Molecular beta-adrenergic signaling abnormalities in failing rabbit heartsafter infarction

We studied alterations in the beta-adrenergic receptor (beta-AR) system of rabbit hearts during the development of heart failure (HF) after myocardial infarction (MI) to determine whether the molecular beta-AR abnormalities a ssociated with human HF exist in this animal model. Rabbit HF was establish ed 3 wk after left circumflex coronary artery (LCX) ligation by in vivo phy siological measurements, and molecular beta-AR signaling was examined in ti ssue and cultured ventricular myocytes. We found that there was a significa nt global reduction in beta-AR density by similar to 50% in both ventricles of MI animals compared with sham-operated control animals and that functio nal beta-AR coupling was significantly reduced. Importantly, as found in hu man HF, myocardial protein levels and activity of the beta-AR kinase (beta- ARK1) and G alpha(i) were found to be significantly elevated in MI rabbits, suggesting that these molecules are contributing to myocardial dysfunction . Thus the myocardial beta-AR system of this rabbit model of HF shares impo rtant biochemical characteristics with human HF and therefore is an ideal l aboratory model to investigate novel therapeutic targets for the treatment of HF.