Adenovirus-mediated genetic manipulation of the myocardial β-adrenergic signaling system in transplanted hearts

Ashish S. Shah, David C. White, Oliver Tai, Jonathan A. Hata, Katrina H. Wilson, Anne Pippen, Alan P. Kypson, Donald D. Glower, Robert J. Lefkowitz, Walter J. Koch

Research output: Contribution to journalArticle

Abstract

Objectives: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the β-adrenergic receptor-signaling system, in which alterations in transgenic mice have elucidated novel means to improve the function of the heart in vivo. The purpose of the current study was to determine the functional consequences of β-adrenergic receptor manipulation in a rabbit model of cardiac allograft transplantation. Methods: New Zealand White rabbits weighing 3 kg served as recipients to 1-kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 adenoviral constructs was administered into the aortic root perfusing the graft. Transgenes delivered encoded either the human β2-adrenergic receptor, a peptide inhibitor of β-adrenergic receptor densensitization, or the marker transgene β-galactosidase. Results: Five days after cervical heterotopic transplantation, left ventricular performance was measured on a Langendorff apparatus. A moderate pattern of rejection was seen in all grafts. Biventricular myocyte expression of β-galactosidase was observed, and β2-adrenergic receptor density was elevated 10-fold in grafts that received adeno-β2-adrenergic receptor. Left ventricular systolic and diastolic performance was significantly increased in grafts transfected with either adeno-β2-adrenergic receptor or adeno-β-adrenergic receptor densensitization compared with control grafts that received adeno-β-galactosidase. Conclusions: Ex vivo adenovirus-mediated gene transfer is feasible in a rabbit allograft model and, more important, genetic manipulation of β-adrenergic receptor signaling either by increasing β2-adrenergic receptor density or blocking endogenous receptor desensitization improves graft function acutely in this allograft model.

Original languageEnglish (US)
Pages (from-to)581-588
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume120
Issue number3
StatePublished - 2000
Externally publishedYes

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Adenoviridae
Adrenergic Agents
Adrenergic Receptors
Transplants
Galactosidases
Allografts
Transgenes
Rabbits
Heterotopic Transplantation
Tissue and Organ Procurement
Heart Transplantation
Muscle Cells
Transgenic Mice
Perfusion
Peptides

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Shah, A. S., White, D. C., Tai, O., Hata, J. A., Wilson, K. H., Pippen, A., ... Koch, W. J. (2000). Adenovirus-mediated genetic manipulation of the myocardial β-adrenergic signaling system in transplanted hearts. Journal of Thoracic and Cardiovascular Surgery, 120(3), 581-588.

Adenovirus-mediated genetic manipulation of the myocardial β-adrenergic signaling system in transplanted hearts. / Shah, Ashish S.; White, David C.; Tai, Oliver; Hata, Jonathan A.; Wilson, Katrina H.; Pippen, Anne; Kypson, Alan P.; Glower, Donald D.; Lefkowitz, Robert J.; Koch, Walter J.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 120, No. 3, 2000, p. 581-588.

Research output: Contribution to journalArticle

Shah, AS, White, DC, Tai, O, Hata, JA, Wilson, KH, Pippen, A, Kypson, AP, Glower, DD, Lefkowitz, RJ & Koch, WJ 2000, 'Adenovirus-mediated genetic manipulation of the myocardial β-adrenergic signaling system in transplanted hearts', Journal of Thoracic and Cardiovascular Surgery, vol. 120, no. 3, pp. 581-588.
Shah, Ashish S. ; White, David C. ; Tai, Oliver ; Hata, Jonathan A. ; Wilson, Katrina H. ; Pippen, Anne ; Kypson, Alan P. ; Glower, Donald D. ; Lefkowitz, Robert J. ; Koch, Walter J. / Adenovirus-mediated genetic manipulation of the myocardial β-adrenergic signaling system in transplanted hearts. In: Journal of Thoracic and Cardiovascular Surgery. 2000 ; Vol. 120, No. 3. pp. 581-588.
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abstract = "Objectives: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the β-adrenergic receptor-signaling system, in which alterations in transgenic mice have elucidated novel means to improve the function of the heart in vivo. The purpose of the current study was to determine the functional consequences of β-adrenergic receptor manipulation in a rabbit model of cardiac allograft transplantation. Methods: New Zealand White rabbits weighing 3 kg served as recipients to 1-kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 adenoviral constructs was administered into the aortic root perfusing the graft. Transgenes delivered encoded either the human β2-adrenergic receptor, a peptide inhibitor of β-adrenergic receptor densensitization, or the marker transgene β-galactosidase. Results: Five days after cervical heterotopic transplantation, left ventricular performance was measured on a Langendorff apparatus. A moderate pattern of rejection was seen in all grafts. Biventricular myocyte expression of β-galactosidase was observed, and β2-adrenergic receptor density was elevated 10-fold in grafts that received adeno-β2-adrenergic receptor. Left ventricular systolic and diastolic performance was significantly increased in grafts transfected with either adeno-β2-adrenergic receptor or adeno-β-adrenergic receptor densensitization compared with control grafts that received adeno-β-galactosidase. Conclusions: Ex vivo adenovirus-mediated gene transfer is feasible in a rabbit allograft model and, more important, genetic manipulation of β-adrenergic receptor signaling either by increasing β2-adrenergic receptor density or blocking endogenous receptor desensitization improves graft function acutely in this allograft model.",
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AU - Tai, Oliver

AU - Hata, Jonathan A.

AU - Wilson, Katrina H.

AU - Pippen, Anne

AU - Kypson, Alan P.

AU - Glower, Donald D.

AU - Lefkowitz, Robert J.

AU - Koch, Walter J.

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N2 - Objectives: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the β-adrenergic receptor-signaling system, in which alterations in transgenic mice have elucidated novel means to improve the function of the heart in vivo. The purpose of the current study was to determine the functional consequences of β-adrenergic receptor manipulation in a rabbit model of cardiac allograft transplantation. Methods: New Zealand White rabbits weighing 3 kg served as recipients to 1-kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 adenoviral constructs was administered into the aortic root perfusing the graft. Transgenes delivered encoded either the human β2-adrenergic receptor, a peptide inhibitor of β-adrenergic receptor densensitization, or the marker transgene β-galactosidase. Results: Five days after cervical heterotopic transplantation, left ventricular performance was measured on a Langendorff apparatus. A moderate pattern of rejection was seen in all grafts. Biventricular myocyte expression of β-galactosidase was observed, and β2-adrenergic receptor density was elevated 10-fold in grafts that received adeno-β2-adrenergic receptor. Left ventricular systolic and diastolic performance was significantly increased in grafts transfected with either adeno-β2-adrenergic receptor or adeno-β-adrenergic receptor densensitization compared with control grafts that received adeno-β-galactosidase. Conclusions: Ex vivo adenovirus-mediated gene transfer is feasible in a rabbit allograft model and, more important, genetic manipulation of β-adrenergic receptor signaling either by increasing β2-adrenergic receptor density or blocking endogenous receptor desensitization improves graft function acutely in this allograft model.

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