Metabolism-dependent Vascular Pathophysiology in Adult Diseases

Abstract

In adult diseases, chronic inflammation-related angiopathy is the main pathological condition of organ disorders such as arteriosclerosis, chronic kidney disease, and non-alcoholic steatohepatitis (NASH). Macrophages play an important role in chronic inflammation. For example, macrophage foaming is important for atherosclerosis development. In our study using Apolipoprotein E knockout mice, hyperglycemia caused by the administration of nicotinamide-streptozotocin, which is a non-obese type 2 diabetes model, promoted arteriosclerosis, while the administration of sodium glucose co-transporter 2 inhibitor markedly reduced lesions. In further studies, arteriosclerosis was ameliorated in resistin like molecule β knockout mice, or by xanthine inhibitors. Xanthine oxidase (XO) inhibitors also improved kidney damage in a diabetic renal disorder model using KK/Ay mice and liver damage in a NASH model using high-fat, high-sucrose trans fatty acid loading. These studies suggested that atherosclerosis can be ameliorated independently of glucose and/or lipid lowering therapy, by interventions targeting macrophages. In a study using J774.1 cells, acetylated low density lipoprotein (LDL), which is a typical denatured LDL, is taken up by macrophages regardless of glucose concentrations, but very low density lipoprotein (VLDL) is taken up into cells in a glucose-dependent manner. The glucose concentration-dependent uptake of VLDL was suppressed by XO inhibitors. In addition, the overexpression of XO increased the VLDL uptake and the VLDLR expression was also increased. The glucose and nucleic acid metabolism, which are associated with its metabolism, are involved in the uptake of VLDL. In conclusion, it was strongly suggested that macrophages regulate inflammation and intracellular lipids depending on metabolism and that they may be involved in angiopathy in adult diseases.