Dilated Cardiomyopathy in Retrovirally Infected Mice: A Novel Model for Silent Viral DCM?

Beischel, Julie; Larson, Douglas F.; Yu, Qianli; Yang, Bo; Sepúlveda, R; Kelley, T.E.; Watson, Ronald R.

doi:10.1385/ct:4:4:317

Cited by 6 publications

(9 citation statements)

References 33 publications

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“…This does not exclude noncardiac sources for these secretory factors. Given that our model did not incorporate myocardial injury, the role of proinflammatory cytokines is not expected to contribute to the induction of MMPs, especially because our previous studies failed to identify inducible nitric oxide synthase and TNF-␣ in cardiac tissues after LP-BM5 treatment (4). Our data also support those of others suggesting that the chronic loss of interstitial collagen is associated with both systolic and diastolic function (26).…”

Section: Mmp and Immune Functionsupporting

confidence: 84%

“…LP-BM5-induced TH2 lymphocyte function is rapid and sustained until the death of the mouse (17,20,28,47,58). We have reported that ventricular dilation and decreased ␤ occurs in the absence of cardiac lymphocytic infiltrates and inflammatory mediators (4,40). Moreover, we have not been able to demonstrate inducible nitric oxide synthase or TNF-␣ overexpression in cardiac tissues of LP-BM5-infected mice (4).…”

Section: H647mentioning

confidence: 77%

“…Moreover, we have not been able to demonstrate inducible nitric oxide synthase or TNF-␣ overexpression in cardiac tissues of LP-BM5-infected mice (4). We have previously demonstrated an increased intracellular space that may account for the ventricular dilation that has been hypothesized to result from the increased production of hydrophilic glycosaminoglycans (4,50). Therefore, it can be concluded that TCR peptides and the LP-BM5 murine model do not induce obvious myocardial pathology, infection, or inflammation.…”

Section: H647mentioning

confidence: 82%

“…We have reported that ventricular dilation and decreased ␤ occurs in the absence of cardiac lymphocytic infiltrates and inflammatory mediators (4,40). Moreover, we have not been able to demonstrate inducible nitric oxide synthase or TNF-␣ overexpression in cardiac tissues of LP-BM5-infected mice (4). We have previously demonstrated an increased intracellular space that may account for the ventricular dilation that has been hypothesized to result from the increased production of hydrophilic glycosaminoglycans (4,50).…”

Section: H647mentioning

confidence: 85%

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A role for T lymphocytes in mediating cardiac diastolic function

Yu¹,

Watson²,

Marchalonis³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (beta) was significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes (P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group (P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.

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Section: Mmp and Immune Functionsupporting

confidence: 84%

Section: H647mentioning

confidence: 77%

Section: H647mentioning

confidence: 82%

Section: H647mentioning

confidence: 85%

See 2 more Smart Citations

A role for T lymphocytes in mediating cardiac diastolic function

Yu¹,

Watson²,

Marchalonis³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Mechanisms such as the release of cytokines or the recruitment of inflammatory cells to the heart may contribute to cardiac damage. However, there are only a limited number of small-animal models of viral-induced myocarditis; these include Coxsackie B3 virus, the ecotropic retrovirus complex LP-BM5, and herpes virus infection in mice (2,3,7,13). …”

mentioning

confidence: 99%

Infection of Cardiomyocytes and Induction of Left Ventricle Dysfunction by Neurovirulent Polytropic Murine Retrovirus

Khaleduzzaman¹,

Francis

Corbin³

et al. 2007

J Virol

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Viral infections of the heart are a causative factor of myocarditis as well as of sudden, unexpected deaths of children, yet the mechanisms of pathogenesis remain unclear, in part due to the relatively few animal models of virus-induced myocarditis. In the current study, we examined the ability of polytropic murine retroviruses to infect the heart and induce cardiac dysfunction. In situ hybridization and immunohistochemistry analysis detected virus-infected cardiomyocytes and macrophages in the heart. A significant decrease in left ventricle function, as measured by fractional shortening, was detected in mice infected with the neurovirulent retrovirus Fr98 but not in mice infected with the nonneurovirulent retrovirus Fr54. Virus infection was not associated with consistent findings of fibrosis or substantial cellular infiltrate. Fr98-induced left ventricle dysfunction was associated with a higher virus load, increased mRNA expression of the macrophage marker F4/80, increased chemokine production, and a small number of apoptotic cells in the heart.

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T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

Vazquez

Zabadi

et al. 2010

Matrix Biology

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Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen crosslinking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen crosslinking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM crosslinking and thereby alter left ventricular function. Threemonth old C57BL/J female mice were treated with selective TH1 lymphocyte inducers -T-cell receptor Vβ peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.

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Dilated Cardiomyopathy in Retrovirally Infected Mice: A Novel Model for Silent Viral DCM?

Cited by 6 publications

References 33 publications

A role for T lymphocytes in mediating cardiac diastolic function

A role for T lymphocytes in mediating cardiac diastolic function

Infection of Cardiomyocytes and Induction of Left Ventricle Dysfunction by Neurovirulent Polytropic Murine Retrovirus

T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

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