Ying Wang, 1 Amy Pei-Ling Chiu, 1 Katharina Neumaier, 1 Fulong Wang, 1 Dahai Zhang, 1 Bahira Hussein, 1 Nathaniel Lal, 1 Andrea Wan, 1 George Liu, 2 Israel Vlodavsky, 3 and Brian Rodrigues 1 Endothelial Cell Heparanase Taken Up by Cardiomyocytes Regulates Lipoprotein Lipase Transfer to the Coronary Lumen After Diabetes Diabetes 2014;63:2643–2655 | DOI: 10.2337/db13-1842 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 us ing 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 trans- location 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 car- diomyopathy observed after diabetes. In diabetes, because glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) exclusively for ATP generation (1). Multiple adaptive mechanisms, either whole-body or intrinsic to the heart, operate to make this achievable, with hydrolysis of triglyceride-rich lipoproteins being the major source of FA to the diabetic heart (2). This critical reaction is cata- lyzed by the vascular content of lipoprotein lipase (LPL), and we were the first to report significantly higher coro- nary LPL activity after diabetes (3). In the heart, LPL is synthesized by cardiomyocytes, transported to heparan sulfate (HS) proteoglycan (HSPG) binding sites on the myocyte surface, and from this temporary reservoir, the enzyme is transferred across the interstitial space to reach endothelial cells (EC) (4,5). Before this transfer, liberation of HSPG-sequestered LPL is a prerequisite and is facili- tated by heparanase, an EC endoglycosidase that can cleave HS side chains on HSPGs in the extracellular ma- trix and on the cell surface to release bound proteins (6). Heparanase is synthesized as a latent 65-kDa precursor. After its secretion and reuptake (7), heparanase enters 1 Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada 2 Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovas- cular Sciences, Peking University, Beijing, China 3 Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel Corresponding author: Brian Rodrigues, rodrigue@mail.ubc.ca. Received 5 December 2013 and accepted 3 March 2014. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1842/-/DC1. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See accompanying article, p. 2600. Diabetes Volume 63, August 2014 2643 METABOLISM