Ventricular dysfunction after cardioplegic arrest is improved after myocardial gene transfer of a beta-adrenergic receptor kinase inhibitor.
BACKGROUND
Acute cardiac contractile dysfunction is common after cardiopulmonary bypass (CPB). A potential molecular mechanism is enhanced beta-adrenergic receptor kinase (betaARK1) activity, because beta-adrenergic receptor (betaAR) signaling is altered in cardiomyocytes after cardioplegia. Therefore, we examined whether adenovirus-mediated intracoronary delivery of a betaARK1 inhibitor (Adv-betaARKct) could prevent post-CPB dysfunction.


RESULTS
Rabbits were randomized to receive 5x10(11) total viral particles of Adv-betaARKct or PBS. After 5 days, hearts were arrested with University of Wisconsin solution, excised, and stored at 4 degrees C for 15 minutes or 4 hours before reperfusion on a Langendorff apparatus. Left ventricular (LV) function measured by end-diastolic pressure response to preload augmentation, contractility (LV dP/dt(max)), and relaxation (LV dP/dt(min)) was assessed by use of increasing doses of isoproterenol and compared with a control group of nonarrested hearts acutely perfused on the Langendorff apparatus. In the PBS-treated hearts, LV function decreased in a temporal manner and was significantly impaired compared with control hearts after 4 hours of cardioplegic arrest. LV function in Adv-betaARKct-treated hearts, however, was significantly enhanced compared with PBS treatment and was similar to control nonarrested hearts even after 4 hours of cardioplegia. Biochemically, several aspects of betaAR signaling were dysfunctional in PBS-treated hearts, whereas they were normalized in betaARKct-overexpressing hearts.


CONCLUSIONS
Myocardial gene transfer of Adv-betaARKct stabilizes betaAR signaling and prevents LV dysfunction induced by prolonged cardioplegic arrest. Thus, betaARK1 inhibition may represent a novel target in limiting depressed ventricular function after CPB.
Tevaearai
H T
HT
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Eckhart
A D
AD
Shotwell
K F
KF
Wilson
K
K
Koch
W J
WJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006324:Heart Arrest, Induced / Q000009:adverse effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins; D016896:Treatment Outcome; D018754:Ventricular Dysfunction / Q000209:etiology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects; D051552:beta-Adrenergic Receptor Kinases
D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; C114043:BARKct protein, recombinant; D051552:beta-Adrenergic Receptor Kinases