those for VCAM-1 [9], E-selectin [10] and proinflammatory cytokines [11].…”

“…The functional role of these soluble forms of RAGE in the circulation remains unclear, but they may reflect the activity of the AGE-RAGE axis. The ligation of RAGE activates the endothelial cell and triggers multiple signalling cascades [8,9], resulting in activation and translocation of nuclear transcription factors and transcription of the target genes, including adhesion molecules [9,10] and proinflammatory cytokines [11]. The activation of RAGE may also lead to nephropathy [12].…”

Ageing in Werner syndrome

“…AGEs tend to accumulate with age in long-lived tissue proteins such as collagen, lens crystalline, immunoglobulin chains, amyloid β-peptide and nucleic acids, partly under the influence of oxidative stress (10,11). The chronic, systemic inflammation tightly associated with ageing such as diabetes mellitus (DM) (12,13), atherosclerosis (14), arthritis (15,16) and hemodialysis (17,18) may accelerate AGEs formation through oxidative reactions. Collectively, the term: inflammaging has been proposed to explain pathophysiology of human ageing and ageing-related diseases (1,19).…”