Abstract
Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. We have shown that macrophages of patients with type 2 diabetes overproduce LPL and that metabolic factors, including glucose, stimulate macrophage LPL secretion. In this study, we determined the effect of advanced glycation end products (AGEs) on LPL expression by macrophages cultured in a high-glucose environment and the molecular mechanisms underlying this effect. Our results demonstrate that AGEs potentiate the stimulatory effect of high glucose on murine and human macrophage LPL gene expression and secretion. Induction of macrophage LPL mRNA levels by AGEs was identical to that elicited by physiologically relevant modified albumin and was inhibited by anti-AGE receptor as well as by antioxidants. Treatment of macrophages with AGEs resulted in protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. Inhibition of these kinases abolished the effect of AGEs on LPL mRNA levels. Finally, exposure of macrophages to AGEs increased the binding of nuclear proteins to the activated protein-1 consensus sequence of the LPL promoter. This effect was inhibited by PKC and MAPK inhibitors. These results demonstrate for the first time that AGEs potentiate the stimulatory effect of high glucose on macrophage LPL expression. This effect appears to involve oxidative stress and PKC/MAPK activation.
Highlights
Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis
advanced glycation end products (AGEs) did not affect the levels of LPL mRNA in J774 macrophages cultured in a low-glucose medium, whereas both AGEs and GlyBSA (200 g/ ml) increased LPL mRNA levels in macrophages cultured in a high-glucose environment (Fig. 1A)
Previous studies have demonstrated that the interaction of AGEs with RAGEs expressed on macrophages induces several biological events linked to the development of vascular lesions [34,35,36]
Summary
Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. Exposure of macrophages to AGEs increased the binding of nuclear proteins to the activated protein-1 consensus sequence of the LPL promoter This effect was inhibited by PKC and MAPK inhibitors. These results demonstrate for the first time that AGEs potentiate the stimulatory effect of high glucose on macrophage LPL expression. This effect appears to involve oxidative stress and PKC/MAPK activation.—Beauchamp, M-C., S-É. Our study demonstrates that AGEs potentiate the stimulatory effect of glucose on macrophage LPL expression This effect appears to involve oxidative stress, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)-dependent pathways, and activated protein-1 (AP-1) activation
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