Published online before print March 29, 2004, doi: 10.1161/01.CIR.0000124227.00670.AB
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(Circulation. 2004;109:1892-1897.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-
–Induced Cardiomyopathy
From the Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia (Y.H., B.S.M., T.O.C., A.M.F.), and Cardiovascular Institute, University of Pittsburgh School of Medicine, Pittsburgh (C.F.M., C.B.F.), Pa.
Correspondence to Arthur M. Feldman, MD, PhD, Department of Medicine, Jefferson Medical College, 1025 Walnut St, Suite 822 College, Philadelphia, PA 19107. E-mail Arthur.Feldman{at}Jefferson.edu
Received October 11, 2003; revision received December 31, 2003; accepted January 6, 2004.
Background— Tumor necrosis factor (TNF)-
plays a pathophysiological role in heart failure. Although both TNF receptor 1 (TNFR1) and 2 (TNFR2) are present in the heart, comparatively little is known about the role of TNFR2.
Methods and Results— We bred TNFR1-knockout (KO) or TNFR2KO mice to transgenic (TG) mice with cardiac-specific overexpression of TNF- and analyzed resultant progeny. Six groups of male and female mice were studied: wild type (WT) with wild receptors (WT/W), TG with wild receptors (TG/W), TG with heterozygous receptor KO (TG/R1+/– or TG/R2+/–), and TG with homozygous receptor KO (TG/R1–/– or TG/R2–/–). Both male and female TG mice displayed cardiac hypertrophy, dilation, and reduced cardiac function. Male TG mice were more severely affected than genotypically matched females and died of heart failure at a younger age. Survival, cardiac function, and remodeling of TG/R1+/– and TG/R1–/– mice were improved relative to TG/W mice in both males and females. However, the survival of female TG/R2+/– and TG/R2–/– mice was worse than that of TG/W mice, with increased left ventricular dimension and left ventricular weight/body weight ratios. The cardiac TNF- protein level was upregulated in TG/R1–/– and TG/R2–/– compared with TG/W mice, whereas the level of TNF receptors was not downregulated in TG/W relative to WT/W mice.
Conclusions— Ablation of the TNFR2 gene exacerbates heart failure and reduces survival, whereas ablation of TNFR1 blunts heart failure and improves survival. Signaling via TNFR2 may play a cardioprotective role in the pathogenesis of cytokine-mediated heart failure.
Key Words: heart failure • receptors • signal transduction
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