HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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 glyLDL-induced 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.
AuthorsGanesh V Sangle, Ruozhi Zhao, Tooru M Mizuno, Garry X Shen
JournalEndocrinology (Endocrinology) Vol. 151 Issue 9 Pg. 4455-66 (Sep 2010) ISSN: 1945-7170 [Electronic] United States
PMID20630999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies
  • Blood Glucose
  • DNA-Binding Proteins
  • Glycation End Products, Advanced
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Hsf1 protein, rat
  • Lipoproteins, LDL
  • Onium Compounds
  • Plasminogen Activator Inhibitor 1
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Transcription Factors
  • glycated lipoproteins, LDL
  • Streptozocin
  • diphenyleneiodonium
  • NADPH Oxidases
  • CYBA protein, human
  • Proto-Oncogene Proteins c-raf
  • ras Proteins
Topics
  • Animals
  • Antibodies (pharmacology)
  • Blood Glucose (metabolism)
  • Blotting, Western
  • Cell Line
  • DNA-Binding Proteins (metabolism)
  • Diabetes Mellitus, Experimental (blood, chemically induced, metabolism)
  • Endothelial Cells (cytology, drug effects, metabolism)
  • Glycation End Products, Advanced
  • Heat Shock Transcription Factors
  • Humans
  • Lipoproteins, LDL (pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidases (genetics, metabolism)
  • Onium Compounds (pharmacology)
  • Plasminogen Activator Inhibitor 1 (genetics, metabolism)
  • Proto-Oncogene Proteins c-raf (metabolism)
  • RNA Interference
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic (immunology, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Streptozocin
  • Transcription Factors (metabolism)
  • ras Proteins (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: