Molecular beta-adrenergic signaling abnormalities in failing rabbit hearts after 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 associated with human HF exist in this animal model. Rabbit HF was established 3 wk after left circumflex coronary artery (LCX) ligation by in vivo physiological measurements, and molecular beta-AR signaling was examined in tissue and cultured ventricular myocytes. We found that there was a significant global reduction in beta-AR density by approximately 50% in both ventricles of MI animals compared with sham-operated control animals and that functional beta-AR coupling was significantly reduced. Importantly, as found in human HF, myocardial protein levels and activity of the beta-AR kinase (beta-ARK1) and Galphai 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 important biochemical characteristics with human HF and therefore is an ideal laboratory model to investigate novel therapeutic targets for the treatment of HF.
Maurice
J P
JP
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Shah
A S
AS
Kypson
A P
AP
Hata
J A
JA
White
D C
DC
Glower
D D
DD
Koch
W J
WJ
D000818:Animals; D002303:Cardiac Output, Low / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases
D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D019204:GTP-Binding Proteins