title: Cardiac oxidative stress in a mouse model of neutral lipid storage disease.
abstract: Cardiac oxidative stress has been implicated in the pathogenesis of hypertrophy, cardiomyopathy and heart failure. Systemic deletion of the gene encoding adipose triglyceride lipase (ATGL), the enzyme that catalyzes the rate-limiting step of triglyceride lipolysis, results in a phenotype characterized by severe steatotic cardiac dysfunction. The objective of the present study was to investigate a potential role of oxidative stress in cardiac ATGL deficiency. Hearts of mice with global ATGL knockout were compared to those of mice with cardiomyocyte-restricted overexpression of ATGL and to those of wildtype littermates. Our results demonstrate that oxidative stress, measured as lucigenin chemiluminescence, was increased ~6-fold in ATGL-deficient hearts. In parallel, cytosolic NADPH oxidase subunits p67phox and p47phox were upregulated 4-5-fold at the protein level. Moreover, a prominent upregulation of different inflammatory markers (tumor necrosis factor α, monocyte chemotactant protein-1, interleukin 6, and galectin-3) was observed in those hearts. Both the oxidative and inflammatory responses were abolished upon cardiomyocyte-restricted overexpression of ATGL. Investigating the effect of oxidative and inflammatory stress on nitric oxide/cGMP signal transduction we observed a ~2.5-fold upregulation of soluble guanylate cyclase activity and a ~2-fold increase in cardiac tetrahydrobiopterin levels. Systemic treatment of ATGL-deficient mice with the superoxide dismutase mimetic Mn(III)tetrakis (4-benzoic acid) porphyrin did not ameliorate but rather aggravated cardiac oxidative stress. Our data suggest that oxidative and inflammatory stress seems involved in lipotoxic heart disease. Upregulation of soluble guanylate cyclase and cardiac tetrahydrobiopterin might be regarded as counterregulatory mechanisms in cardiac ATGL deficiency.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, 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, Institute of Pharmaceutical Sciences, 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, Institute of Pharmaceutical Sciences, 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: guenter.haemmerle@uni-graz.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, 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, Institute of Pharmaceutical Sciences, 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 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, Institute of Pharmaceutical Sciences, 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: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D016113:Ichthyosiform Erythroderma, Congenital / Q000378:metabolism*; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009135:Muscular Diseases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D000217:Acyltransferases
chemical_list: D008049:Lipase; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: (s)GC; (soluble) guanylate cyclase; 2,2-diethyl-1-nitroso-oxyhydrazine; ATGL; ATGL(−/−); Adipose triglyceride lipase; BH(2); BH(4); Cardiac hypertrophy; DAG; DEA/NO; FFA; GAPDH; IL-6; Inflammation; MCP-1; Mac-2; Mn(III)tetrakis (4-benzoic acid) porphyrin chloride; MnTBAP; NADPH; NADPH oxidase; NO; NOX; ONOO(−); Oxidative stress; PBS; PKC; PPARα; SOD; TG; TNFα; VASP; adipose triglyceride lipase; adipose triglyceride lipase knockout; diacylglycerol; dihydrobiopterin, [2-amino-6-(1,2-dihydroxypropyl)-7,8-dihydro-1H-pteridin-4-one]; eNOS; endothelial nitric oxide synthase; free fatty acid; galectin-3; glyceraldehyde-3-phosphate dehydrogenase; iNOS; inducible nitric oxide synthase; interleukin 6; monocyte chemotactic protein-1; nNOS; neuronal nitric oxide synthase; nicotinamide adenine dinucleotide phosphate; nitric oxide; pVASP; peroxisome proliferator receptor α; peroxynitrite; phosphate-buffered saline; phosphorylated vasodilator-stimulated phosphoprotein; protein kinase C; superoxide dismutase; tetrahydrobiopterin, [(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-one]; triacylglycerol; tumor necrosis factor α; vasodilator-stimulated phosphoprotein