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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 HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>HG promoted both HepL and HepA secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepL reuptake. 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 HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2 induced 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1093\/cvr\/cvw211","type":"journal-article","created":{"date-parts":[[2016,11,19]],"date-time":"2016-11-19T04:05:52Z","timestamp":1479528352000},"page":"656-668","source":"Crossref","is-referenced-by-count":15,"title":["High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature"],"prefix":"10.1093","volume":"112","author":[{"given":"Fulong","family":"Wang","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Jia","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 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