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84 CELL-SPECIFIC RESPONSES IN AN APOPTOTIC MODEL OF VIRAL MYOCARDITIS.
  1. S. D. Miyamoto1,
  2. B. A. Robinson2,
  3. K. L. Tyler1,2,
  4. R. D. Brown1,
  5. C. S. Long1,
  6. R. L. DeBiasi1,2
  1. 1University of Colorado, Denver, CO
  2. 2Veterans' Affairs Medical Center, Denver, CO

Abstract

Viral myocarditis results in chronic dilated cardiomyopathy or death in up to 20% of affected children and 50% of affected adults. The pathogenesis is poorly understood and proposed mechanisms of cardiac injury include direct virus-mediated cellular toxicity as well as secondary host-mediated immune responses. The reovirus model of myocarditis provides an excellent system to study direct virus-mediated injury. Prior studies show that apoptosis (APO) occurs in hearts of reovirus-infected animals and inhibition of APO protects against myocarditis. We hypothesized that induction of cardiac myocyte and fibroblast APO are both potentially important co-determinants of myocarditic phenotype. Primary rat cardiac myocytes and fibroblasts were separately infected with 6 reovirus strains that differ in their capacity to induce myocarditis in vivo. We evaluated the presence and extent of virus-induced APO in these two cell types by assessing nuclear morphology/cellular viability, caspase-3 activation, and annexin V binding. Using the percentage of cells binding annexin V, at 48 hours post-infection, myocarditic reovirus strains 8B and T3A induced high levels of APO in myocytes (78.4 ± 1.1 and 50.2 ± 1.6, respectively, compared to mock-infected control cells, p < .01) with less APO evident in fibroblasts (7.9 ± 0.3 and 3.3 ± 0.3, NS). Nonmyocarditic strains T1L and T3D did not induce significant APO in either cell type (myocytes 21.9 ± 1.8 and 23.2 ± 1.7; fibroblasts 3.4 ± 1.1, and 7.2 ± 1.2, all NS). Nonmyocarditic strains DB188 and DB93A induced high levels of APO in both cell types (myocytes 46.8 ± 1.2, p < .01 and 42.5 ± 5.1, p < .05; fibroblasts 35.5 ± 1.9, and 41.5 ± 2.9, both p < .01). These results suggest that there are clear myocardial cell-specific responses to viral infection, and we postulate that these may be critical co-determinants of myocarditic potential. Although myocyte apoptosis is necessary for a reoviral strain to be myocarditic, that alone is not sufficient. Cardiac fibroblast response to infection may play an important role in determining the myocarditic potential of reovirus strains. From our results, we conclude that a myocarditic reoviral strain causes apoptosis of cardiac myocytes and results in more apoptosis in myocytes relative to fibroblasts. Study of the mechanisms by which these cells interact, such as secretion of key growth factors and cytokines, co-culture, and conditioned medium experimentation, is in progress.

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