Tumor necrosis factor-α mediates cardiac remodeling and ventricular dysfunction after pressure overload state

M Sun, M Chen, F Dawood, U Zurawska, JY Li… - Circulation, 2007 - Am Heart Assoc
M Sun, M Chen, F Dawood, U Zurawska, JY Li, T Parker, Z Kassiri, LA Kirshenbaum…
Circulation, 2007Am Heart Assoc
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)-α after aortic banding in the myocardium is
known. In the present study, we tested our hypothesis that TNF-α regulates the cardiac
inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in …
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)-α after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF-α regulates the cardiac inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in response to mechanical overload and contributes to ventricular dysfunction.
Methods and 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-α 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-α contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.
Am Heart Assoc