Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype

Dibbs, Ziad; Diwan, Abhinav; Nemoto, Shintaro; DeFreitas, Gilberto; Abdellatif, Maha; Carabello, Blasé A.; Spinale, Francis G.; Feuerstein, Giora; Sivasubramanian, Natarajan; Mann, Douglas L.

doi:10.1161/01.cir.0000085203.46621.f4

Cited by 60 publications

(43 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…18 Interestingly, TG overexpression of mTNF produces a concentric cardiac hypertrophy without progression to cardiac dilation and failure. 19 Thus, one might speculate that preferential stimulation of the TNFR2 receptor through sequestration of sTNF, absence of the TNFR1 protein, or exclusive overexpression of mTNF may drive the cardiac hypertrophy observed in these various studies.…”

Section: Discussionmentioning

confidence: 97%

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

Higuchi¹,

et al. 2004

View full text Add to dashboard Cite

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 ϩ/Ϫ or TG/R2 ϩ/Ϫ ), and TG with homozygous receptor KO (TG/R1 Ϫ/Ϫ or TG/R2 Ϫ/Ϫ ). 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 ϩ/Ϫ and TG/R1 Ϫ/Ϫ mice were improved relative to TG/W mice in both males and females. However, the survival of female TG/R2 ϩ/Ϫ and TG/R2 Ϫ/Ϫ 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

show abstract

Section: Discussionmentioning

confidence: 97%

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

Higuchi¹,

et al. 2004

View full text Add to dashboard Cite

show abstract

“…4,17 It reduces cardiac contractility, 41 induces hypertrophy 42 and apoptosis. 43 In patients with DCM, both TACE and TNF␣ levels are significantly elevated 5 as in our aortic-banded timp-3 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Combination of Tumor Necrosis Factor-α Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice

Kassiri

Oudit

Sánchez

et al. 2005

Circulation Research

151

158

View full text Add to dashboard Cite

Abstract-Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 Ϫ/Ϫ mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNF␣ converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-␣ (TNF␣) processing. In addition, TNF␣ production increased in timp-3 Ϫ/Ϫ -AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 Ϫ/Ϫ -AB myocardium. Timp-3 Ϫ/Ϫ / tnf␣ Ϫ/Ϫ mice were generated and subjected to AB for comparative analyses with timp-3 Ϫ/Ϫ -AB mice. This revealed the critical role of TNF␣ in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNF␣, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNF␣, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 Ϫ/Ϫ -AB mice. Notably, combining TNF␣ ablation with MMP inhibition completely rescued heart disease in timp-3 Ϫ/Ϫ -AB mice. This study provides a basis for anti-TNF␣ and MMP inhibitor combination therapy in heart disease. Ⅲ matrix metalloproteinase Ⅲ tumor necrosis factor-␣ C ardiovascular disease is the major cause of death in the Western world and is predicted to be the leading cause of mortality worldwide by 2020. 1 A close relationship between the severity of cardiac dysfunction, development of heart failure, and cardiac expression of tumor necrosis factor-␣ (TNF␣) has been demonstrated. 2,3 TNF␣ is a pleiotropic cytokine and is found elevated in patients with dilated cardiomyopathy (DCM), 4,5 ischemic heart disease, and congestive heart failure (CHF). 3 Based on the potential importance of TNF␣ in heart disease, anti-TNF␣ therapy has been attempted in patients with heart failure although significant benefits of this therapy remain to be demonstrated. 6,7 This suggests that other factors play key roles in the progression of heart failure. Maladaptive extracellular matrix (ECM) remodeling is a common feature of ventricular remodeling in patients with DCM and CHF. 8 Matrix metalloproteinases (MMPs) are the primary ECM remodeling enzymes, 9 and a disintegrin and metalloproteinase, ADAM-17/TACE (TNF␣ converting enzyme) converts membrane bound TNF␣ to its soluble form. 10,11 Furthermore, TNF␣ signaling is known to induce the transcription of metalloproteinases, 9,12 evoking a potentially important but overlooked interaction between TNF␣ signaling and ECM remodeling. Whether a direct relatio...

show abstract

“…17 The characterization of the probes for α-myosin heavy chain (α-MHC), β-myosin heavy and SERCA2a have been reported previously. 18 …”

Section: Fetal Gene Expressionmentioning

confidence: 99%

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Sakata¹,

Chancey²,

Divakaran³

et al. 2007

Basic Res Cardiol

Self Cite

View full text Add to dashboard Cite

The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a proinflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.

show abstract

Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype

Cited by 60 publications

References 31 publications

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

Combination of Tumor Necrosis Factor-α Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Contact Info

Product

Resources

About