metallothionein and Cardiomyopathy--Dilated

The Epstein-Barr virus nuclear antigen-leader protein (EBNA-LP) is required for high efficiency B lymphocyte growth transformation by the virus. To test the potential contribution of EBNA-LP to tumorigenesis in vivo, we produced transgenic mice carrying an EBNA-LP cDNA construct, using the widely expressed metallothionein promoter. Expression of EBNA-LP was detected in liver, kidney, heart, lung and spleen. There were no apparent oncogenic consequences of EBNA-LP expression. Unexpectedly however, at ages ranging from about 4 months to over a year, transgenic mice developed symptoms of congestive heart failure, including left ventricular dilatation, right ventricular hypertrophy, left atrial thrombosis, pulmonary oedema and hydrothorax. Fibrillation was not apparent in the electrocardiograph; however a reduction in T-wave amplitude suggested that the development of an abnormality of ventricular repolarization may precede the manifestation of overt symptoms. The highly predictable development of dilated heart failure in these transgenic mice suggests they may be a useful model for the pathophysiological changes associated with human dilated cardiomyopathy.

Topics: Animals; Antigens, Viral; Blotting, Southern; Blotting, Western; Cardiomyopathy, Dilated; Cloning, Molecular; DNA-Binding Proteins; DNA, Viral; Electrocardiography; Epstein-Barr Virus Nuclear Antigens; Growth Hormone; Heart; Herpesvirus 4, Human; Humans; Metallothionein; Mice; Mice, Transgenic; Myocardium; Organ Specificity; Protein Sorting Signals; Restriction Mapping

One of the early genes of polyomavirus, large T-antigen (PVLT), has been classified in vitro as an immortalizing gene. In order to determine the ability of PVLT to cause the formation of hyperplasia or tumors in vivo, we generated transgenic mice harboring the cDNA for PVLT linked to the heavy-metal responsive metallothionein-1 promoter (MT). The transgene was primarily expressed in testes and seminal vesicles, but expression was also detected in heart of a single transgenic line. The expression of the transgene in the heart of MT-PVLT line 8 mice was correlated with cardiomyopathy and atrial thrombus formation leading to premature death at approximately 160 days due to cardiac failure. The heart of affected animals was from 1.5 to 5.2 fold greater in weight and 2 fold greater in dimensions than normal nontransgenic mice. Affected hearts fell short of frank tumor phenotype and no macroscopic nor microscopic focal growth was found. Histologically the heart has a heterogenous cardiomyocyte population with markedly enlarged cells mixed with relatively normal cells. Both cell types express PVLT protein. The primary cell type affected is the cardiomyocyte however, as heart proportions are maintained, interstitial and non-myocyte cells must be affected either directly or indirectly. Expression of PVLT has upset normal strict control of cell growth in these hearts to result in a new model of congestive cardiomyopathy.

Topics: Animals; Antigens, Viral, Tumor; Base Sequence; Cardiomyopathy, Dilated; DNA, Recombinant; Gene Expression; Immunohistochemistry; Kidney; Male; Metallothionein; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Molecular Sequence Data; Myocardium; Organ Size; Phenotype; Polyomavirus; Promoter Regions, Genetic; Ribonuclease, Pancreatic