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Interaction of glycated protein and DFO mimicked hypoxia in cellular responses of HUVECs.

Abstract
The accelerated non-enzymatic modification of proteins by Maillard reaction during prolonged hyperglycemia is a key player in the diabetes associated pathology. In addition, hypoxia has been implicated in the recent past as a modulating factor. Therefore we have examined the interaction of glycation modified human serum albumin (AGE-HSA) and deferoxamine (DFO) mimicked hypoxia on the expression of hypoxia inducible factor 1α (HIF-1α), and the role of RAGE (receptor for AGE) signaling in up-regulation of HIF-1α. Expression of VEGF (a downstream target of HIF-1α) and sICAM-1 (inflammatory marker) was also detected. When HUVEC were subjected to hypoxia, highest expression of HIF-1α was observed. When treated with AGE-HSA at two concentrations, higher expression was found vis-a-vis control, with 0.2 mg ml(-1) than 2.0 mg ml(-1) which was mediated in part by RAGE as determined by RAGE silencing. However, when the cells were exposed to a combination treatment of hypoxia and AGE-HSA, a biphasic effect at the two different concentrations was observed as compared to the individual treatments. VEGF was synergistically up-regulated by hypoxia and AGE-HSA. On the other hand sICAM-1 was up-regulated by AGE-HSA but down-regulated by hypoxia. These results show that AGE-HSA functions as a non-hypoxic factor which modulates the expression of HIF-1α in a concentration dependent manner in the range studied. It can be concluded that glycated serum proteins may activate HIF-1α independently in diabetes. Further, when both glycated proteins and hypoxic conditions are present, they act in opposition in regulation of HIF-1α.
AuthorsKanchan Bala, Nivedita Karmakar Gohil
JournalMolecular bioSystems (Mol Biosyst) Vol. 8 Issue 10 Pg. 2657-63 (Oct 2012) ISSN: 1742-2051 [Electronic] England
PMID22790884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drug Combinations
  • Glycation End Products, Advanced
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Serum Albumin
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • advanced glycation end products-human serum albumin
  • Intercellular Adhesion Molecule-1
  • Deferoxamine
  • Oxygen
  • Serum Albumin, Human
Topics
  • Deferoxamine (pharmacology)
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Female
  • Gene Expression (drug effects)
  • Glycation End Products, Advanced (pharmacology)
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia (metabolism)
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Immunohistochemistry
  • Intercellular Adhesion Molecule-1 (genetics, metabolism)
  • Models, Biological
  • Oxygen (pharmacology)
  • RNA, Small Interfering (genetics)
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic (antagonists & inhibitors, genetics, metabolism)
  • Serum Albumin (pharmacology)
  • Serum Albumin, Human
  • Signal Transduction (drug effects)
  • Vascular Endothelial Growth Factor A (genetics, metabolism)

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