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PLoS One ; 10(9): e0138222, 2015.
Article in English | MEDLINE | ID: mdl-26375467

ABSTRACT

Coxsackievirus type B3 (CVB3) is a cardiotropic enterovirus. Infection causes cardiomyocyte necrosis and myocardial inflammation. The damaged tissue that results is replaced with fibrotic or calcified tissue, which can lead to permanently altered cardiac function. The extent of pathogenesis among individuals exposed to CVB3 is dictated by a combination of host genetics, viral virulence, and the environment. Here, we aimed to identify genes that modulate cardiopathology following CVB3 infection. 129S1 mice infected with CVB3 developed increased cardiac pathology compared to 129X1 substrain mice despite no difference in viral burden. Linkage analysis identified a major locus on chromosome 7 (LOD: 8.307, P<0.0001) that controlled the severity of cardiac calcification and necrosis following infection. Sub-phenotyping and genetic complementation assays identified Abcc6 as the underlying gene. Microarray expression profiling identified genotype-dependent regulation of genes associated with mitochondria. Electron microscopy examination showed elevated deposition of hydroxyapatite-like material in the mitochondrial matrices of infected Abcc6 knockout (Abcc6-/-) mice but not in wildtype littermates. Cyclosporine A (CsA) inhibits mitochondrial permeability transition pore opening by inhibiting cyclophilin D (CypD). Treatment of Abcc6 -/- mice with CsA reduced cardiac necrosis and calcification by more than half. Furthermore, CsA had no effect on the CVB3-induced phenotype of doubly deficient CypD-/-Abcc6-/- mice. Altogether, our work demonstrates that mutations in Abcc6 render mice more susceptible to cardiac calcification following CVB3 infection. Moreover, we implicate CypD in the control of cardiac necrosis and calcification in Abcc6-deficient mice, whereby CypD inhibition is required for cardioprotection.


Subject(s)
ATP-Binding Cassette Transporters/physiology , Calcinosis/drug therapy , Coxsackievirus Infections/drug therapy , Cyclosporine/pharmacology , Enterovirus B, Human/drug effects , Inflammation/drug therapy , Myocarditis/drug therapy , Animals , Calcinosis/pathology , Calcinosis/virology , Coxsackievirus Infections/pathology , Coxsackievirus Infections/virology , Peptidyl-Prolyl Isomerase F , Cyclophilins/metabolism , Female , Immunosuppressive Agents/pharmacology , Inflammation/pathology , Inflammation/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron, Transmission , Mitochondrial Membrane Transport Proteins/drug effects , Mitochondrial Permeability Transition Pore , Multidrug Resistance-Associated Proteins , Myocarditis/pathology , Myocarditis/virology , Necrosis
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