title: Tumor necrosis factor alpha stimulates p62 accumulation and enhances proteasome activity independently of ROS.
abstract: Circulating TNF-α levels are elevated in a wide variety of cardiovascular pathologies including congestive heart failure (CHF). This cytokine is one of the leading mediators of the immune inflammatory response with widespread biological functions regulated by membrane receptors. The pathophysiological implication of the downstream effects of activating the TNF-α system in CHF appears to depend on its direct effects on the heart and endothelium. Evidence supporting the notion that circulating TNF-α promotes protein breakdown was initially obtained from studies utilizing transgenic animals overexpressing TNF-α, animals with experimental diseases that augment TNF-α and in animals treated with exogenous TNF-α. It was then demonstrated that TNF-α acts directly on cultured myotubes to stimulate catabolism; however, whether the effects are the same in the heart remains poorly understood. The present study shows that TNF-α treatment induces autophagy, but clearance through this pathway appears obstructed and, consequently, results in increased protein ubiquitination. Furthermore, prolonged TNF-α treatment enhanced E3 ubiquitin ligase expression but reduced activity of the proteasome. These results suggest that TNF-α induces sarcomeric dysfunction and remodeling by disrupting autophagy and elevating the degradation of myofibrillar proteins. Therefore, myocardial remodeling, as a consequence to reduced contractile proteins, contributes to contractile dysfunction, a symptom often observed in the end stages of CHF.
authors.affiliation: Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
authors.forename: Caleigh M
authors.initials: CM
authors.lastname: Opperman
authors.forename: Balindiwe J N
authors.initials: BJ
authors.lastname: Sishi
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D017382:Reactive Oxygen Species; D044843:SKP Cullin F-Box Protein Ligases; D000071456:Sequestosome-1 Protein; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; C526109:Anxa3 protein, rat; C491079:Sqstm1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C486692:Fbxo32 protein, rat; C499086:Trim63 protein, rat