Advanced glycation end-products induce heparanase expression in endothelial cells by the receptor for advanced glycation end products and through activation of the FOXO4 transcription factor.

Abstract

As an endo-β (1-4)-D: -glucuronidase, heparanase can specifically cleave carbohydrate chains of heparan sulfate (HS) and has been implicated in development of endothelial cells dsyfunction. The advanced glycation end products (AGEs) play a pivotal role in the pathology of diabetic complications. In the present study, we investigated the effect of AGE-bovine serum albumin (AGE-BSA) on heparanase expression in human microvascular endothelial cells (HMVECs) and the underlying molecular mechanisms. The results indicated that in vitro direct exposure of HMVECs to AGE-BSA (300, 1000, and 3000 μg/ml) could increase heparanase mRNA and protein expression in a dose and time-dependent manner. The effect of 1000 μg/ml AGE-BSA could be abolished by neutralization with antibody of the receptor for advanced glycation end products (RAGE). Moreover, pretreatment with inhibitors of nuclear factor-κB (NF-κB) or PI3-kinase did not affect heparanase expression induced by AGE-BSA. Nevertheless, small interference RNA (siRNA) for transcriptional factor FOXO4 could reduce the increase of heparanase expression in HMVECs induced by 1000 μg/ml AGE-BSA. These results suggest that AGEs could induce heparanase expression in HMVECs by RAGE and predominantly through activation of the FOXO4 transcription factor.

• Authors: Xiao-Fei An, Lei Zhou, Peng-Jun Jiang, Ming Yan, Yu-Jun Huang, Su-Na Zhang, Yun-Fei Niu, Shi-Chao Ten, Jiang-Yi Yu
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 354 Issue 1-2 Pg. 47-55 (Aug 2011) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 21461610 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• FOXO4 protein, human
• Forkhead Transcription Factors
• Glycation End Products, Advanced
• NF-kappa B
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic
• Transcription Factors
• Serum Albumin, Bovine
• L-Lactate Dehydrogenase
• heparanase
• Glucuronidase

Topics

• Animals
• Cattle
• Cell Cycle Proteins
• Diabetic Nephropathies (metabolism)
• Endothelial Cells (metabolism)
• Endothelium, Vascular (cytology)
• Forkhead Transcription Factors
• Glucuronidase (genetics, metabolism)
• Glycation End Products, Advanced (metabolism, pharmacology)
• Humans
• L-Lactate Dehydrogenase (metabolism)
• Microvessels (cytology)
• NF-kappa B (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic (metabolism)
• Serum Albumin, Bovine (metabolism, pharmacology)
• Transcription Factors (metabolism)
• Transcription, Genetic