PMID- 35983756
OWN - NLM
STAT- MEDLINE
DCOM- 20220922
LR  - 20230921
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 146
IP  - 12
DP  - 2022 Sep 20
TI  - Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in 
      Doxorubicin-Cardiomyopathy.
PG  - 934-954
LID - 10.1161/CIRCULATIONAHA.121.058411 [doi]
AB  - BACKGROUND: Cytokines such as tumor necrosis factor-alpha (TNFalpha) have been implicated 
      in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although 
      TNFalpha can elicit different cellular responses, including survival or death, the 
      mechanisms underlying these divergent outcomes in the heart remain cryptic. The 
      E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical 
      signaling platform for K63-linked polyubiquitination of RIPK1 (receptor 
      interacting protein 1), crucial for nuclear factor-kappaB (NF-kappaB) activation by TNFalpha 
      and survival. Here, we investigate alterations in TNFalpha-TRAF2-NF-kappaB signaling in 
      the pathogenesis of DOX cardiotoxicity. METHODS: Using a combination of in vivo 
      (4 weekly injections of DOX 5 mg.kg(-1).wk(-1)) in C57/BL6J mice and in vitro 
      approaches (rat, mouse, and human inducible pluripotent stem cell-derived cardiac 
      myocytes), we monitored TNFalpha levels, lactate dehydrogenase, cardiac 
      ultrastructure and function, mitochondrial bioenergetics, and cardiac cell 
      viability. RESULTS: In contrast to vehicle-treated mice, ultrastructural defects, 
      including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFalpha 
      levels, were observed in the hearts of mice treated with DOX. While investigating 
      the involvement of TNFalpha in DOX cardiotoxicity, we discovered that NF-kappaB was 
      readily activated by TNFalpha. However, TNFalpha-mediated NF-kappaB activation was impaired 
      in cardiac myocytes treated with DOX. This coincided with loss of K63- linked 
      polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. 
      Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients 
      with cancer treated with DOX. We further established that the reciprocal actions 
      of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of 
      apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated 
      the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An 
      E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of 
      function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell 
      death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for 
      K63-linked polyubiquitination of RIPK1, restored NF-kappaB signaling and suppressed 
      DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of 
      TRAF2 (cardiac troponin T-adeno-associated virus 9-TRAF2) in vivo protected 
      against mitochondrial defects and cardiac dysfunction induced by DOX. 
      CONCLUSIONS: Our findings reveal a novel signaling axis that functionally 
      connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. 
      Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac 
      myocytes to TNFalpha-mediated necrotic cell death and DOX cardiotoxicity.
FAU - Dhingra, Rimpy
AU  - Dhingra R
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Rabinovich-Nikitin, Inna
AU  - Rabinovich-Nikitin I
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Rothman, Sonny
AU  - Rothman S
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Guberman, Matthew
AU  - Guberman M
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Gang, Hongying
AU  - Gang H
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Margulets, Victoria
AU  - Margulets V
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Jassal, Davinder S
AU  - Jassal DS
AUID- ORCID: 0000-0002-3639-9047
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Alagarsamy, Keshav Narayan
AU  - Alagarsamy KN
AUID- ORCID: 0000-0002-7363-9345
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
AD  - Regenerative Medicine Program (K.N.A., S.D.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Dhingra, Sanjiv
AU  - Dhingra S
AUID- ORCID: 0000-0002-2664-7633
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
AD  - Regenerative Medicine Program (K.N.A., S.D.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
FAU - Valenzuela Ripoll, Carla
AU  - Valenzuela Ripoll C
AD  - Center for Cardiovascular Research and Cardiovascular Division, Department of 
      Internal Medicine, Washington University School of Medicine, St. Louis, MO 
      (C.V.R., A.D., A.J.).
FAU - Billia, Filio
AU  - Billia F
AUID- ORCID: 0000-0002-2824-1215
AD  - Peter Munk Cardiac Center, University Health Network, Toronto, ON, Canada (F.B.).
FAU - Diwan, Abhinav
AU  - Diwan A
AUID- ORCID: 0000-0001-7554-4772
AD  - John Cochran VA Medical Center, St. Louis, MO (A.J.).
FAU - Javaheri, Ali
AU  - Javaheri A
AUID- ORCID: 0000-0001-6657-331X
AD  - Center for Cardiovascular Research and Cardiovascular Division, Department of 
      Internal Medicine, Washington University School of Medicine, St. Louis, MO 
      (C.V.R., A.D., A.J.).
AD  - John Cochran VA Medical Center, St. Louis, MO (A.J.).
FAU - Kirshenbaum, Lorrie A
AU  - Kirshenbaum LA
AUID- ORCID: 0000-0002-9617-5803
AD  - Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research 
      Centre, Department of Physiology and Pathophysiology (R.D., I.R.-N., S.R., M.G., 
      H.G., V.M., D.S.J., K.N.A., S.D., L.A.K.), Rady Faculty of Health Sciences, 
      University of Manitoba, Winnipeg, Canada.
AD  - Department of Pharmacology and Therapeutics (L.A.K.), Rady Faculty of Health 
      Sciences, University of Manitoba, Winnipeg, Canada.
LA  - eng
GR  - R01 HL143431/HL/NHLBI NIH HHS/United States
GR  - R01 HL107594/HL/NHLBI NIH HHS/United States
GR  - R01 HL155344/HL/NHLBI NIH HHS/United States
GR  - K08 HL138262/HL/NHLBI NIH HHS/United States
GR  - I01 BX004235/BX/BLRD VA/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220819
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (NF-kappa B)
RN  - 0 (PSMD2 protein, human)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Troponin T)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.1.- (Lactate Dehydrogenases)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.- (USP19 protein, human)
RN  - EC 3.4.19.12 (Deubiquitinating Enzymes)
RN  - EC 3.4.19.12 (Ubiquitin-Specific Proteases)
SB  - IM
EIN - Circulation. 2022 Oct 11;146(15):e224. PMID: 36214137
CIN - Circulation. 2023 Mar 28;147(13):1051-1052. PMID: 36972342
CIN - Circulation. 2023 Mar 28;147(13):1050. PMID: 36972345
MH  - Animals
MH  - Apoptosis
MH  - *Cardiomyopathies/metabolism
MH  - Cardiotoxicity
MH  - Deubiquitinating Enzymes/metabolism
MH  - Doxorubicin/toxicity
MH  - Endopeptidases
MH  - Humans
MH  - Lactate Dehydrogenases/metabolism
MH  - Mice
MH  - Mitochondria/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - *NF-kappa B/metabolism
MH  - Rats
MH  - *TNF Receptor-Associated Factor 2/genetics
MH  - Troponin T/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - Ubiquitin-Specific Proteases/metabolism/pharmacology
PMC - PMC10043946
MID - NIHMS1862359
OTO - NOTNLM
OT  - TNF receptor-associated factor 2
OT  - doxorubicin
OT  - inhibitor of apoptosis proteins
OT  - mitochondria
OT  - myocytes, cardiac
OT  - proteasome endopeptidase complex
OT  - tumor necrosis factor-alpha
COIS- Competing interests No competing interests.
EDAT- 2022/08/20 06:00
MHDA- 2022/09/23 06:00
PMCR- 2023/09/20
CRDT- 2022/08/19 05:02
PHST- 2022/08/20 06:00 [pubmed]
PHST- 2022/09/23 06:00 [medline]
PHST- 2022/08/19 05:02 [entrez]
PHST- 2023/09/20 00:00 [pmc-release]
AID - 10.1161/CIRCULATIONAHA.121.058411 [doi]
PST - ppublish
SO  - Circulation. 2022 Sep 20;146(12):934-954. doi: 10.1161/CIRCULATIONAHA.121.058411. 
      Epub 2022 Aug 19.