title: Cyclosporine A Treatment Inhibits Abcc6-Dependent Cardiac Necrosis and Calcification following Coxsackievirus B3 Infection in Mice.
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.
authors.affiliation: Department of Human Genetics and Complex Traits Group, McGill University, Montreal, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marton
authors.affiliation: Department of Human Genetics and Complex Traits Group, McGill University, Montreal, Canada.
authors.forename: Danica
authors.initials: D
authors.lastname: Albert
authors.affiliation: Department of Human Genetics and Complex Traits Group, McGill University, Montreal, Canada.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Wiltshire
authors.affiliation: Department of Human Genetics and Complex Traits Group, McGill University, Montreal, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Park
authors.affiliation: Department of Ophthalmogenetics, The Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors.forename: Arthur
authors.initials: A
authors.lastname: Bergen
authors.affiliation: The Center for Host Resistance and the Division of Experimental Medicine, McGill University, Montreal, Canada.
authors.forename: Salman
authors.initials: S
authors.lastname: Qureshi
authors.affiliation: Department of Human Genetics and Complex Traits Group, McGill University, Montreal, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Malo
authors.affiliation: Faculty of Pharmacy, University of Montreal, Montreal, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Burelle
authors.affiliation: Department of Human Genetics and Complex Traits Group, McGill University, Montreal, Canada.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D002114:Calcinosis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D029822:Enterovirus B, Human / Q000187:drug effects*; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009205:Myocarditis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009336:Necrosis
chemical_list: D018528:ATP-Binding Cassette Transporters; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C504743:Abcc6 protein, mouse; C000631446:PPIF protein, mouse