Endothelial Heparanase Regulates Heart Metabolism by Stimulating Lipoprotein Lipase Secretion From Cardiomyocytes

Abstract

A fter diabetes mellitus, the heart has an increased reliance on fatty acids (FAs) for generation of energy.1 The majority of these FAs come from breakdown of circulating triglyceride-rich lipoproteins, a process catalyzed by lipoprotein lipase (LPL) located at the luminal side of vascular endothelial cells (ECs).2-4 ECs do not express LPL. In the heart, LPL is synthesized in cardiomyocytes and secreted to ECs. 5 We have previously reported an increase of coronary LPL in animal models of type 1 diabetes mellitus, an effect that was evident in the absence of any change in myocyte LPL gene expression. 6,7 We concluded that the augmented coronary LPL was a result of increased secretion of the enzyme from myocytes toward the coronary lumen. Regarding secretion, LPL is first transported from an intracellular pool in the myocyte to the cell surface, where it binds to heparan sulfate proteoglycans (HSPGs). 8 We have shown that this intracellular transport depends on actin cytoskeleton polymerization, a process that is magnified after diabetes mellitus.9,10 The subsequent process by which myocyte surface LPL is translocated to the coronary lumen, in addition to its replenishment after this onward movement, has not been completely elucidated.Myocyte surface HSPGs serve as a temporary docking site and an auxiliary reservoir of LPL. HSPGs are proteoglycans bearing HS side chains attached to specific serine residues of a protein core.11 Core proteins can be attached to the cell surface through a glycosylphosphatidyl inositol anchor in case of glypican, or can traverse the membrane as observed with the syndecan family.12,13 The HS side chains are polymers of repeating disaccharides which interact with multiple ligands, including antithrombin, fibroblast growth factor, and LPL. Objective-After diabetes mellitus, transfer of lipoprotein lipase (LPL) from cardiomyocytes to the coronary lumen increases, and this requires liberation of LPL from the myocyte surface heparan sulfate proteoglycans with subsequent replenishment of this reservoir. At the lumen, LPL breaks down triglyceride to meet the increased demand of the heart for fatty acid. Here, we examined the contribution of coronary endothelial cells (ECs) toward regulation of cardiomyocyte LPL secretion. Approach and Results-Bovine coronary artery ECs were exposed to high glucose, and the conditioned medium was used to treat cardiomyocytes. EC-conditioned medium liberated LPL from the myocyte surface, in addition to facilitating its replenishment. This effect was attributed to the increased heparanase content in EC-conditioned medium. Of the 2 forms of heparanase secreted from EC in response to high glucose, active heparanase released LPL from the myocyte surface, whereas latent heparanase stimulated reloading of LPL from an intracellular pool via heparan sulfate proteoglycanmediated RhoA activation. Conclusions-Endothelial heparanase is a participant in facilitating LPL increase at the coronary lumen. These observations provide an insight into the cross-talk between ECs ...

Endothelial Cell Heparanase Taken Up by Cardiomyocytes Regulates Lipoprotein Lipase Transfer to the Coronary Lumen After Diabetes

“…As we previously reported (18), glucose stimulated secretion of the latent and active forms of heparanase from EC (Fig. 7A).…”

“…In CHO cells, latent heparanase triggers clustering of both syndecan-1 and -4, followed by rapid internalization of the heparanase-HSPG complex (31). Because we have previously reported clustering of syndecan-4 when cardiomyocytes are exposed to latent heparanase (18), it is possible that such a heparanase-HSPG complex is also responsible for endocytosis of this enzyme in cardiomyocytes. Nevertheless, we cannot rule out the contributive effects of other receptors, such as LDL receptor-related proteins and mannose 6-phosphate receptors, in this heparanase-uptake process (32).…”

“…Interestingly, human fibroblasts that do not express heparanase can take up exogenous latent heparanase and convert it into active heparanase (17). Thus, an immediate response to hyperglycemia is an EC secretion of active heparanase to facilitate translocation of LPL from the myocyte surface to the coronary lumen (18). Given that the active heparanase pool in EC is limited and may not meet the demand for a sustained LPL transfer after diabetes, it is possible that latent heparanase could be taken up and converted to active heparanase in cardiomyocytes.…”

High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature

“…[10][11][12][13][14] More recently, we established a novel role for Hep A in modulating cardiac metabolism during diabetes. 10,15 The above studies in cancer and diabetes fixated on the effects of Hep A , incorrectly assuming that only the HSPG-hydrolyzing ability of heparanase was of importance. Intriguingly, Hep L also has some remarkable properties, including its ability to activate signalling elements like Erk1/2, PI3K-AKT, RhoA, and Src, which in turn can contribute to changes in transcription.…”

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

“…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).…”