Cardiomyocyte-targeted overexpression of the coxsackie-adenovirus receptor causes a cardiomyopathy in association with beta-catenin signaling.
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.
Cell Biology Program, Research Institute, Division of Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, Canada.
Laura
L
Caruso
Stella
S
Yuen
Julie
J
Smith
Mansoor
M
Husain
Mary Anne
MA
Opavsky
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006984:Hypertrophy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011991:Receptors, Virus / Q000096:biosynthesis*; D012508:Sarcolemma / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
C568772:CLMP protein, mouse; D015820:Cadherins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt