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 act as a mediator of lipotoxicity in chronic diabetes. To this extent, the authors show that MMP-9 cleaves the myocyte surface proteoglycan, syndecan1. This is a key finding that explains how a vicious cycle of events is stimulated following endothelial exposure to hyperglycemia and thus turning on an endothelial2cardiomyocyte cross talk through the mediation of heparanase. Earlier studies in this area were focused on the transcription of LPL gene and regulation of this protein in the cardiac tissue in metabolic stress (8). Only in the past decade has interest grown in the mechanism of LPL shuttling from cardiomyocytes to the endothelial barrier surface, where it performs triglyceride breakdown. The same group has previously shown that there was an increased occupancy of LPL on the capillary endothelial cells in streptozotocin-induced diabetic animals (2). However, the exact signaling mechanism, which pushes LPL from cardiomyocyte to the membrane surface of endothelial cells, was not evident. Earlier studies from this group further showed that activation of AMPK-p38 MAP kinase leading to heat-shock protein 25 (Hsp25) phosphorylation and F-actin polymerization plays a role in recruiting LPL from cardiomyocyte inner side to the membrane surface (9). They further demonstrated the process of vesicular fission from the Golgi bodies, where the mature enzyme is emitted (10). A common target for both the processes was found to be Hsp25 (9,10). Phosphorylation of Hsp25 detaches it from protein kinase C d (PKCd); the dissociated PKCd activates downstream molecule protein kinase D, with subsequent stimulation of vesicular fission of LPL and transport to the membrane surface (10). Although information on how a cardiomyocyte surface LPL could reach the endothelial surface remained a mystery, several consequences of heparanase release were identified. Wang et al. (11) previously showed that the active form of heparanase, derived from the endothelial cells, helps in cleaving and releasing LPL from the heparin sulfate proteoglycans on cardiomyocyte cell surface, whereas the inactive form serves in bringing the intracellular LPL pool to the membrane surface following RhoA activation. Active heparanase also was found to release vascular endothelial growth factor (VEGF) from the same proteoglycan holder (12). The released VEGF may stimulate an autocrine signaling by signaling through VEGF receptors present on the cardiomyocyte cell surface, turning on the