(Circulation. 2000;101:408.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Intracoronary Adenovirus-Mediated Delivery and Overexpression of the ß2-Adrenergic Receptor in the Heart
Prospects for Molecular Ventricular Assistance
From the Departments of General and Thoracic Surgery (A.S.S., R.E.L., A.P.K., O.T., J.A.H., S.C.S., D.D.G, W.J.K.), Pharmacology and Cancer Biology (W.J.K.), Medicine and Biochemistry (A.P., R.J.L.), and The Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, NC.
Correspondence to Walter J. Koch, PhD, Laboratory of Molecular Cardiovascular Biology, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of ß2-adrenergic receptors (ß2ARs) 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 ß2AR 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-ßGal) or the ß2AR
(Adeno-ß2AR). 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-ß2AR resulted in
10-fold overexpression in a chamber-specific manner. Delivery of
Adeno-ßGal did not alter in vivo left ventricular (LV)
systolic function, whereas overexpression of
ß2ARs in the LV improved global LV
contractility, as measured by dP/dtmax, 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 ß2AR. 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.
Key Words: gene therapy • myocardium • receptors, adrenergic, ß • ventricles • heart failure • signal transduction
This article has been cited by other articles:
 |
|
 |
|
  L. E. Vinge, P. W. Raake, and W. J. Koch Gene Therapy in Heart Failure Circ. Res., June 20, 2008; 102(12): 1458 - 1470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. DeSantiago, X. Ai, M. Islam, G. Acuna, M. T. Ziolo, D. M. Bers, and S. M. Pogwizd Arrhythmogenic Effects of {beta}2-Adrenergic Stimulation in the Failing Heart Are Attributable to Enhanced Sarcoplasmic Reticulum Ca Load Circ. Res., June 6, 2008; 102(11): 1389 - 1397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Barbato, M. Penicka, L. Delrue, F. Van Durme, B. De Bruyne, M. Goethals, W. Wijns, M. Vanderheyden, and J. Bartunek Thr164Ile polymorphism of {beta}2-adrenergic receptor negatively modulates cardiac contractility: implications for prognosis in patients with idiopathic dilated cardiomyopathy Heart, July 1, 2007; 93(7): 856 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Birks, P. D. Tansley, J. Hardy, R. S. George, C. T. Bowles, M. Burke, N. R. Banner, A. Khaghani, and M. H. Yacoub Left Ventricular Assist Device and Drug Therapy for the Reversal of Heart Failure N. Engl. J. Med., November 2, 2006; 355(18): 1873 - 1884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Logeart, L. Vinet, T. Ragot, M. Heimburger, L. Louedec, J.-B. Michel, B. Escoubet, and J.-J. Mercadier Percutaneous intracoronary delivery of SERCA gene increases myocardial function: a tissue Doppler imaging echocardiographic study Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1773 - H1779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Jones, J. A. Petrofski, K. H. Wilson, C. Steenbergen, W. J. Koch, and C. A. Milano {beta}2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery Eur. J. Cardiothorac. Surg., December 1, 2004; 26(6): 1161 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Roth, N. C. Lai, M. H. Gao, J. D. Drumm, J. Jimenez, J. R. Feramisco, and H. K. Hammond Indirect intracoronary delivery of adenovirus encoding adenylyl cyclase increases left ventricular contractile function in mice Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H172 - H177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. G. MELO, A. S. PACHORI, D. KONG, M. GNECCHI, K. WANG, R. E. PRATT, and V. J. DZAU Gene and cell-based therapies for heart disease FASEB J, April 1, 2004; 18(6): 648 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Emani, A. S. Shah, M. K. Bowman, D. C. White, S. Emani, D. D. Glower, and W. J. Koch Right ventricular targeted gene transfer of a {beta}-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding J. Thorac. Cardiovasc. Surg., March 1, 2004; 127(3): 787 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Champion, D. Georgakopoulos, S. Haldar, L. Wang, Y. Wang, and D. A. Kass Robust Adenoviral and Adeno-Associated Viral Gene Transfer to the In Vivo Murine Heart: Application to Study of Phospholamban Physiology Circulation, December 2, 2003; 108(22): 2790 - 2797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Foerster, F. Groner, J. Matthes, W. J. Koch, L. Birnbaumer, and S. Herzig Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through {beta}2-adrenoceptors PNAS, November 25, 2003; 100(24): 14475 - 14480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bekeredjian, S. Chen, P. A. Frenkel, P. A. Grayburn, and R. V. Shohet Ultrasound-Targeted Microbubble Destruction Can Repeatedly Direct Highly Specific Plasmid Expression to the Heart Circulation, August 26, 2003; 108(8): 1022 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. D. Cox, C. A. Thompson, and S. N. Oesterle Biointerventional cardiovascular therapy Eur. Heart J., November 2, 2002; 23(22): 1753 - 1756. [Full Text] [PDF]
|
|
|
|
|
|
M. C. LaPointe, X.-P. Yang, O. A. Carretero, and Q. He Left ventricular targeting of reporter gene expression in vivo by human BNP promoter in an adenoviral vector Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1439 - H1445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M.L Janssen, W. Schillinger, J.K. Donahue, O. Zeitz, S. Emami, S. E Lehnart, J. Weil, T. Eschenhagen, G. Hasenfuss, and J. Prestle Intracellular {beta}-blockade: overexpression of G{alpha}i2 depresses the {beta}-adrenergic response in intact myocardium Cardiovasc Res, August 1, 2002; 55(2): 300 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. T. Tevaearai, A. D. Eckhart, G. B. Walton, J. R. Keys, K. Wilson, and W. J. Koch Myocardial Gene Transfer and Overexpression of {beta}2-Adrenergic Receptors Potentiates the Functional Recovery of Unloaded Failing Hearts Circulation, July 2, 2002; 106(1): 124 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Bridges, J. M. Burkman, R. Malekan, S. M. Konig, H. Chen, C. B. Yarnall, T. J. Gardner, A. S. Stewart, M. M. Stecker, T. Patterson, et al. Global cardiac-specific transgene expression using cardiopulmonary bypass with cardiac isolation Ann. Thorac. Surg., June 1, 2002; 73(6): 1939 - 1946. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A Thompson and S. N Oesterle Biointerventional cardiology: the future interface of interventional cardiovascular medicine and bioengineering Vascular Medicine, May 1, 2002; 7(2): 135 - 140. [Abstract] [PDF]
|
|
|
|
|
|
J.M. Jones, K.H. Wilson, W.J. Koch, and C.A. Milano Adenoviral gene transfer to the heart during cardiopulmonary bypass: effect of myocardial protection technique on transgene expression Eur. J. Cardiothorac. Surg., May 1, 2002; 21(5): 847 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ikeda, Y. Gu, Y. Iwanaga, M. Hoshijima, S. S. Oh, F. J. Giordano, J. Chen, V. Nigro, K. L. Peterson, K. R. Chien, et al. Restoration of Deficient Membrane Proteins in the Cardiomyopathic Hamster by In Vivo Cardiac Gene Transfer Circulation, January 29, 2002; 105(4): 502 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaugg, M. C. Schaub, T. Pasch, and D. R. Spahn Modulation of {beta}-adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action Br. J. Anaesth., January 1, 2002; 88(1): 101 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Emani, A. S. Shah, D. C. White, D. D. Glower, and W. J. Koch Right ventricular gene therapy with a {beta}-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding Ann. Thorac. Surg., November 1, 2001; 72(5): 1657 - 1661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Port and M. R. Bristow beta -Adrenergic Receptors, Transgenic Mice, and Pharmacological Model Systems Mol. Pharmacol., October 1, 2001; 60(4): 629 - 631. [Full Text] [PDF]
|
|
|
|
|
|
A. S. Shah, D. C. White, S. Emani, A. P. Kypson, R. E. Lilly, K. Wilson, D. D. Glower, R. J. Lefkowitz, and W. J. Koch In Vivo Ventricular Gene Delivery of a {beta}-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction Circulation, March 6, 2001; 103(9): 1311 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Small, K. M. Brown, S. L. Forbes, and S. B. Liggett Modification of the beta 2-Adrenergic Receptor to Engineer a Receptor-Effector Complex for Gene Therapy J. Biol. Chem., August 17, 2001; 276(34): 31596 - 31601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Wellner-Kienitz, K. Bender, and L. Pott Overexpression of beta 1 and beta 2 Adrenergic Receptors in Rat Atrial Myocytes. DIFFERENTIAL COUPLING TO G PROTEIN-GATED INWARD RECTIFIER K+ CHANNELS VIA Gs AND Gi/o J. Biol. Chem., September 28, 2001; 276(40): 37347 - 37354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-L. Laugwitz, H.-J. Weig, A. Moretti, E. Hoffmann, P. Ueblacker, I. Pragst, K. Rosport, A. Schomig, and M. Ungerer Gene Transfer of Heterologous G Protein-Coupled Receptors to Cardiomyocytes : Differential Effects on Contractility Circ. Res., April 13, 2001; 88(7): 688 - 695. [Abstract] [Full Text] [PDF]
|
|