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

Abstract

After diabetes, the heart has a singular reliance on fatty acid (FA) for energy production, which is achieved by increased coronary lipoprotein lipase (LPL) that breaks down circulating triglycerides. Coronary LPL originates from cardiomyocytes, and to translocate to the vascular lumen, the enzyme requires liberation from myocyte surface heparan sulfate proteoglycans (HSPGs), an activity that needs to be sustained after chronic hyperglycemia. We investigated the mechanism by which endothelial cells (EC) and cardiomyocytes operate together to enable continuous translocation of LPL after diabetes. EC were cocultured with myocytes, exposed to high glucose, and uptake of endothelial heparanase into myocytes was determined. Upon uptake, the effect of nuclear entry of heparanase was also investigated. A streptozotocin model of diabetes was used to expand our in vitro observations. In high glucose, EC-derived latent heparanase was taken up by cardiomyocytes by a caveolae-dependent pathway us ing HSPGs. This latent heparanase was converted into an active form in myocyte lysosomes, entered the nucleus, and upregulated gene expression of matrix metalloproteinase-9. The net effect was increased shedding of HSPGs from the myocyte surface, releasing LPL for its onwards translocation to the coronary lumen. EC-derived heparanase regulates the ability of the cardiomyocyte to send LPL to the coronary lumen. This adaptation, although acutely beneficial, could be catastrophic chronically because excess FA causes lipotoxicity. Inhibiting heparanase function could offer a new strategy for managing cardiomyopathy observed after diabetes.In diabetes, because glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) exclusively for ATP generation (1). Multiple adaptive mechanisms, either whole-body or intrinsic to the heart, operate to make this achievable, with hydrolysis of triglyceride-rich lipoproteins being the major source of FA to the diabetic heart (2). This critical reaction is catalyzed by the vascular content of lipoprotein lipase (LPL), and we were the first to report significantly higher coronary LPL activity after diabetes (3). In the heart, LPL is synthesized by cardiomyocytes, transported to heparan sulfate (HS) proteoglycan (HSPG) binding sites on the myocyte surface, and from this temporary reservoir, the enzyme is transferred across the interstitial space to reach endothelial cells (EC) (4,5). Before this transfer, liberation of HSPG-sequestered LPL is a prerequisite and is facilitated by heparanase, an EC endoglycosidase that can cleave HS side chains on HSPGs in the extracellular matrix and on the cell surface to release bound proteins (6).Heparanase is synthesized as a latent 65-kDa precursor. After its secretion and reuptake (7), heparanase enters

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

“…5,[7][8][9] Following its nuclear entry, Hep A also influences transcription by cleaving nuclear HSPG, mitigating the suppressive effect of heparan sulphate on histone acetyltransferase. [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.…”

“…[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.…”

The role of triacylglycerol in cardiac energy provision

“…14 translational (?heparanase-mediated) mechanisms, with increased H-LPL in diabetes [22,23] as a consequence of the hyperglycemia [53].…”

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

“…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.…”

“…The released VEGF may stimulate an autocrine signaling by signaling through VEGF receptors present on the cardiomyocyte cell surface, turning on the AMPK-p38 MAP kinase pathway and rearranging cytoskeleton to propagate the LPL vesicles from inside of cardiomyocyte to the outer membrane (12). Wang et al (7) showed that heparanase augments cellular transcriptional machinery through increased histone acetyl transferase (HAT) activity (Fig. 1).…”