A novel role for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the development of cardiac dysfunction and failure.
BACKGROUND
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, is a multifunctional cytokine known to regulate cellular functions in contexts of injury and disease through its receptor, fibroblast growth factor-inducible molecule 14 (Fn14). Although many of the processes and downstream signals regulated by the TWEAK/Fn14 pathway have been implicated in the development of cardiac dysfunction, the role of TWEAK in the cardiovascular system is completely unknown.


RESULTS
Herein, we demonstrate that mouse and human cardiomyocytes express the TWEAK receptor Fn14. Furthermore, we determine that elevated circulating levels of TWEAK, induced via transgenic or adenoviral-mediated gene expression in mice, result in dilated cardiomyopathy with subsequent severe cardiac dysfunction. This phenotype was mediated exclusively by the Fn14 receptor, independent of tumor necrosis factor-alpha, and was associated with cardiomyocyte elongation and cardiac fibrosis but not cardiomyocyte apoptosis. Moreover, we find that circulating TWEAK levels were differentially upregulated in patients with idiopathic dilated cardiomyopathy compared with other forms of heart disease and normal control subjects.


CONCLUSIONS
Our data suggest that TWEAK/Fn14 may be important in regulating myocardial structural remodeling and function and may play a role in the pathogenesis of dilated cardiomyopathy.
Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mohit
M
Jain
Aniela
A
Jakubowski
Lei
L
Cui
Jianru
J
Shi
Lihe
L
Su
Michael
M
Bauer
Jian
J
Guan
Chee Chew
CC
Lim
Yoshiro
Y
Naito
Jeffrey S
JS
Thompson
Flora
F
Sam
Christine
C
Ambrose
Michael
M
Parr
Thomas
T
Crowell
John M
JM
Lincecum
Monica Z
MZ
Wang
Yen-Ming
YM
Hsu
Timothy S
TS
Zheng
Jennifer S
JS
Michaelson
Ronglih
R
Liao
Linda C
LC
Burkly
D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size; D003327:Coronary Disease / Q000378:metabolism / Q000473:pathology; D000074049:Cytokine TWEAK; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000074050:TWEAK Receptor; D014161:Transduction, Genetic; D048069:Tumor Necrosis Factors / Q000097:blood / Q000235:genetics / Q000502:physiology*
D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors