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Cardiac oxidative stress in a mouse model of neutral lipid storage disease
Authors:Astrid Schrammel  Marion Mussbacher  Sarah Winkler  Guenter Haemmerle  Heike Stessel  Gerald Wölkart  Rudolf Zechner  Bernd Mayer
Institution:1. Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria;2. Department of Molecular Biosciences, University of Graz, Heinrichstraße 31, 8010 Graz, Austria
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.
Keywords:ATGL  adipose triglyceride lipase  ATGL(&minus  /&minus  )  adipose triglyceride lipase knockout  BH2  dihydrobiopterin  [2-amino-6-(1  2-dihydroxypropyl)-7  8-dihydro-1H-pteridin-4-one]  BH4  tetrahydrobiopterin  [(6R)-2-amino-6-[(1R  2S)-1  2-dihydroxypropyl]-5  6  7  8-tetrahydropteridin-4(1H)-one]  DEA/NO  2  2-diethyl-1-nitroso-oxyhydrazine  DAG  diacylglycerol  eNOS  endothelial nitric oxide synthase  FFA  free fatty acid  GAPDH  glyceraldehyde-3-phosphate dehydrogenase  (s)GC  (soluble) guanylate cyclase  IL-6  interleukin 6  Mac-2  galectin-3  MCP-1  monocyte chemotactic protein-1  MnTBAP  Mn(III)tetrakis (4-benzoic acid) porphyrin chloride  NADPH  nicotinamide adenine dinucleotide phosphate  iNOS  inducible nitric oxide synthase  nNOS  neuronal nitric oxide synthase  NO  nitric oxide  NOX  NADPH oxidase  ONOO&minus    peroxynitrite  PBS  phosphate-buffered saline  PKC  protein kinase C  PPARα  peroxisome proliferator receptor α  SOD  superoxide dismutase  TG  triacylglycerol  TNFα  tumor necrosis factor α  VASP  vasodilator-stimulated phosphoprotein  pVASP  phosphorylated vasodilator-stimulated phosphoprotein
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