Right ventricular targeted gene transfer of a beta-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding.
OBJECTIVE
Abrupt increases in right ventricular afterload occur after cardiac transplantation and pulmonary artery banding, which can result in right ventricular hypertrophy and dilatation. Right ventricular dysfunction is also accompanied by beta-adrenergic receptor desensitization. We sought to determine whether selective right ventricular expression of a transgene encoding a beta-adrenergic receptor kinase inhibitor can improve right ventricular remodeling early after pulmonary artery banding.


METHODS
Rabbits underwent pulmonary artery banding 3 days after percutaneous right coronary artery injection of empty adenovirus (n = 19), a control adenovirus containing the beta-galactosidase transgene (n = 10), or an adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene (n = 14). Sham-operated animals (n = 7) underwent instrumentation without deployment of the pulmonary artery band. Right ventricular function was assessed in each rabbit before and 7 days after pulmonary artery banding. Right ventricular mass and dimensions (surface area and volume) were obtained, and biochemical analysis was performed to confirm transgene expression and to characterize beta-adrenergic receptor signaling.


RESULTS
Right ventricular mass was increased in animals treated with adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene, adenovirus containing the beta-galactosidase transgene, and empty adenovirus after banding when compared with results in sham-operated animals. However, right ventricular volume and surface area, as measures of dilatation, were significantly lower in pulmonary artery banded rabbits pretreated with adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene when compared with those treated with empty adenovirus or adenovirus containing the beta-galactosidase transgene. Right ventricular contractility and defective beta-adrenergic receptor signaling were significantly enhanced in rabbits expressing the beta-adrenergic receptor kinase inhibitor after pulmonary artery banding.


CONCLUSIONS
Right ventricular preconditioning with the beta-adrenergic receptor kinase inhibitor transgene can attenuate the early right ventricular dilatation and dysfunction associated with pulmonary artery banding. Thus beta-adrenergic receptor kinase inhibition might represent a novel target for limiting ventricular remodeling after increased right ventricular afterload.
Emani
Sitaram M
SM
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Shah
Ashish S
AS
Bowman
Michael K
MK
White
David C
DC
Emani
Sitaramesh
S
Glower
Donald D
DD
Koch
Walter J
WJ
D000256:Adenoviridae; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008026:Ligation; D010455:Peptides; D011651:Pulmonary Artery / Q000601:surgery*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011994:Recombinant Proteins; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control
D002352:Carrier Proteins; D010455:Peptides; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide