title: High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature.
abstract: The secretion of enzymatically active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepLfrom the endothelial cell (EC), HepLuptake and function can protect the cardiomyocyte by modifying its cell death signature.
  
  
  
  HG promoted both HepLand HepAsecretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepLreuptake. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition using small interfering RNA (siRNA), receptor-associated protein, or an LRP1 neutralizing antibody significantly reduced uptake. In cardiomyocytes, which have a negligible amount of heparanase gene expression, LRP1 also participated in the uptake of HepL. Exogenous addition of HepLto rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes.
  
  
  
  Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Jia
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lal
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Amy Pei-Ling
authors.initials: AP
authors.lastname: Chiu
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Bahira
authors.initials: B
authors.lastname: Hussein
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3 rodrigue@interchange.ubc.ca.
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D058065:Diabetic Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin; D013997:Time Factors; D059467:Transcriptome; D014162:Transfection; D000099175:Heparanase
chemical_list: D057134:Antibodies, Neutralizing; D005947:Glucose; D005966:Glucuronidase; D011973:Receptors, LDL; D013311:Streptozocin; D000099175:Heparanase
keywords: Cardiomyocyte; Cell death; Diabetes; Endothelial cell; Hyperglycemia; LRP1