**5.4 Circulating sRAGE and esRAGE in diseases**

### **A. Circulating sRAGE and cardiovascular diseases**

Since sRAGE and esRAGE may be involved in feedback regulation of the toxic effects of RAGE-mediated signaling, recent clinical studies have focused on the potential significance of circulating sRAGE and esRAGE in a variety of pathophysiological conditions, including atherosclerotic disorders, diabetes, hypertension, Alzheimer's dieases and chronic kidney diseases (Table 2). First, Falcone et al 106 reported that total sRAGE levels are significantly lower in patients with angiographically proven coronary artery disease (CAD) than in age-matched healthy controls. The association between circulating sRAGE and angiographic observations was shown to be dose-dependent, with individuals in the lowest quartile of sRAGE exhibiting the highest risk for CAD. Importantly, this cohort consisted of a non-diabetic population, suggesting that the potential significance of sRAGE is not confined to diabetes. Falcone et al also showed that the association between sRAGE and the risk of CAD was independent of other classical risk factors. Their findings are reproduced later by several research groups in larger numbers of subjects, and are also extended to other atherosclerotic diseases, such as carotid atherosclerosis, cerebral ischemia, and aortic valve stenosis (Table 2). Patients with


Alzheimer disease have also lower levels of sRAGE in plasma than patients with vascular dementia and controls, suggesting a role for the RAGE axis in this clinical entity as well 107.

Table 2. Levels of circulating soluble RAGE in cardiovascular and metabolic diseases.
