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.

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