**7. AGEs and arteriosclerosis**

In addition to the three major complications of diabetes (i.e., diabetic retinopathy, diabetic nephropathy, and DN), if hyperglycaemia continues for a long time, ischaemic heart disease, cerebral infarction, and macroangiopathy (peripheral arterial disease progression) can occur due to arteriosclerosis in large blood vessels, such as the heart and brain. Inflammation in the blood vessel wall is critical for the onset and progression of arteriosclerosis. AGEs produced in a hyperglycaemic environment bind to RAGE in vascular endothelial cells and activate AGE/RAGE signalling. As a result, the expression of inflammatory cytokine genes is enhanced by NF-κB signalling and the phosphorylation of JNK because of the production of ROS by NADPH oxidase, causing inflammation of the blood vessel wall [117]. Recent studies showed that vascular endothelial growth factor is involved in increases in atheroma in atherosclerotic lesions [118]. Moreover, AGEs induce angiogenesis by promoting the production of vascular endothelial growth factor autocrine signalling in endothelial cells, enhancing inflammation in blood vessels, and increasing atheroma [117]. Excess sRAGE has been reported to inhibit AGE/RAGE signalling and suppress the onset and progression of arteriosclerosis [119–121]. Furthermore, AGEs have been detected in cultures of mouse or human aortic endothelial cells in a hypoxic state, suggesting that RAGE signalling is activated by hypoxia in aortic endothelial cells [122]. Early growth response-1 expression under hypoxic conditions, PKC translocation, and JNK phosphorylation are inhibited by sRAGE or anti-AGE antibodies, and *RAGE* is downregulated by aminoguanidine and siRNA.
