Ventricular dysfunction after cardioplegic arrest is improved after myocardial gene transfer of a beta-adrenergic receptor kinase inhibitor.

Abstract

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.

METHODS AND 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.

• Authors: H T Tevaearai, A D Eckhart, K F Shotwell, K Wilson, W J Koch
• Journal: Circulation (Circulation) Vol. 104 Issue 17 Pg. 2069-74 (Oct 23 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11673348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Peptide Fragments
• RNA, Messenger
• Recombinant Proteins
• Cyclic AMP-Dependent Protein Kinases
• BARKct protein, recombinant
• beta-Adrenergic Receptor Kinases

Topics

• Adenoviridae (genetics)
• Animals
• Cyclic AMP-Dependent Protein Kinases (administration & dosage, antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Gene Expression
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage, genetics)
• Heart Arrest, Induced (adverse effects)
• Hemodynamics (drug effects)
• In Vitro Techniques
• Male
• Myocardial Contraction (drug effects)
• Myocardial Reperfusion
• Myocardium (metabolism)
• Peptide Fragments (administration & dosage, biosynthesis, genetics)
• RNA, Messenger (metabolism)
• Rabbits
• Recombinant Proteins
• Treatment Outcome
• Ventricular Dysfunction (etiology, prevention & control)
• Ventricular Function, Left (drug effects)
• beta-Adrenergic Receptor Kinases