betaARK1 inhibition improves survival in a mouse model of heart failure induced by myocardial infarction

Abstract

Heart failure (HF) is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including an increase in betaAR kinase 1 (betaARK1) levels and activity. Gene therapy using a peptide inhibitor of betaARK1 (betaARKct) in infarcted rabbit hearts has improved compromised cardiac function. To determine whether betaARK1 inhibition improves survival in a mouse model of HF induced by myocardial infarction (MI), we studied wild-type (WT) and transgenic (TG) mice overexpressing betaARKct following MI. There was no difference in infarct size. Survival of WT mice with MI was 25% at 26 weeks. In contrast, 92% of betaARKct TG mice with MI survived (P = 0.01). betaARKct TG mice with MI at 8 weeks showed significantly higher fractional shortening compared with WT mice with MI (25.1 +/- 2.7% versus 14.2 +/- 1.0%; P < 0.05). Moreover, the biochemical betaAR abnormalities in WT mice with MI were prevented in betaARKct TG mice with MI. In conclusion, betaARK1 inhibition results in a marked increase in survival and improved cardiac function in a mouse model of HF induced by MI.