title: Hyperglycemia-induced secretion of endothelial heparanase stimulates a vascular endothelial growth factor autocrine network in cardiomyocytes that promotes recruitment of lipoprotein lipase.
abstract: OBJECTIVE
  During diabetes mellitus, coronary lipoprotein lipase increases to promote the predominant use of fatty acids. We have reported that high glucose stimulates active heparanase secretion from endothelial cells to cleave cardiomyocyte heparan sulfate and release bound lipoprotein lipase for transfer to the vascular lumen. In the current study, we examined whether heparanase also has a function to release cardiomyocyte vascular endothelial growth factor (VEGF), and whether this growth factor influences cardiomyocyte fatty acid delivery in an autocrine manner.
  
  
  RESULTS
  Acute, reversible hyperglycemia was induced in rats, and a modified Langendorff heart perfusion was used to separate the coronary perfusate from the interstitial effluent. Coronary artery endothelial cells were exposed to high glucose to generate conditioned medium, and VEGF release from isolated cardiomyocytes was tested using endothelial cell conditioned medium or purified active and latent heparanase. Autocrine signaling of myocyte-derived VEGF on cardiac metabolism was studied. High glucose promoted latent and active heparanase secretion into endothelial cell conditioned medium, an effective stimulus for releasing cardiomyocyte VEGF. Intriguingly, latent heparanase was more efficient than active heparanase in releasing VEGF from a unique cell surface pool. VEGF augmented cardiomyocyte intracellular calcium and AMP-activated protein kinase phosphorylation and increased heparin-releasable lipoprotein lipase.
  
  
  CONCLUSIONS
  Our data suggest that the heparanase-lipoprotein lipase-VEGF axis amplifies fatty acid delivery, a rapid and adaptive mechanism that is geared to overcome the loss of glucose consumption by the diabetic heart. If prolonged, the resultant lipotoxicity could lead to cardiovascular disease in humans.
authors.affiliation: From the Faculty of Pharmaceutical Sciences (D.Z., A.W., A.P.-L.C., Y.W., F.W., K.N., N.L., B.R.), and Department of Cellular and Physiological Sciences (M.J.B., J.D.J.), University of British Columbia, Canada; and Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Israel (I.V.).
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.forename: Amy Pei-Ling
authors.initials: AP
authors.lastname: Chiu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.forename: Katharina
authors.initials: K
authors.lastname: Neumaier
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bround
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000201:enzymology*; D017077:Culture Media, Conditioned / Q000378:metabolism; D003981:Diazoxide; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D004734:Energy Metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000201:enzymology*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D055372:AMP-Activated Protein Kinases; D001786:Blood Glucose; D002118:Calcium; D017077:Culture Media, Conditioned; D003981:Diazoxide; D005227:Fatty Acids; D005966:Glucuronidase; D008071:Lipoprotein Lipase; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C467498:vascular endothelial growth factor A, rat
keywords: heparanase; hyperglycemia; lipoprotein lipase; metabolism; vascular endothelial growth factor A