title: Endothelial cell heparanase taken up by cardiomyocytes regulates lipoprotein lipase transfer to the coronary lumen after diabetes.
abstract: After diabetes, the heart has a singular reliance on fatty acid (FA) for energy production, which is achieved by increased coronary lipoprotein lipase (LPL) that breaks down circulating triglycerides. Coronary LPL originates from cardiomyocytes, and to translocate to the vascular lumen, the enzyme requires liberation from myocyte surface heparan sulfate proteoglycans (HSPGs), an activity that needs to be sustained after chronic hyperglycemia. We investigated the mechanism by which endothelial cells (EC) and cardiomyocytes operate together to enable continuous translocation of LPL after diabetes. EC were cocultured with myocytes, exposed to high glucose, and uptake of endothelial heparanase into myocytes was determined. Upon uptake, the effect of nuclear entry of heparanase was also investigated. A streptozotocin model of diabetes was used to expand our in vitro observations. In high glucose, EC-derived latent heparanase was taken up by cardiomyocytes by a caveolae-dependent pathway using HSPGs. This latent heparanase was converted into an active form in myocyte lysosomes, entered the nucleus, and upregulated gene expression of matrix metalloproteinase-9. The net effect was increased shedding of HSPGs from the myocyte surface, releasing LPL for its onwards translocation to the coronary lumen. EC-derived heparanase regulates the ability of the cardiomyocyte to send LPL to the coronary lumen. This adaptation, although acutely beneficial, could be catastrophic chronically because excess FA causes lipotoxicity. Inhibiting heparanase function could offer a new strategy for managing cardiomyopathy observed after diabetes.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Amy Pei-Ling
authors.initials: AP
authors.lastname: Chiu
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Katharina
authors.initials: K
authors.lastname: Neumaier
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Bahira
authors.initials: B
authors.lastname: Hussein
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lal
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University, Beijing, China.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada rodrigue@mail.ubc.ca.
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D021941:Caveolae / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000099175:Heparanase
chemical_list: D034281:Dynamins; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D008071:Lipoprotein Lipase; D011505:Protein-Tyrosine Kinases; D000099175:Heparanase