title: The coxsackie-adenovirus receptor induces an inflammatory cardiomyopathy independent of viral infection.
abstract: The coxsackie-adenovirus receptor (CAR) is a viral receptor for Group B coxsackieviruses (CVBs) and adenoviruses. CAR has been linked with the innate immune response to CVB myocarditis, and with activation of inflammatory cells in vitro. We hypothesized that CAR activates signals that promote inflammation in the myocardium independent of viral infection. To test this we conditionally overexpressed murine CAR in cardiomyocytes of adult binary transgenic mice under the control of a tetracycline-responsive (tet-off) α-myosin heavy chain (αMtTA) promoter (mCAR(+)/αMtTA(+) mice). An inflammatory cardiomyopathy developed in both lines generated (6-mCAR(+)/αMtTA(+) and 12-mCAR(+)/αMtTA(+)) following withdrawal of doxycycline. Cardiac CAR was upregulated at 4weeks of age in 6-mCAR(+)/αMtTA(+) mice and induced a mild inflammatory infiltrate (score 1.3 of 4.0±0.3) at 6weeks, with 95% of mice surviving to that time. In the second line, 12-mCAR(+)/αMtTA(+) mice, CAR was upregulated in the majority of mice by 3weeks of age, and by 5weeks of age more severe cardiac inflammation (score 2.8 of 4.0±0.4) developed with only 56% of mice surviving. The cardiac inflammatory infiltrate was primarily natural killer cells and macrophages in both mCAR(+)/αMtTA(+) lines. A proinflammatory cytokine response with increased cardiac interferon-γ, interleukin (IL)-12, IL-1β, tumor necrosis factor-α and IL-6 was detected by real-time RT-PCR. CAR has been linked to signaling via the inflammatory mitogen-activated protein kinase (MAPK) cascades; therefore, we evaluated the response of these pathways in hearts with upregulated CAR. Both stress-activated JNK and p38MAPK were activated in mCAR(+)/αMtTA(+) hearts prior to onset of inflammation and in isolated mCAR(+)/αMtTA(+) cardiomyocytes. In conclusion, we show for the first time that CAR upregulation in the adult mouse heart induces cardiac inflammation reminiscent of early viral myocarditis. CAR-induced stress-activated MAPK signaling may contribute to the development of cardiac inflammation unrelated to viral infection per se.
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Stella
authors.initials: S
authors.lastname: Yuen
authors.forename: Julie
authors.initials: J
authors.lastname: Smith
authors.forename: Laura
authors.initials: L
authors.lastname: Caruso
authors.forename: Marko
authors.initials: M
authors.lastname: Balan
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Opavsky
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D018995:Myosin Heavy Chains