Tumor necrosis factor alpha stimulates p62 accumulation and enhances proteasome activity independently of ROS
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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.
KeywordsAutophagy Catabolism Proteasome TNF-α Ubiquitin
Congestive heart failure
Forkhead homeobox type O
Microtubule-associated protein 1A/1B-light chain 3
Muscle atrophy F-box
Muscle ring finger-1
Reactive oxygen species
Tumor necrosis factor-alpha
Tumor necrosis factor receptor 1/2
The authors would like to thank Stellenbosch University for funding this project.
- Bradham WS, Bozkurt B, Gunasinghe H, Mann D, Spinale FG. Tumor necrosis factor-alpha and myocardial remodelling in progression of heart failure: a current prospective. Science. 2002;53:822–30.Google Scholar
- Pandy UB. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447:859–63.Google Scholar