Abstract
Methylglyoxal (MGO) is a reactive dicarbonyl metabolite of glucose, and its plasma levels are elevated in patients with diabetes. Studies have shown that MGO combines with the amino and sulphhydryl groups of proteins to form stable advanced glycation end products (AGEs), which are associated with vascular endothelial cell (EC) injury and may contribute to the progression of atherosclerosis. In this study, MGO induced apoptosis in a dose‐dependent manner in HUVECs, which was attenuated by pre‐treatment with z‐VAD, a pan caspase inhibitor. Treatment with MGO increased ROS levels, followed by dose‐dependent down‐regulation of c‐FLIPL. In addition, pre‐treatment with the ROS scavenger NAC prevented the MGO‐induced down‐regulation of p65 and c‐FLIPL, and the forced expression of c‐FLIPL attenuated MGO‐mediated apoptosis. Furthermore, MGO‐induced apoptotic cell death in endothelium isolated from mouse aortas. Finally, MGO was found to induce apoptosis by down‐regulating p65 expression at both the transcriptional and posttranslational levels, and thus, to inhibit c‐FLIPL mRNA expression by suppressing NF‐κB transcriptional activity. Collectively, this study showed that MGO‐induced apoptosis is dependent on c‐FLIPL down‐regulation via ROS‐mediated down‐regulation of p65 expression in endothelial cells.
Highlights
Biological glycation has been investigated in the context of microvascular complications of diabetes, such as neuropathy, retinopathy and atherosclerosis [1]
These results suggest that MGO-induced cell death was mediated by caspasedependent cell death pathways in human umbilical vein endothelial cells (HUVECs)
MGO was found to be cytotoxic to both HUVECs and transformed human umbilical vein endothelial cell (EC), and MGO-mediated apoptosis was found to be dependent on the generation of reactive oxygen species (ROS) and subsequent down-regulation of the NF-jB pathway and of c-FLIPL expression in human ECs
Summary
Biological glycation has been investigated in the context of microvascular complications of diabetes, such as neuropathy, retinopathy and atherosclerosis [1]. MGO promotes the generation of reactive oxygen species (ROS) directly [5, 6]. MGO is known to accumulate in various tissues at an accelerated rate under diabetic conditions, such as hyperglycaemia. The cytotoxic effects of MGO on tissues and cells have been attributed to its ability to induce apoptosis [9, 10]. Previous studies have shown that MGO induces apoptosis of human umbilical vein endothelial cells (HUVECs) by activating caspases, generating ROS, and activating MAP kinases [11, 12]
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