title: Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice.
abstract: Systemic deletion of the gene encoding for adipose triglyceride lipase (ATGL) in mice leads to severe cardiac dysfunction due to massive accumulation of neutral lipids in cardiomyocytes. Recently, impaired peroxisome proliferator-activated receptor α (PPARα) signaling has been described to substantially contribute to the observed cardiac phenotype. Disturbances of the ubiquitin-proteasome system (UPS) have been implicated in numerous cardiac diseases including cardiomyopathy, ischemic heart disease, and heart failure. The objective of the present study was to investigate the potential role of UPS in cardiac ATGL deficiency. Our results demonstrate prominent accumulation of ubiquitinated proteins in hearts of ATGL-deficient mice, an effect that was abolished upon cardiomyocyte-directed overexpression of ATGL. In parallel, cardiac protein expression of the ubiquitin-activating enzyme E1a, which catalyzes the first step of the ubiquitination cascade, was significantly upregulated in ATGL-deficient hearts. Dysfunction of the UPS was accompanied by activation of NF-κB signaling. Moreover, the endoplasmic reticulum (ER)-resident chaperon protein disulfide isomerase was significantly upregulated in ATGL-deficient hearts. Chronic treatment of ATGL-deficient mice with the PPARα agonist Wy14,643 improved proteasomal function, prevented NF-κB activation and decreased oxidative stress. In summary, our data point to a hitherto unrecognized link between proteasomal function, PPARα signaling and cardiovascular disease.
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-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, A-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, A-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, A-8010 Graz, Austria. Electronic address: guenter.haemmerle@uni-graz.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.affiliation: Department of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-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, A-8010 Graz, Austria. Electronic address: mayer@uni-graz.at.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
authors.affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: astrid.schrammel-gorren@uni-graz.at.
authors.forename: Astrid
authors.initials: A
authors.lastname: Schrammel
mesh_terms: D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000201:enzymology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D008049:Lipase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; D047493:PPAR alpha; D011743:Pyrimidines; D057149:Ubiquitinated Proteins; C006253:pirinixic acid; D008049:Lipase; D046988:Proteasome Endopeptidase Complex
keywords: Adipose triglyceride lipase; Cardiac dysfunction; Inflammation; NF-κB; Peroxisome proliferator-activated receptor α