TNF-knockout mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis, and improved cardiac function compared to wild-type mice.
Does TNF-alpha knockout attenuate cardiac remodeling and ventricular dysfunction after pressure overload in mice?
TNF-alpha mediates adverse left ventricular remodeling and ventricular dysfunction during pressure overload, as its absence in knockout mice attenuates these pathological responses.
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. 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-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 et al. (2007) studied Pressure overload-induced cardiac remodeling and ventricular dysfunction. TNF-alpha knockout vs. Wild-type was evaluated on Cardiac apoptosis, hypertrophy, inflammatory response, reparative fibrosis, and cardiac function. TNF-knockout mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis, and improved cardiac function compared to wild-type mice.