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: To investigate the mechanism underlying cardiac inflammation in ATGL deficiency  we analyzed crucial parameters of canonical NF-κB signaling (for review, see ). As illustrated in Fig. 2A, cardiac ATGL deficiency led to increased protein expression of the IκB kinase (IKK) complex as IKKα protein levels were significantly elevated in homogenates of AKO mice. By contrast, IKKβ protein expression was similar in all experimental groups (Fig. 2B). Furthermore, AKO hearts showed a more than 3-fold increased NF-κB RelA/p65 protein expression that was normalized to WT levels in hearts of AKO/cTg mice (Fig. 2C). Phosphorylation of NF-κB RelA/p65 at serine 536, which is thought to activate the NF-κB complex independently of IκB release , was also markedly elevated in AKO hearts (Fig. 2D). However, the ratio of phosphorylated to total NF-κB protein was unaffected by ATGL knockout (data not shown). Cardiac protein levels of IκB (which reacts with NF-κB to form an inactive cytosolic complex) were increased nearly 2-fold in AKO mice (Fig. 2E). All markers of NF-κB signaling that were increased in AKO mice were restored in AKO/cTg mice. Representative Western blots are shown in Fig. 2F. Activation of cardiac NF-κB signaling was supported by qPCR experiments showing that mRNA levels of selected NF-κB target genes including TNFα, monocyte chemoattractant protein-1 (MCP-1), IL-6, heme oxygenase-1 (HO-1), and GTP cyclohydrolase 1 (GTPCH-1) were significantly increased in AKO hearts (Fig. 2G).
Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: firstname.lastname@example.org.