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Updated: Jul 6, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in
Yoshihiro Higuchi1, Charles F McTiernan, Carole B Frye
1Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia 19107, USA.
Background:
Tumor necrosis factor (TNF)-alpha 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-alpha 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-alpha 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.
Insights
Tumor necrosis factor receptor 2 (TNFR2) signaling appears protective in heart failure, as its absence worsens outcomes. Conversely, blocking tumor necrosis factor receptor 1 (TNFR1) improves heart function and survival in this condition.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Tumor necrosis factor (TNF)-alpha contributes to heart failure pathophysiology.
- Both TNF receptor 1 (TNFR1) and TNFR2 are present in the heart, but TNFR2's role is less understood.
Purpose of the Study:
- To investigate the distinct roles of TNFR1 and TNFR2 in the development of heart failure.
- To determine the impact of TNFR1 and TNFR2 ablation on cardiac function and survival in a mouse model of heart failure.
Main Methods:
- Generated double-transgenic mice with cardiac-specific TNF-alpha overexpression and TNFR1 or TNFR2 knockout.
- Assessed cardiac function, hypertrophy, dilation, survival rates, and cardiac TNF-alpha protein levels.
Main Results:
- Cardiac-specific TNF-alpha overexpression induced heart failure in male and female mice, with males being more severely affected.
- TNFR1 knockout (TG/R1-/-) significantly improved survival, cardiac function, and cardiac remodeling compared to wild-type controls.
- TNFR2 knockout (TG/R2-/-) exacerbated heart failure in female mice, leading to worse survival and increased cardiac dimensions.
Conclusions:
- TNFR1 signaling appears detrimental in cytokine-mediated heart failure.
- TNFR2 signaling may play a cardioprotective role, as its ablation worsens heart failure outcomes.
- Targeting TNFR1 and TNFR2 offers potential therapeutic strategies for heart failure.
