title: 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: Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, 155 Han-Zhong Road, Nanjing 210029, China.
authors: Xiao-Fei
authors: XF
authors: An
authors: Lei
authors: L
authors: Zhou
authors: Peng-Jun
authors: PJ
authors: Jiang
authors: Ming
authors: M
authors: Yan
authors: Yu-Jun
authors: YJ
authors: Huang
authors: Su-Na
authors: SN
authors: Zhang
authors: Yun-Fei
authors: YF
authors: Niu
authors: Shi-Chao
authors: SC
authors: Ten
authors: Jiang-Yi
authors: JY
authors: Yu
mesh_terms: D000818:Animals; D002417:Cattle; D018797:Cell Cycle Proteins; D003928:Diabetic Nephropathies / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology*; D051858:Forkhead Transcription Factors; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D055806:Microvessels / Q000166:cytology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000099175:Heparanase
chemical_list: D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D005966:Glucuronidase; D017127:Glycation End Products, Advanced; D007770:L-Lactate Dehydrogenase; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012710:Serum Albumin, Bovine; D014157:Transcription Factors; D000099175:Heparanase; C108803:FOXO4 protein, human