Relationship between reduced expression of beta-adrenergic receptor and thyroid hormone receptors in human failing cardiomyocytes

Background: Thyroid hormone (T3) is an important regulator of cardiac contractile function and was reported to enhance myocardial response to beta adrenergic stimuli. In addition the cardiac gene expression pattern of hypothyroidism resemble those described in heart failure. However, information regarding the relationship between the status of thyroid hormone receptors and adrenergic receptors (AR) in human failing cardiomyocytes are lacking. Aims: To investigate 1) the relationship between the expression levels of thyroid hormone and beta-adrenergic receptors in human failing cardiomyocytes and 2) the capability of T3 to enhance myocyte contractile properties by increasing the expression of AR in adult rat cardiomyocytes. Methods: Cardiomyocytes were isolated from patients undergoing cardiac transplantation for dilated cardiomyopathy (DCM, n=5) and from tentative donors (C, n=3), not transplanted for non cardiac reasons, served as controls. mRNAs for T3 receptors (TRalfa1, TRalfa2 and TRbeta1) and AR (ARB1 and ARB2) was measured by RT-PCR and data are expressed as GAPDH ratio. In separate sets of experiments the effects preincubation (3h) with T3 (10 nM) on the isoproterenol (100 nM) induced myocytes contractility were assessed with an IonOptix SoftEdge system. Results: In failing cardiomyocytes the reduced expression of ARB1 (0.600.02 vs 0.950.03 in C, p<0.05, -37%) and ARB2 (0.350.01 vs 0.600.03 in C, p<0.05, -41%) was associated with a 57% reduction (0.650.49 vs 1.520.13, p<0.05) of the messenger for THRA1, the active form of T3 receptor. These findings were confirmed at the protein level by both Western blots and binding studies.In in vitro experiments, preincubation with T3 significantly increased the effects of isoproterenol on myocyte shortening extent (+26%), shortening velocity (+45%), and lenghtening velocity (+22%) (p<0.05 for all). These effects were antagonized by preincubation with ciclohexymide and actinomycin D. Conclusions: These data reveals that in non failing cardiomyocyte T3 enhances the synthesis of AR and that in failing cardiomyocytes the reduced beta adrenergic receptor population is closely associated with a reduced expression of thyroid hormone receptors.