Dilated Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Tumor Necrosis Factor-α

Abstract

The failing human heart expresses tumor necrosis factor-alpha (TNF-alpha). However, its pathophysiological significance is not clear. We previously reported that robust overexpression of TNF-alpha in the murine heart causes lethal myocarditis. In this study, we modified the transgene to reduce the production of TNF-alpha by preserving the destabilizing sequence in TNF-alpha cDNA. Expression was driven by the murine alpha-myosin heavy chain promoter. Use of this modified construct allowed to the establish a mutine transgenic line (TG). TG offspring were examined at 6, 12, and 24 weeks. All showed a significantly higher heart weight-to-body weight ratio. Northern blot analysis confirmed the expression of transgene in the heart, and enzyme-linked immunosorbent assay demonstrated the presence of TNF-alpha protein. The TG heart demonstrated a mild, diffuse, lymphohistiocytic interstitial inflammatory infiltrate. Cardiomyocyte necrosis and apoptosis were present but not abundant. Magnetic resonance imaging showed that the TG heart was significantly dilated with reduced ejection fraction. Although the left ventricular dP/dtmax was not different at baseline, its responsiveness to isoproterenol was significantly blunted in TG. Atrial natriuretic factor was expressed in the TG ventricle. A group of TG died spontaneously, and subsequent autopsies revealed exceptional dilation of the heart, increased lung weight, and pleural effusion, suggesting that they died of congestive heart failure. The cumulative mortality rate at 6 months was 23%. In conclusion, the mouse overexpressing TNF-alpha recapitulated the phenotype of congestive heart failure. This provides a novel model to elucidate the role of this cytokine in the development of congestive heart failure.

CXCR4 modulates contractility in adult cardiac myocytes

“…Sepsis-associated cardiac dysfunction was thought to be mediated, in part, by circulating or "humoral" myocardial depressants that were subsequently identified as predominantly inflammatory cytokines (including tumor necrosis factor-1alpha (TNF-1α), interleukin-1beta, (IL-1β) [25], IL-6 [26], IL-2 [27] and interferon-gamma (IFN-γ)). These ideas were supported by numerous animal [28][29][30] and by in vitro studies [25,31,32]. However, clinical trials (reviewed by Anker et al [33]), that used "targeted" approaches to neutralize cytokines, such as TNF, were unsuccessful in treating patients with moderate to advanced heart failure.…”

Inflammatory markers are associated with left ventricular hypertrophy and diastolic dysfunction in a population-based sample of elderly men and women

“…24,25 Cardiac-specific overexpression of TNF-a causes myocardial inflammation and remodeling, resulting in the development of congestive heart failure. 26 As LVH might be related to later heart failure, early myocardial overexpression of proinflammatory cytokines might be one mechanism.…”

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

“…[1][2][3] Although the progressive LV dilation in these mice has been attributed to TNFinduced activation of matrix metalloproteinases (MMPs) with subsequent degradation of fibrillar collagen, the mechanisms that are responsible for the progressive myocardial fibrosis that accrues in these mice is not all understood. Given that TNF inhibits collagen gene expression and/or collagen synthesis in cardiac fibroblasts, 4,5 the increased myocardial fibrosis observed in the transgenic models with cardiac restricted overexpression of TNF is unlikely to be a direct effect of TNF-mediated signaling.…”