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Regulation and function of heparanase in the heart Wang, Fulong

Abstract

Enzymatically-active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation 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. HG promoted both HepL and HepA secretion from EC, with subsequent uptake of HepL into cardiomyocytes. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition significantly reduced uptake. 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. We also tested if overexpression of heparanase can protect the heart against chemically induced or ischemia/reperfusion (I/R) injury. Mice overexpressing heparanase (Hep-tg) displayed physiological cardiac hypertrophy and changes in expression of genes related to the stress response, immune response, cell death, and development. These transcriptomic alterations were associated with promotion of unfolded protein response (UPR), autophagy, and oxidative stress resistance in a pro-survival direction. The UPR activation was adaptive and not apoptotic, and together with mTOR inhibition, induced autophagy. Subjecting wild type mice to thapsigargin evoked a transition from adaptive to apoptotic UPR, an effect attenuated in Hep-tg hearts. When exposed to I/R, infarct size and apoptosis were significantly lower in the Hep-tg heart, an effect reversed by inhibitors of UPR and autophagy. 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. Moreover, we established that the mechanisms by which heparanase promotes cell survival in cancer could be uniquely beneficial to the heart and exploited as a therapeutic target for the treatment of heart disease.

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