Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state.
BACKGROUND
Pressure overload is accompanied by cardiac myocyte apoptosis, hypertrophy, and inflammatory/fibrogenic responses that lead to ventricular remodeling and heart failure. Despite incomplete understanding of how this process is regulated, the upregulation of tumor necrosis factor (TNF)-alpha after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF-alpha regulates the cardiac inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in response to mechanical overload and contributes to ventricular dysfunction.


RESULTS
C57/BL wild-type mice and TNF-knockout (TNF-/-) mice underwent descending aortic banding or sham operation. Compared with sham-operated mice, wild-type mice with aortic banding showed a significant increase in cardiac TNF-alpha levels, which coincided with myocyte apoptosis, inflammatory response, and cardiac hypertrophy in week 2 and a significant elevation in matrix metalloproteinase-9 activity and impaired cardiac function in weeks 2 and 6. Compared with wild-type mice with aortic banding, TNF-/- mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis. These mice also showed reduced cardiac matrix metalloproteinase-9 activity and improved cardiac function.


CONCLUSIONS
Findings from the present study have suggested that TNF-alpha contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.
Sun
Mei
M
The Heart and Stroke/Richard Lewar Centre of Excellence and Toronto General University Health Network, Toronto, Ontario, Canada.
Chen
Manyin
M
Dawood
Fayez
F
Zurawska
Urszula
U
Li
Jeff Y
JY
Parker
Thomas
T
Kassiri
Zamaneh
Z
Kirshenbaum
Lorrie A
LA
Arnold
Malcolm
M
Khokha
Rama
R
Liu
Peter P
PP
D000818:Animals; D001011:Aorta; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9