Phenotype of early cardiomyopathic changes induced by active immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the human β1-adrenergic receptor

In the failing human heart, due to idiopathic dilated cardiomyopathy, it has been suggested that the beta(1)-adrenergic receptor (beta(1)AR) is a potential pathogenic autoantigen. The aim of the present study was to investigate whether immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the beta(1)AR (beta(1)AR ECII) was able to induce the early stage of cardiomyopathy and also to investigate immunological and receptor functional parameters at a transcriptional level to permit insights into the autoimmune mechanism in cardiomyopathy. Eleven Whistar Fur rats were immunized with a beta(1)AR ECII peptide (H26R) once a month during 12 months and seven control rats were injected with vehicle according to the same procedure used for the immunized group. Cardiac function, beta(1)AR autoantibodies and their functional effects on cardiomyocytes were analysed. beta(1)AR receptor signalling, immunological and cardiomyocyte stretch markers were determined on transcriptional level. In H26R immunized rats, beta(1)AR autoantibodies were shown to be present and functionally active, cardiac functions in terms of fractional shortening were decreased and beta(1)-adrenergic receptor kinase (GRK2) mRNA were increased compared with the control group. These data have shown that immunization of rats with a putative antigenic peptide was able to induce an early stage phenotype of cardiomyopathy in the form of cardiac dysfunction and up-regulation of GRK2 as the first step in the desensitization process of the beta(1)AR, implying the pathological importance of the beta(1)AR autoantibody.