AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation

• Published in: International journal of molecular sciences Vol. 21; no. 23; p. 9263
• Main Authors: Yashima, Hironori, Terasaki, Michishige, Sotokawauchi, Ami, Matsui, Takanori, Mori, Yusaku, Saito, Tomomi, Osaka, Naoya, Kushima, Hideki, Hiromura, Munenori, Ohara, Makoto, Fukui, Tomoyasu, Yamagishi, Sho-Ichi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.12.2020; MDPI
• Subjects: Acetylcysteine; Advanced glycosylation end products; AGEs; Animals; Antioxidants; Apoptosis; Aptamers; Aptamers, Nucleotide; Arteriosclerosis; Atherosclerosis; Cardiovascular disease; Cardiovascular diseases; CD36; CD36 antigen; CD36 Antigens - genetics; CD36 Antigens - metabolism; Cdk5; Cell adhesion & migration; Cell cycle; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-dependent kinases; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; DNA; Gene expression; Glycation End Products, Advanced - metabolism; Glycosylation; Humans; Inflammation; Kinases; Lipoproteins, LDL - metabolism; Low density lipoprotein; Macrophages; Macrophages - metabolism; Melanoma; Middle age; Models, Biological; Oxidative Stress; RAGE-aptamer; Receptor for Advanced Glycation End Products - metabolism; U937 Cells; macrophages; AGEs; CD36; Cdk5; RAGE-aptamer
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21239263

Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and and gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). and gene expression levels were correlated with each other. An antioxidant, -acetyl-l-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5-CD36 pathway via RAGE-mediated oxidative stress.