Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice.
Bottom Line: Dysfunction of the UPS was accompanied by activation of NF-κB signaling.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.
Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: email@example.com.Show MeSH
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Mentions: Our current working hypothesis is depicted in Scheme 1. ATGL deficiency in cardiomyocytes results in massively reduced triacylglyceride hydrolysis and consequently decreased production of lipid ligands for PPARα activation (e.g. fatty acids, acyl-CoA and various fatty acid-derived compounds) . As PPARα signaling is an important key player in energy metabolism and inflammation, its downregulation leads to deleterious consequences such as disrupted mitochondrial substrate oxidation and consequent decreased ATP production. Since ATP is required for 19S-mediated channel opening and substrate unfolding, limited ATP availability causes decreased activation of the 26S proteasome (path 1). Proteasomal dysfunction entails insufficient degradation of target proteins, thus resulting in accumulation and aggregation of ubiquitinated products. In a circulus vitiosus, these aggregates further inhibit proteasomal activities, which causes additional cellular stress . Considering the presence of oxidative inflammatory stress in AKO animals, disturbances of the cardiac UPS might also originate from oxidative modifications of critical residues within the catalytic core of the proteasome (path 2). Recent studies have shown that distinct subunits are susceptible to oxidative modifications, including carbonylation, hydroxynonenal-mediated alkylation, and S-glutathionylation [23,30–32]. In addition, enhanced superoxide production may also cause protein crosslinking through formation of Schiff bases and/or disulfide bridges  which might lead to saturation of the proteasome by non-degradable aggregates (path 3). Defective proteasomal activity together with mitochondrial dysfunction is implicated in the development of cardiac dysfunction and premature death of AKO animals. Pharmacological intervention with the PPARα agonist Wy14,643 improves mitochondrial and proteasomal functions as well as oxidative and inflammatory stress.
Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: firstname.lastname@example.org.