Objective To evaluate the effects of chronic β3-adrenoreceptor (β3-AR) agonism and antagonism on the expression of β3-AR in a isoproterenol (ISO)-induced heart failure (HF) rat model and to investigate the myocardial fibrosis and calcium regulation in failing heart.
Methods 60 rats were randomly divided into four groups: eight rats were chosen as controls. The HF group 52 rats received a subcutaneous injection of ISO (340 mg/kg), which was administered on two consecutive days (a total of two injections). Following eight weeks, 31 rats in the HF group survived and were randomly divided into three groups: ISO group (n = 8), BRL group (BRL37344, β3-AR agonist, n = 12), SR group (SR59230A, β3-AR antagonist, n = 11). The following indexes were measured: echocardiography, collagen volume fraction (CVF) in myocardium (using Masson staining), phospholamban (PLB) mRNA, Na+/Ca2+ exchanger (NCX1), Sarco/Endoplasmic Reticulum Ca2+ ATPase-2a (SERCA2a), and total myocardial protein analysed using RT-PCR and Western Blot. The expression of extracellular signal regulated kinases (ERK1, ERK2) were assessed by immunohistochemistry.
Results Compared with the control group, collagen volume fraction (CVF) and the expression of extracellular signal regulated kinases (ERK1, ERK2) increased dramatically in ISO and BRL groups. mRNA and protein expression of NCX1 and PLB increased significantly, whereas the expression of SERCA2a decreased dramatically. SR59230A significantly decreased CVF, while the expression of ERK1 and ERK2 dramatically inhibited mRNA and protein expression of NCX1 and PLB. SR59230A could also increase the mRNA and protein expression of SERCA2a.
Conclusions β3-AR mediated cell proliferation through ERKs signalling, and β3-AR agonist promoted cardiac fibrosis and aggravated cardiac function. Whereas, β3-ARs antagonist inhibited cardiac fibrosis and improved cardiac function, while reversing left ventricular remodelling. β3-AR antagonists have the potential to be a new target to improve heart failure. The expression levels of NCX1 and PLB were significantly decreased in the myocardium of heart failure rats, however the expression level of SERCA2a was obviously decreased. A β3-AR agonist could increase the expression levels of NCX1 and PLB, whereas it decreased the expression level of SERCA2a. β3-AR expression was also correlated with calcium channel activity.