Evaluation of the Coxsackievirus and Adenovirus Receptor (CAR) as a therapeutic target in cardiac disease

The coxsackievirus and adenovirus receptor (CAR) is a type I transmembrane protein involved in virus uptake and the maintenance of cell-cell contacts. It is predominantly expressed in the developing brain and heart, and re-induced upon cardiac remodeling in heart disease. Coxsackievirus B3 (CVB3) infections are frequent causes of human acute myocarditis, often resulting in chronic cardiomyopathy with fibrosis and reduced contractile function that may progress into terminal heart failure. The coxsackievirus and adenovirus receptor (CAR) is involved in virus uptake into various cell types and has therefore been suggested as a therapeutic target to prevent or treat CVB3 induced diseases such as myocarditis and cardiomyopathy. To understand the role of CAR in the pathogenesis of inflammatory heart disease we used conditional knockout approach. The inducible heart-specific and the complete knockout model enabled us to study CAR’s role in embryonic development and in the adult animal heart. The complete CAR-knockout was embryonic lethal at midgestation (E11.5) with cardiac malformation such as ventricular hypertrophy and atrial dilation. Apolipoproteins were accumulated in the knockout heart, indicating a role for CAR in lipid uptake. Connexin expression was decreased in the knockout, suggesting an abnormal cell-cell communication secondary to the loss of CAR. Using the MerCreMer transgene we were able to obtain adult animals that can be induced with tamoxifen to progressively lose CAR expression in the heart. The role of CAR in murine viral myocarditis was investigated using the inducible CAR-knockout infected with CVB3. Unlike control animals exposed to CVB3, the cardiac inducible knockout mice did not exhibit structural changes such as monocyte infiltration and fibrosis following CVB3 infection, or increased production of markers of inflammation. While CVB3 infection resulted in severe con-