Heparanase Shakes Hands With Lipoprotein Lipase: A Tale of Two Cells

Altered metabolism with excess provision of lipid substrates may be a major pathogenetic factor linking diabetes with cardiovascular disease—lipoprotein lipase (LPL) being one facilitator of such a process (1,2). Hyperlipidemia, by itself, plays a major role in lipid-provoked cardiovascular pathologies, largely mediated through LPL (3). Under physiological state, due to their presence on the endothelial cell surface, LPLs break down triglyceride lipoproteins in the circulation and provide tissues, like heart and skeletal muscle, with the required fatty acid substrates to derive ATP (3,4). A large volume of data, using genetically manipulated animal models and clinical studies, has found that LPL homeostasis is required for normal cardiac metabolism and function (5,6). In diabetes, increased metabolic demand of the heart is met by the breakdown of fatty acids by coronary LPL. LPL is produced by cardiomyocytes, which need endothelial-derived heparanase for LPL production. In this issue, Wang et al. (7) demonstrated that endothelial heparanase is taken up by the cardiomyocytes through caveolae and is converted to an active form in the lysosomal compartments of these cells. Endothelium-derived heparanase is instrumental for cleaving and releasing LPL from the heparan sulfate proteoglycans on the cardiomyocyte cell surface. Activated heparanase further translocates in the nucleus, increases histone acetylation, and augments matrix metalloproteinase-9 (MMP-9) production. Although this is an adaptive mechanism, increased MMP-9 may …