Evidence for rapid “metabolic switching” through lipoprotein lipase occupation of endothelial-binding sites

Pulinilkunnil, Thomas; Abrahani, Ashraf; Varghese, Jospy; Chan, Nathan; Tang, I Jian-Zhong; Ghosh, Sanjoy; Kulpa, Jerzy E.; Allard, Michael F.; Brownsey, Roger W.; Rodrigues, Brian

doi:10.1016/s0022-2828(03)00205-0

Cited by 45 publications

(56 citation statements)

References 45 publications

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“…8). Interestingly, we have previously shown that when compared with D55, animals with acute hyperglycemia (28.2 6 2.3 mmol/L compared with 5.9 6 1.0 mmol/L in controls) induced by diazoxide (4 h) are unable to maintain their high LPL activity at the vascular lumen after enzyme release by heparin (46). Because cardiomyocytes from diazoxide hearts do not increase MMP-9 expression ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2014

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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

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Section: Discussionmentioning

confidence: 92%

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

et al. 2014

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“…LPL activity is expressed as nanomoles oleate released per hour per milliliter. LPL gene expression was measured using RT-PCR (26), and protein expression was determined using the 5D2 monoclonal mouse anti-bovine LPL (generously provided by Dr. J. Brunzell, University of Washington, Seattle, WA) (27,28). Western blotting.…”

Section: Methodsmentioning

confidence: 99%

“…Isolated cardiac myocytes. Ventricular calcium-tolerant myocytes were prepared by a previously described procedure (23,28). Briefly, myocytes were made calcium tolerant by successive exposure to increasing concentrations of calcium.…”

Section: Methodsmentioning

confidence: 99%

Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization

et al. 2008

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OBJECTIVE-Heart disease is a leading cause of death in diabetes and could occur because of excessive use of fatty acid for energy generation. Our objective was to determine the mechanisms by which AMP-activated protein kinase (AMPK) augments cardiac lipoprotein lipase (LPL), the enzyme that provides the heart with the majority of its fatty acid.RESEARCH DESIGN AND METHODS-We used diazoxide in rats to induce hyperglycemia or used 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) and thrombin to directly stimulate AMPK and p38 mitogen-activated protein kinase (MAPK), respectively, in cardiomyocytes.RESULTS-There was a substantial increase in LPL at the coronary lumen following 4 h of diazoxide. In these diabetic animals, phosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actin cytoskeleton rearrangement to facilitate LPL translocation to the myocyte surface and, eventually, the vascular lumen. AICAR activated AMPK, p38 MAPK, and Hsp25 in a pattern similar to that seen with diabetes. AICAR also appreciably enhanced LPL, an effect reduced by preincubation with the p38 MAPK inhibitor SB202190 or by cytochalasin D, which inhibits actin polymerization. Thrombin activated p38 MAPK in the absence of AMPK phosphorylation. Comparable with diabetes, activation of p38 MAPK and, subsequently, Hsp25 phosphorylation and F-actin polymerization corresponded with an enhanced LPL activity. SB202190 and silencing of p38 MAPK also prevented these effects induced by thrombin and AICAR, respectively. CONCLUSIONS-We propose that AMPK recruitment of LPL to the cardiomyocyte surface (which embraces p38 MAPK activation and actin cytoskeleton polymerization) represents an immediate compensatory response by the heart to guarantee fatty acid supply when glucose utilization is compromised. Diabetes 57: 64-76, 2008

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“…The plasma LCAT activity was measured by determination of the amount of radioactivity in each spot calculating the free cholesterol/ total cholesterol ratio in each plasma sample before and after the LCAT reaction and thus estimating the esterification rate [28]. The fractional esterification rate (% .…”

Section: Experiments Designmentioning

confidence: 99%

Antioxidant Complexes and Lipoprotein Metabolism – Experience of Grape Extracts Application Under Metabolic Syndrome and Neurogenic Stress

Zagayko¹,

Kravchenko²,

Krasilnikova³

2012

Lipoproteins - Role in Health and Diseases

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Evidence for rapid “metabolic switching” through lipoprotein lipase occupation of endothelial-binding sites

Cited by 45 publications

References 45 publications

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

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

Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization

Antioxidant Complexes and Lipoprotein Metabolism – Experience of Grape Extracts Application Under Metabolic Syndrome and Neurogenic Stress

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