betaARK1 inhibition improves survival in a mouse model of heart failure induced by myocardial infarction.
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.
Suzuki
Yoshiyuki
Y
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. suzukiysy@chugai-pharm.co.jp
Nakano
Kiyotaka
K
Sugiyama
Masakazu
M
Imagawa
Jun-ichi
J
D000818:Animals; D023921:Coronary Stenosis / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000627:therapeutic use; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D006333:Heart Failure / Q000150:complications / Q000401:mortality* / Q000517:prevention & control*; D006342:Heart Rupture, Post-Infarction / Q000209:etiology / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control; D006579:Heterozygote; D006720:Homozygote; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D009203:Myocardial Infarction / Q000150:complications / Q000401:mortality* / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013599:Systole / Q000187:drug effects / Q000502:physiology; D051552:beta-Adrenergic Receptor Kinases
D047428:Protein Kinase Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases