title: Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus.
abstract: OBJECTIVE
  Lipoprotein lipase (LPL)-mediated triglyceride hydrolysis is the major source of fatty acid for cardiac energy. LPL, synthesized in cardiomyocytes, is translocated across endothelial cells (EC) by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Previously, we have reported an augmentation in coronary LPL, which was linked to an increased expression of GPIHBP1 following moderate diabetes mellitus. We examined the potential mechanism by which hyperglycemia amplifies GPIHBP1.
  
  
  RESULTS
  Exposure of rat aortic EC to high glucose induced GPIHBP1 expression and amplified LPL shuttling across these cells. This effect coincided with an elevated secretion of heparanase. Incubation of EC with high glucose or latent heparanase resulted in secretion of vascular endothelial growth factor (VEGF). Primary cardiomyocytes, being a rich source of VEGF, when cocultured with EC, restored EC GPIHBP1 that is lost because of cell passaging. Furthermore, recombinant VEGF induced EC GPIHBP1 mRNA and protein expression within 24 hours, an effect that could be prevented by a VEGF neutralizing antibody. This VEGF-induced increase in GPIHBP1 was through Notch signaling that encompassed Delta-like ligand 4 augmentation and nuclear translocation of the Notch intracellular domain. Finally, cardiomyocytes from severely diabetic animals exhibiting attenuation of VEGF were unable to increase EC GPIHBP1 expression and had lower LPL activity at the vascular lumen in perfused hearts.
  
  
  CONCLUSIONS
  EC, as the first responders to hyperglycemia, can release heparanase to liberate myocyte VEGF. This growth factor, by activating EC Notch signaling, is responsible for facilitating GPIHBP1-mediated translocation of LPL across EC and regulating LPL-derived fatty acid delivery to the cardiomyocytes.
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Amy Pei-Ling
authors.initials: AP
authors.lastname: Chiu
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lal
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.).
authors.forename: Bahira
authors.initials: B
authors.lastname: Hussein
authors.affiliation: From the Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada (A.P.-L.C., A.W., N.L., D.Z., F.W., B.H., B.R.); and Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel (I.V.). rodrigue@mail.ubc.ca.
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000201:enzymology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D042783:Endothelial Cells / Q000201:enzymology*; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019899:Paracrine Communication; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D001786:Blood Glucose; D005966:Glucuronidase; D047908:Intracellular Signaling Peptides and Proteins; D008071:Lipoprotein Lipase; D008565:Membrane Proteins; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C579044:GPIHBP1 protein, rat; C064045:delta protein; C467498:vascular endothelial growth factor A, rat
keywords: Notch; heparanase; hyperglycemia; lipoprotein lipase; receptors; triglycerides