The
coxsackie-adenovirus receptor (CAR) is an adhesion molecule found at the intercalated disc of cardiomyocytes in association with other adherens and
tight junction proteins. CAR expression is increased at cardiomyocyte junctions in patients with
heart failure. It is not known what contribution elevated CAR expression makes to cardiac pathology. We generated a binary transgenic mouse enabling cardiac-restricted
doxycycline-regulated expression of Flag-tagged murine CAR (mCAR(+)/alpha
MtTA(+) mice). Myocardial CAR levels were increased 6-fold in mCAR(+)/alpha
MtTA(+) mice, localizing to intercalated discs and sarcolemma. Well at birth, mCAR(+)/alpha
MtTA(+) mice developed a severe
cardiomyopathy and died by 4 weeks. Cardiomyocyte
hypertrophy was evident at 1 week, with increased heart:
body weight ratios by 3 weeks. Disorganization and degeneration of cardiomyocytes were evident with disrupted adherens junctions.
Doxycycline administration turned off transgene expression and rescued mice from the development of the cardiomyopathic phenotype. In CAR-overexpressing mCAR(+)/alpha
MtTA(+) mice, adherens junction
proteins were abnormally expressed.
N-cadherin protein levels were 83% lower in mCAR(+)/alpha
MtTA(+) hearts vs controls at 1 week, with levels subsequently increased above controls at 3 weeks.
beta-catenin expression was 90% and 135% above controls at 1 and 3 weeks, respectively. Nuclear translocation of
beta-catenin in cardiomyocytes of mCAR(+)/alpha
MtTA(+) mice was associated with increased c-myc
RNA, a target of active
beta-catenin known to be associated with
cardiac hypertrophy. Our study is the first to demonstrate that increased CAR expression can induce a
cardiomyopathy and supports a model whereby the pathogenesis is determined by CAR stimulated
beta-catenin signaling, and/or disruption of the adherens junction.