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

• Published in: Molecular and cellular biochemistry Vol. 354; no. 1-2; pp. 47 - 55
• Main Authors: An, Xiao-Fei, Zhou, Lei, Jiang, Peng-Jun, Yan, Ming, Huang, Yu-Jun, Zhang, Su-Na, Niu, Yun-Fei, Ten, Shi-Chao, Yu, Jiang-Yi
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.08.2011; Springer; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biological products; Biomedical and Life Sciences; Cardiology; Cattle; Cells; Diabetic Nephropathies - metabolism; Endothelial Cells - metabolism; Endothelium; Endothelium, Vascular - cytology; Gene expression; Glucuronidase - genetics; Glucuronidase - metabolism; Glycation End Products, Advanced - metabolism; Glycation End Products, Advanced - pharmacology; Glycosylation; Humans; L-Lactate Dehydrogenase - metabolism; Life Sciences; Medical Biochemistry; Microvessels - cytology; Neurons; Neutralization; NF-kappa B - genetics; NF-kappa B - metabolism; Oncology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; RNA; Serum Albumin, Bovine - metabolism; Serum Albumin, Bovine - pharmacology; Sulfates; Transcription Factors - metabolism; Transcription, Genetic; Heparanase; Advanced glycation end-products; RAGE; FOXO4
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-011-0804-7

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.