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Cardiac lipoprotein lipase function following diabetes is regulated by cardiomyocytes and endothelial cells

University of British Columbia

In diabetes, when glucose consumption is restricted, the heart adapts to use fatty acid (FA) exclusively. The majority of FA provided to the heart comes from breakdown of circulating triglyceride, a process catalyzed by lipoprotein lipase (LPL) located at the vascular lumen. Transfer of LPL from cardiomyocytes to the coronary lumen requires liberation of LPL from the myocyte surface heparan sulfate proteoglycans (HSPGs) with subsequent replenishment of this reservoir. We examined the contribution of coronary endothelial cells (EC) and cardiomyocytes towards regulation of LPL function following diabetes. To induce acute hyperglycemia, diazoxide (DZ), a selective ATP-sensitive K+ channel opener was used. For chronic diabetes, streptozotocin (STZ), a β-cell specific toxin was administered at doses of 55 (D55) or 100 (D100) mg/kg to generate moderate and severe diabetes, respectively. Cardiac LPL processing into active dimers and breakdown at the vascular lumen was investigated. Following acute hyperglycemia and moderate diabetes, more LPL is processed into an active dimeric form, which involves the endoplasmic reticulum chaperone calnexin in cardiomyocytes. Severe diabetes results in increased conversion of LPL into inactive monomers at the vascular lumen, a process mediated by FA-induced expression of angiopoietin-like protein 4. On exposure of bovine coronary artery EC to high glucose, both latent and active heparanase were released into the medium, termed ECCM. ECCM liberated LPL from the myocyte surface, in addition to facilitating its replenishment. Of the two 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 HSPG-mediated RhoA activation. Latent heparanase can be also taken up by cardiomyocytes, converted into active heparanase in lysosomes, and its nuclear entry likely to modulate gene expression. Results from this study advance our understanding of how the cross-talk between EC and cardiomyocytes facilitate LPL secretion and how diabetes influences coronary LPL maturation and turnover. Pharmaceutical manipulation of these pathways could potentially provide an additional strategy to limit FA delivery to the heart, and prevent cardiomyopathy seen with chronic diabetes.

Text

2014-03-20

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/46261

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/