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.