|Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2002: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2001: ¥9,100,000 (Direct Cost: ¥9,100,000)
In the Maillard reaction, the reaction of proteins with glucose or other reduced sugars leads, through the Schiff base and Amadori product, to the formation of advanced glycation endproducts (AGE). Recent studies of AGE-structures in vivo as well as the AGE-receptors have emphasized the involvement of post-translational AGE-modification in aging and age-enhanced disease processes such as diabetic complications and atherosclerosis. Three AGE-receptors such as SR-A (type A scavenger receptor), galectin-3 and RAGE (receptor tor AGE) were known. Our recent studies identified CD36 and SR-BI as novel AGE-receptors; CD36-overexpressed CHO cells showed endocytic uptake and subsequent intracellular degradation of AGE-proteins, suggesting that AGE-proteins ate recognized by CD36, which might contribute to the pathogenesis of diabetic vascular complications. By using SR-BI-overexpressed CHO cells (SR-BI-CHO), we showed that SR-BI-mediated selective uptake of cholesteryl esters of HDL as well as H
DL-mediated cholesterol efflux from SR-BI-CHO cells were effectively inhibited by AGE-proteins, indicating that AGE-proteins play a significant role in HDL-mediated reverse cholesterol
In the present study, we examined effects of AGE-ligands on the function of CD36 and SR-BI. The following results were obtained (i) In addition to glucose-modified AGE-proteins, proteins modified by glyeolaldehyde and methylglyoxal, intermediate aldehydes mediating the AGE-formation in vivo, could induce not only the expression of CD36 in human monocyte macrophages at mRNA and protein levels, but also accelerate ox-LDL-induced foam cell formation. These phenomena were effectively inhibited (neutralized) by anti-CD36 antibody, (ii) These AGB-proteins generated by glycolaldehyde and methylglyoxal could inhibit the selective CE-uptake by mouse primary hepatocytes from HDL.
These results have clarified that AGE-ligands generated in vivo might enhance the atherogenic process both by accelerating CD36-mediated atherogenic functions and by inhibiting SR-BI-mediated anti-atherogenic functions. Less