title: Endothelial dysfunction in adipose triglyceride lipase deficiency.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: astrid.schrammel-gorren@uni-graz.at.
authors.forename: Astrid
authors.initials: A
authors.lastname: Schrammel
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: marion.mussbacher@uni-graz.at.
authors.forename: Marion
authors.initials: M
authors.lastname: Mussbacher
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: gerald.woelkart@uni-graz.at.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wölkart
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: heike.stessel@uni-graz.at.
authors.forename: Heike
authors.initials: H
authors.lastname: Stessel
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: karoline.pail@uni-graz.at.
authors.forename: Karoline
authors.initials: K
authors.lastname: Pail
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: sarah.winkler@uni-graz.at.
authors.forename: Sarah
authors.initials: S
authors.lastname: Winkler
authors.affiliation: Department of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria. Electronic address: tina.schweiger@uni-graz.at.
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: Department of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria. Electronic address: guenter.haemmerle@uni-graz.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8010 Graz, Austria. Electronic address: wael.alzoughbi@stud.medunigraz.at.
authors.forename: Wael
authors.initials: W
authors.lastname: Al Zoughbi
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8010 Graz, Austria. Electronic address: gerald.hoefler@medunigraz.at.
authors.forename: Gerald
authors.initials: G
authors.lastname: Höfler
authors.affiliation: Department of Cell Biology and Physiology, Vessel and Muscle Research Unit, University of Salzburg, Hellbrunnerstrasse 34, 5020 Salzburg, Austria. Electronic address: Alois.Lametschwandtner@sbg.ac.at.
authors.forename: Alois
authors.initials: A
authors.lastname: Lametschwandtner
authors.affiliation: Department of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria. Electronic address: rudolf.zechner@uni-graz.at.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: mayer@uni-graz.at.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008049:Lipase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D009765:Obesity / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D008049:Lipase; D019001:Nitric Oxide Synthase; D047493:PPAR alpha; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: Adipose triglyceride lipase; Endothelial NO synthase; Endothelial dysfunction; Perivascular inflammation; Vascular proteasome