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Cell Biology and Toxicology

, Volume 31, Issue 2, pp 83–94 | Cite as

Tumor necrosis factor alpha stimulates p62 accumulation and enhances proteasome activity independently of ROS

  • Caleigh M. Opperman
  • Balindiwe J. N. Sishi
Original Research

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.

Keywords

Autophagy Catabolism Proteasome TNF-α Ubiquitin 

Abbreviations

ATP

Adenosine triphosphate

CHF

Congestive heart failure

FoxO

Forkhead homeobox type O

LC3

Microtubule-associated protein 1A/1B-light chain 3

MAFbx

Muscle atrophy F-box

MuRF-1

Muscle ring finger-1

ROS

Reactive oxygen species

SQSTM1

Sequestosome 1

TNF-α

Tumor necrosis factor-alpha

TNF-R1/2

Tumor necrosis factor receptor 1/2

UPP

Ubiquitin–proteasome pathway

Notes

Acknowledgments

The authors would like to thank Stellenbosch University for funding this project.

Supplementary material

10565_2015_9295_MOESM1_ESM.doc (54 kb)
Supplementary Figure 1 The cytotoxicity of different concentrations of TNF-α on H9C2 cells over a total period of 48 hr. All values are expressed as a percentage of control. *p < 0.01, # p < 0.001, p < 0.0001 vs. respective control (C), n = 6. (DOC 53 kb)
10565_2015_9295_MOESM2_ESM.doc (156 kb)
Supplementary Figure 2 TNF-R1 protein expression as measured by western blot in H9C2 cells following treatment with TNF-α. TNF-R1 is expressed as a percentage of the control. p = 0.0001 vs. respective control (C), n = 4. (DOC 155 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Department of Physiological SciencesStellenbosch UniversityStellenboschSouth Africa

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