Sphingosine-1-Phosphate

Abstract

See related article, pages 731–739 A key question in unlocking the mystery of accelerated atherosclerosis that often accompanies types1 and 2 diabetes and leads to increased incidence and severity of heart attacks and strokes is, what are the precise biochemical and molecular signaling pathways that perturb the diabetic blood vessel leading to acceleration of vascular inflammation and atherosclerosis? Extensive evidence implicates elevated levels of glucose as a critical culprit in these phenomena. Beyond a critical threshold, it is apparent that increased glucose levels significantly exceed homeostatic requirements, and divert fundamental pathways leading to untoward nonphysiological effects in the cells. Glucose may be dangerous, not solely because of its direct effects, but because of its long-term consequences. The studies of the Diabetes Control Clinical Trials (DCCT) and the Epidemiology of Diabetes Interventions and Complications Research (EDIC) Groups showed definitively that earlier rigorous glycemic control, despite eventual normalization of glucose levels compared with conventionally-treated type 1 diabetic subjects, exerted long-term protection against surrogate (carotid intima-media thickness) and frank end points (cardiovascular events and death) of cardiovascular disease.1–2 Why is the diabetic vessel so vulnerable to increased glucose? A plausible hypothesis is that it’s not just glucose; rather, excessive glucose is accompanied by clever accomplices in the pathways leading to irreversible vascular injury, some of which may be directly influenced by adverse signals emitted by hyperglycemia. For example, the nonenzymatic glycation and oxidation of proteins and lipids results in the generation of Advanced Glycation Endproducts (AGEs), key signaling species that perturb endothelium, smooth muscle cells and monocytes to ignite vascular inflammation and contribute to accelerated atherogenesis and the development and progression of vulnerable atherosclerotic plaques.3 AGEs, by virtue of their interaction with Receptor for AGE (RAGE), trigger generation of oxidative species and activation of downstream proinflammatory and prothrombotic pathways. Importantly, …