Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells

Abstract

Atherothrombotic cardiovascular diseases are the predominant causes of mortality of diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glycated low-density lipoprotein (glyLDL) were detected in patients with diabetes. Previous studies in our laboratory demonstrated that heat shock factor-1 (HSF1) is involved in glyLDL-induced PAI-1 overproduction in vascular endothelial cells (EC). The present study investigated transmembrane signaling mechanisms involved in glyLDL-induced HSF1 and PAI-1 up-regulation in cultured human vascular EC and streptozotocin-induced diabetic mice. Receptor for advanced glycation end products (RAGE) antibody prevented glyLDL-induced increase in the abundance of PAI-1 in EC. GlyLDL significantly increased the translocation of V-Ha-Ras Harvey rat sarcoma viral oncogene homologue (H-Ras) from cytoplasm to membrane compared with LDL. Farnesyltransferase inhibitor-277 or small interference RNA against H-Ras inhibited glyLDL-induced increases in HSF1 and PAI-1 in EC. Treatment with diphenyleneiodonium, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, blocked glyLDL-induced translocation of H-Ras, elevated abundances of HSF1 and PAI-1 in EC, and increased release of hydrogen peroxide from EC. Small interference RNA for p22 phox prevented glyLDL-induced expression of NOX2, HSF1, and PAI-1 in EC. GlyLDL significantly increased V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) phosphorylation. Treatment with Raf-1 inhibitor blocked glyLDLinduced increase of PAI-1 mRNA in EC. The levels of RAGE, H-Ras, NOX4, HSF1, and PAI-1 were increased in hearts of streptozotocin-diabetic mice and positively correlated with plasma glucose. The results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. (Endocrinology 151: 4455-4466, 2010)

Receptor for advanced glycation end products (RAGE) partially mediates HMGB1-ERKs activation in clear cell renal cell carcinoma

“…These effects are likely the result of RAGE activating the cellular signaling pathways that regulate these functions. The main signaling pathways include PI3K (Huang et al 2011), different MAPKs (Tanikawa et al 2009Kim et al 2010;Shang et al 2010), Rho GTPases and ROS (Sangle et al 2010). On the level of transcriptional regulation, NF-jB, AP-1 and Stat3 have emerged as crucial targets of RAGE signaling (Gebhardt et al 2008;Villarreal et al 2011).…”

Activation of the AGE/RAGE system in the brains of rats and in SH-SY5Y cells exposed to high level of fluoride might connect to oxidative stress

“…RAGE is expressed by many different types of cells, including endothelial and vascular smooth muscle cells (Poirier et al, 2001). Extensive evidence indicates that the AGE/RAGE system can promote oxidative stress and activate certain downstream signaling pathways, in particular those involving NOX 2 , a membrane-bound enzyme complex (Sangle et al, 2010;Yamagishi et al, 2012). Our present findings reveal that the levels of both RAGE protein and mRNA are elevated in the brains of rats with chronic fluorosis and in SH-SY5Y cells treated with excessive fluoride, suggesting an activation of the AGE/RAGE pathway by this ion.…”

Polymorphism of the RAGE Affects the Serum Inflammatory Levels and Risk of Ischemic Stroke in a Chinese Population

“…AGE has the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis [59]. RAGE is one of the key factors implicated in the up-regulation of PAI-1 in vascular endothelial cells under diabetes-associated metabolic stress [60]. In the present study, we found that the 82S/S homozygote carriers had a lower sRAGE level, higher IL-6, hs-CRP and PAI-1 levels, suggesting a higher inflammatory status in 82S/S carriers compared with the G/S and G/G genotype carriers.…”