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Fatty Acid-Induced Nuclear Translocation of Heparanase Uncouples Glucose Metabolism in Endothelial Cells.
MedLine Citation:
PMID:  22116097     Owner:  NLM     Status:  Publisher    
OBJECTIVE: Heparanase is an endoglycosidase that specifically cleaves carbohydrate chains of heparan sulfate. We have recently reported that high fatty acid increased the nuclear content of endothelial heparanase. Here, we examined the mechanism and the consequences behind this nuclear translocation of heparanase. METHODS AND RESULTS: Bovine coronary artery endothelial cells were grown to confluence and incubated with palmitic acid. Palmitic acid induced rapid nuclear accumulation of heparanase that was dependent on Bax activation and lysosome permeabilization. Heat shock protein 90 was an important mediator of palmitic acid-induced shuttling of heparanase to the nucleus. Nuclear heparanase promoted cleavage of heparan sulfate, a potent inhibitor of histone acetyltransferase activity and gene transcription. A TaqMan gene expression assay revealed an increase in genes related to glucose metabolism and inflammation. In addition, glycolysis was uncoupled from glucose oxidation, resulting in accumulation of lactate. CONCLUSIONS: The results presented in this study demonstrate that fatty acid can provoke lysosomal release of heparanase, its nuclear translocation, activation of genes controlling glucose metabolism, and accumulation of lactate. Given that lactate and inflammation have been implicated in the progression of atherosclerosis, our data may serve to reduce the associated cardiovascular complications seen during diabetes.
Fang Wang; Ying Wang; Dahai Zhang; Prasanth Puthanveetil; James D Johnson; Brian Rodrigues
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-23
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  -     ISSN:  1524-4636     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Molecular and Cellular Pharmacology Group, Faculty of Pharmaceutical Sciences, Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada.
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