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Molecular Medicine

, Volume 20, Issue 1, pp 313–328 | Cite as

Modulation of Poly(ADP-Ribose) Polymerase-1 (PARP-1)-Mediated Oxidative Cell Injury by Ring Finger Protein 146 (RNF146) in Cardiac Myocytes

  • Domokos Gerö
  • Petra Szoleczky
  • Athanasia Chatzianastasiou
  • Andreas Papapetropoulos
  • Csaba Szabo
Research Article

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) activation is a hallmark of oxidative stress-induced cellular injury that can lead to energetic failure and necrotic cell death via depleting the cellular nicotinamide adenine dinucleotide (NAD+) and ATP pools. Pharmacological PARP-1 inhibition or genetic PARP-1 deficiency exert protective effects in multiple models of cardiomyocyte injury. However, the connection between nuclear PARP-1 activation and depletion of the cytoplasmic and mitochondrial energy pools is poorly understood. By using cultured rat cardiomyocytes, here we report that ring finger protein 146 (RNF146), a cytoplasmic E3-ubiquitin ligase, acts as a direct interactor of PARP-1. Overexpression of RNF146 exerts protection against oxidant-induced cell death, whereas PARP-1-mediated cellular injury is augmented after RNF146 silencing. RNF146 translocates to the nucleus upon PARP-1 activation, triggering the exit of PARP-1 from the nucleus, followed by rapid degradation of both proteins. PARP-1 and RNF146 degradation occurs in the early phase of myocardial ischemia-reperfusion injury; it precedes the induction of heat shock protein expression. Taken together, PARP-1 release from the nucleus and its rapid degradation represent newly identified steps of the necrotic cell death program induced by oxidative stress. These steps are controlled by the ubiquitin-proteasome pathway protein RNF146. The current results shed new light on the mechanism of necrotic cell death. RNF146 may represent a distinct target for experimental therapeutic intervention of oxidant-mediated cardiac injury.

Notes

Acknowledgments

This work was supported by the National Institutes of Health (to C Szabo) (R01GM056687).

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Authors and Affiliations

  • Domokos Gerö
    • 1
  • Petra Szoleczky
    • 1
  • Athanasia Chatzianastasiou
    • 2
  • Andreas Papapetropoulos
    • 2
  • Csaba Szabo
    • 1
  1. 1.Department of AnesthesiologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Faculty of PharmacyUniversity of AthensAthensGreece

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