Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice

Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine with negative inotropic effects, can be detected in myocardium with end-stage heart failure, after endotoxin administration, and during transplant rejection. Various studies suggest that TNF-alpha participates in the pathogenesis of cardiac dysfunction. To test this hypothesis, transgenic mice were made that selectively overexpress TNF-alpha in cardiomyocytes.

A transgene construct was made containing the murine alpha-myosin heavy chain promoter and the coding sequence of murine TNF-alpha, followed by the simian virus 40 T-antigen intron and polyadenylation signals. Injection of this construct into fertilized eggs yielded three transgenic mice, all of which died spontaneously before the completion of weaning. Gross pathologic analysis of these mice demonstrated a decrease in body weight with markedly increased heart weight. Histologic examination of the heart revealed a substantial, diffuse lymphohistiocytic inflammatory infiltrate, associated with interstitial edema. Reverse transcriptase polymerase chain reaction showed that the transgene was expressed in the heart. Enzyme-linked immunosorbent assay demonstrated a substantial amount of TNF-alpha protein in the transgenic heart.

Overexpression of TNF-alpha in the heart leads to severe myocarditis and cardiomegaly. These results support the hypothesis that myocardial expression of TNF-alpha can contribute to the pathogenesis of cardiac dysfunction.