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(Circulation. 2007;115:1398-1407.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Tumor Necrosis Factor- Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload State

Mei Sun, MD, PhD; Manyin Chen, MD, MSc; Fayez Dawood, DVM; Urszula Zurawska, BSc; Jeff Y. Li, BSc; Thomas Parker, MD; Zamaneh Kassiri, PhD; Lorrie A. Kirshenbaum, PhD; Malcolm Arnold, MD; Rama Khokha, PhD; Peter P. Liu, MD

From The Heart and Stroke/Richard Lewar Centre of Excellence and Toronto General University Health Network (M.S., M.C., F.D., U.Z., J.Y.L., P.P.L.), St Michael’s Hospital (T.P.), and Department of Medical Biophysics, Ontario Cancer Institute (Z.K., R.K.), University of Toronto, Toronto, Ontario, Canada; Institute of Cardiovascular Sciences, University of Manitoba, Manitoba, Canada (L.A.K.); Lawson Research Institute, University of Western Ontario, London, Ontario, Canada (M.A.); and Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto and Ottawa, Ontario, Canada (P.P.L.).

Correspondence to Dr Peter Liu, Institute of Circulatory and Respiratory Health, CIHR, NCSB 11-1266, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada. E-mail peter.liu{at}utoronto.ca

Received June 2, 2006; accepted November 17, 2006.

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)- after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF- 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- 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- contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.

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