Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart

Prospects for molecular ventricular assistance

Ashish S. Shah, R. Eric Lilly, Alan P. Kypson, Oliver Tai, Jonathan A. Hata, Anne Pippen, Scott C. Silvestry, Robert J. Lefkowitz, Donald D. Glower, Walter J. Koch

Research output: Contribution to journalArticle

Abstract

Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β2AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. Methods and Results - Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β2AR (Adeno-β2AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. Conclusions - Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β2AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.

Original languageEnglish (US)
Pages (from-to)408-414
Number of pages7
JournalCirculation
Volume101
Issue number4
StatePublished - Feb 1 2000
Externally publishedYes

Fingerprint

Adenoviridae
Adrenergic Receptors
Ventricular Function
Transgenes
Left Ventricular Function
Catheterization
Coronary Vessels
Heart Failure
Human Adenoviruses
Isoproterenol
Cardiac Myocytes
Transgenic Mice
Genes
Myocardium
Therapeutics
Catheters
Complementary DNA
Rabbits

Keywords

  • Gene therapy
  • Heart failure
  • Myocardium
  • Receptors, adrenergic, β
  • Signal transduction
  • Ventricles

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Shah, A. S., Lilly, R. E., Kypson, A. P., Tai, O., Hata, J. A., Pippen, A., ... Koch, W. J. (2000). Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart: Prospects for molecular ventricular assistance. Circulation, 101(4), 408-414.

Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart : Prospects for molecular ventricular assistance. / Shah, Ashish S.; Lilly, R. Eric; Kypson, Alan P.; Tai, Oliver; Hata, Jonathan A.; Pippen, Anne; Silvestry, Scott C.; Lefkowitz, Robert J.; Glower, Donald D.; Koch, Walter J.

In: Circulation, Vol. 101, No. 4, 01.02.2000, p. 408-414.

Research output: Contribution to journalArticle

Shah, AS, Lilly, RE, Kypson, AP, Tai, O, Hata, JA, Pippen, A, Silvestry, SC, Lefkowitz, RJ, Glower, DD & Koch, WJ 2000, 'Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart: Prospects for molecular ventricular assistance', Circulation, vol. 101, no. 4, pp. 408-414.
Shah, Ashish S. ; Lilly, R. Eric ; Kypson, Alan P. ; Tai, Oliver ; Hata, Jonathan A. ; Pippen, Anne ; Silvestry, Scott C. ; Lefkowitz, Robert J. ; Glower, Donald D. ; Koch, Walter J. / Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart : Prospects for molecular ventricular assistance. In: Circulation. 2000 ; Vol. 101, No. 4. pp. 408-414.
@article{d8769ceb36384133948e7ff3b6486fb1,
title = "Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart: Prospects for molecular ventricular assistance",
abstract = "Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β2AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. Methods and Results - Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β2AR (Adeno-β2AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. Conclusions - Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β2AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.",
keywords = "Gene therapy, Heart failure, Myocardium, Receptors, adrenergic, β, Signal transduction, Ventricles",
author = "Shah, {Ashish S.} and Lilly, {R. Eric} and Kypson, {Alan P.} and Oliver Tai and Hata, {Jonathan A.} and Anne Pippen and Silvestry, {Scott C.} and Lefkowitz, {Robert J.} and Glower, {Donald D.} and Koch, {Walter J.}",
year = "2000",
month = "2",
day = "1",
language = "English (US)",
volume = "101",
pages = "408--414",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart

T2 - Prospects for molecular ventricular assistance

AU - Shah, Ashish S.

AU - Lilly, R. Eric

AU - Kypson, Alan P.

AU - Tai, Oliver

AU - Hata, Jonathan A.

AU - Pippen, Anne

AU - Silvestry, Scott C.

AU - Lefkowitz, Robert J.

AU - Glower, Donald D.

AU - Koch, Walter J.

PY - 2000/2/1

Y1 - 2000/2/1

N2 - Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β2AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. Methods and Results - Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β2AR (Adeno-β2AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. Conclusions - Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β2AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.

AB - Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β2AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. Methods and Results - Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β2AR (Adeno-β2AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. Conclusions - Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β2AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.

KW - Gene therapy

KW - Heart failure

KW - Myocardium

KW - Receptors, adrenergic, β

KW - Signal transduction

KW - Ventricles

UR - http://www.scopus.com/inward/record.url?scp=17344389993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17344389993&partnerID=8YFLogxK

M3 - Article

VL - 101

SP - 408

EP - 414

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 4

ER -