PMID- 26280121
OWN - NLM
STAT- MEDLINE
DCOM- 20151208
LR  - 20220410
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 21
IP  - 9
DP  - 2015 Sep
TI  - Tumor necrosis factor-alpha confers cardioprotection through ectopic expression of 
      keratins K8 and K18.
PG  - 1076-84
LID - 10.1038/nm.3925 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha), one of the major stress-induced proinflammatory 
      cytokines, is upregulated in the heart after tissue injury, and its sustained 
      expression can contribute to the development of heart failure. Whether TNF-alpha also 
      exerts cytoprotective effects in heart failure is not known. Here we provide 
      evidence for a cardioprotective function of TNF-alpha in a genetic heart failure 
      model, desmin-deficient mice. The cardioprotective effects of TNF-alpha are a 
      consequence of nuclear factor-kappaB (NF-kappaB)-mediated ectopic expression in 
      cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific 
      intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an 
      alternative cytoskeletal network that localized mainly at intercalated discs 
      (IDs) and conferred cardioprotection by maintaining normal ID structure and 
      mitochondrial integrity and function. Ectopic induction of K8/K18 expression in 
      cardiomyocytes also occurred in other genetic and experimental models of heart 
      failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype 
      following transverse aortic constriction. In human failing myocardium, where 
      TNF-alpha expression is upregulated, K8/K18 were also ectopically expressed and 
      localized primarily at IDs, which did not contain detectable amounts of desmin. 
      Thus, TNF-alpha- and NF-kappaB-mediated formation of an alternative, stress-induced 
      intermediate filament cytoskeleton has cardioprotective function in mice and 
      potentially in humans.
FAU - Papathanasiou, Stamatis
AU  - Papathanasiou S
AD  - Center of Basic Research, Biomedical Research Foundation, Academy of Athens, 
      Athens, Greece.
FAU - Rickelt, Steffen
AU  - Rickelt S
AD  - Helmholtz Group for Cell Biology, German Cancer Research Center, Heidelberg, 
      Germany.
FAU - Soriano, Maria Eugenia
AU  - Soriano ME
AD  - Department of Biology, University of Padova, Padova, Italy.
FAU - Schips, Tobias G
AU  - Schips TG
AD  - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, Ohio, USA.
FAU - Maier, Harald J
AU  - Maier HJ
AD  - Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
FAU - Davos, Constantinos H
AU  - Davos CH
AD  - Clinical, Experimental Surgery &Translational Research Center, Biomedical 
      Research Foundation, Academy of Athens, Athens, Greece.
FAU - Varela, Aimilia
AU  - Varela A
AD  - Clinical, Experimental Surgery &Translational Research Center, Biomedical 
      Research Foundation, Academy of Athens, Athens, Greece.
FAU - Kaklamanis, Loukas
AU  - Kaklamanis L
AD  - Department of Pathology, Onassis Cardiac Surgery Center, Athens, Greece.
FAU - Mann, Douglas L
AU  - Mann DL
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
FAU - Capetanaki, Yassemi
AU  - Capetanaki Y
AD  - Center of Basic Research, Biomedical Research Foundation, Academy of Athens, 
      Athens, Greece.
LA  - eng
GR  - R01 HL058081/HL/NHLBI NIH HHS/United States
GR  - R01 HL089543/HL/NHLBI NIH HHS/United States
GR  - R01 HL111094/HL/NHLBI NIH HHS/United States
GR  - R01 HL 111094/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150817
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Desmin)
RN  - 0 (Keratin-18)
RN  - 0 (Keratin-8)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Cardiomegaly/prevention & control
MH  - Desmin/physiology
MH  - Female
MH  - Humans
MH  - Keratin-18/*physiology
MH  - Keratin-8/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/physiology
MH  - Tumor Necrosis Factor-alpha/*physiology
PMC - PMC5419049
MID - NIHMS845977
EDAT- 2015/08/19 06:00
MHDA- 2015/12/15 06:00
PMCR- 2017/05/05
CRDT- 2015/08/18 06:00
PHST- 2015/02/20 00:00 [received]
PHST- 2015/07/15 00:00 [accepted]
PHST- 2015/08/18 06:00 [entrez]
PHST- 2015/08/19 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2017/05/05 00:00 [pmc-release]
AID - nm.3925 [pii]
AID - 10.1038/nm.3925 [doi]
PST - ppublish
SO  - Nat Med. 2015 Sep;21(9):1076-84. doi: 10.1038/nm.3925. Epub 2015 Aug 17.