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

Heart failure (HF) is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including an increase in βAR kinase 1 (βARK1) levels and activity. Gene therapy using a peptide inhibitor of βARK1 (βARKct) ininfarcted rabbit hearts has improved compromised cardiac function. To determine whether PARKI inhibition improves survival in a mouse model of HF induced by myocardial infarction (MI), we studied wild-type (WT) and transgenic (TG) mice overexpressing βARKct following MI. There was no difference in infarct size. Survival of WT mice with MI was 25% at 26 weeks. In contrast, 92% of βARKct TG mice with Ml survived (P = 0.01). βARKct 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 βAR abnormalities in WT mice with MI were prevented in βARKct TG mice with MI. In conclusion, βARK1 inhibition results in a marked increase in survival and improved cardiac function in a mouse model of HF induced by Ml.