Endothelial dysfunction in adipose triglyceride lipase deficiency
| Autor: | Schrammel, Astrid, Mussbacher, Marion, Wölkart, Gerald, Stessel, Heike, Pail, Karoline, Winkler, Sarah, Schweiger, Martina, Haemmerle, Guenter, Al Zoughbi, Wael, Höfler, Gerald, Lametschwandtner, Alois, Zechner, Rudolf, Mayer, Bernd |
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| Jazyk: | angličtina |
| Předmět: |
PVAT
perivascular adipose tissue PDI protein disulfide isomerase XBP1 X-box-binding protein 1 Mac-2 galectin-3 Hsp90 heat shock protein 90 Perivascular inflammation Adipose triglyceride lipase PEG polyethyleneglycol Mice IRE-1α inostitol-requiring enzyme 1α Endothelial dysfunction HO-1 heme oxygenase-1 Mice Knockout CPP coronary perfusion pressure Endothelial NO synthase eNOS endothelial nitric oxide synthase WAT white adipose tissue MCP-1 monocyte chemotactic protein-1 NOX NADPH oxidase TG triacylglycerol TNFα tumor necrosis factor α IL-6 interleukin 6 Adipose Tissue GAPDH glyceraldehyde-3-phosphate dehydrogenase BK bradykinin NLSDM neutral lipid storage disease with myopathy pVASP phosphorylated vasodilator-stimulated phosphoprotein Myocytes Smooth Muscle PBS phosphate-buffered saline DMEM Dulbecco's Modified Eagle Medium Article Gene Expression Regulation Enzymologic α-SMA α-smooth muscle actin Organ Culture Techniques SOD superoxide dismutase Animals Humans PPAR alpha Obesity Molecular Biology Triglycerides DEA/NO 2 2-diethyl-1-nitroso-oxyhydrazine Heart Failure ATGL adipose triglyceride lipase EDTA ethylenediaminetetraacetic acid ACh acetylcholine Lipase Cell Biology Vascular proteasome Lipid Metabolism WT wild-type BIP binding immunoglobulin protein Disease Models Animal Oxidative Stress AKO adipose triglyceride lipase knockout H&E hematoxylin and eosin BSA bovine serum albumin CL chemiluminescence PPARα peroxisome proliferator receptor α U 46619 9 11-dideoxy-9α 11α-epoxy-methanoprostaglandin F2α CD31 cluster of differentiation 31 Nitric Oxide Synthase VASP vasodilator-stimulated phosphoprotein |
| Zdroj: | Biochimica et Biophysica Acta |
| ISSN: | 1388-1981 |
| DOI: | 10.1016/j.bbalip.2014.03.005 |
| Popis: | Systemic knockout of adipose triglyceride lipase (ATGL), the pivotal enzyme of triglyceride lipolysis, results in a murine phenotype that is characterized by progredient cardiac steatosis and severe heart failure. Since cardiac and vascular dysfunction have been closely related in numerous studies we investigated endothelium-dependent and -independent vessel function of ATGL knockout mice. Aortic relaxation studies and Langendorff perfusion experiments of isolated hearts showed that ATGL knockout mice suffer from pronounced micro- and macrovascular endothelial dysfunction. Experiments with agonists directly targeting vascular smooth muscle cells revealed the functional integrity of the smooth muscle cell layer. Loss of vascular reactivity was restored ~ 50% upon treatment of ATGL knockout mice with the PPARα agonist Wy14,643, indicating that this phenomenon is partly a consequence of impaired cardiac contractility. Biochemical analysis revealed that aortic endothelial NO synthase expression and activity were significantly reduced in ATGL deficiency. Enzyme activity was fully restored in ATGL mice treated with the PPARα agonist. Biochemical analysis of perivascular adipose tissue demonstrated that ATGL knockout mice suffer from perivascular inflammatory oxidative stress which occurs independent of cardiac dysfunction and might contribute to vascular defects. Our results reveal a hitherto unrecognized link between disturbed lipid metabolism, obesity and cardiovascular disease. Graphical abstract Highlights • AKO mice suffer from severe micro- and macrovascular endothelial dysfunction. • Aortic eNOS protein is downregulated in ATGL deficiency due to enhanced proteasomal degradation. • PVAT of AKO mice exhibits characteristics of chronic inflammatory oxidative stress. • At least two independent mechanisms are involved in the endothelial defect. |
| Databáze: | OpenAIRE |
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