This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lai, N. C. Articles by Hammond, H. K. Search for Related Content PubMed PubMed Citation Articles by Lai, N. C. Articles by Hammond, H. K. Related Collections Congestive Cell signalling/signal transduction Heart failure - basic studies Gene therapy

(Circulation. 2000;102:2396.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Intracoronary Delivery of Adenovirus Encoding Adenylyl Cyclase VI Increases Left Ventricular Function and cAMP-Generating Capacity

N. Chin Lai, PhD; David M. Roth, PhD, MD; Mei Hua Gao, PhD; Suzanne Fine, MS; Brian P. Head, BA; Jian Zhu, BS; M. Dan McKirnan, PhD; Christopher Kwong, BS; Nancy Dalton, BA; Kazushi Urasawa, MD; David A. Roth, PhD; H. Kirk Hammond, MD

From San Diego VA Healthcare System (D.M.R., B.P.H., J.Z., C.K., H.K.H.); the Departments of Medicine (N.D., H.K.H.) and Anesthesia (D.M.R.), University of California at San Diego; the Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan (K.U.); and Collateral Therapeutics, Inc, San Diego, Calif (N.C.L., M.H.G., S.F., M.D.M., D.A.R.).

Correspondence to H. Kirk Hammond, MD, VAMC-San Diego (111-A), 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail khammond{at}ucsd.edu

Background—We tested the hypothesis that intracoronary injection of a recombinant adenovirus encoding adenylyl cyclase type VI (AC_VI) would increase cardiac function in pigs.

Methods and Results—Left ventricular (LV) dP/dt and cardiac output in response to isoproterenol and NKH477 stimulation were assessed in normal pigs before and 12 days after intracoronary delivery of histamine followed by intracoronary delivery of an adenovirus encoding lacZ (control) or AC_VI (1.4x10¹² vp). Animals that had received AC_VI gene transfer showed increases in peak LV dP/dt (average increase of 1267±807 mm Hg/s; P=0.0002) and cardiac output (average increase of 39±20 mL · kg^-1 · min^-1; P<0.0001); control animals showed no changes. Increased LV dP/dt was evident 6 days after gene transfer and persisted for at least 57 days. Basal heart rate, blood pressure, and LV dP/dt were unchanged, despite changes in cardiac responsiveness to catecholamine stimulation. Twenty-three hour ECG recordings showed no change in mean heart rate or ectopic beats and no arrhythmias. LV homogenates from animals receiving AC_VI gene transfer showed increased AC_VI protein content (P=0.0007) and stimulated cAMP production (P=0.0006), confirming transgene expression and function; basal LV AC activity was unchanged. Increased cAMP-generating capacity persisted for at least 18 weeks (P<0.0002).

Conclusions—Intracoronary injection of a recombinant adenovirus encoding AC provides enduring increases in cardiac function.

Key Words: receptors, adrenergic, beta • gene transfer • heart failure • histamine • myocardial contraction

This article has been cited by other articles:

				J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]

				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]

				R. A. Bundey and P. A. Insel Adenylyl Cyclase 6 Overexpression Decreases the Permeability of Endothelial Monolayers via Preferential Enhancement of Prostacyclin Receptor Function Mol. Pharmacol., November 1, 2006; 70(5): 1700 - 1707. [Abstract] [Full Text] [PDF]

				R. Fischmeister, L. R.V. Castro, A. Abi-Gerges, F. Rochais, J. Jurevicius, J. Leroy, and G. Vandecasteele Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases Circ. Res., October 13, 2006; 99(8): 816 - 828. [Abstract] [Full Text] [PDF]

				A. Sastry, E. Arnold, H. Gurji, A. Iwasa, H. Bui, A. Hassankhani, H. H. Patel, J. R. Feramisco, D. M. Roth, N. C. Lai, et al. Cardiac-Directed Expression of Adenylyl Cyclase VI Facilitates Atrioventricular Nodal Conduction J. Am. Coll. Cardiol., August 1, 2006; 48(3): 559 - 565. [Abstract] [Full Text] [PDF]

				G. Suzuki, T.-C. Lee, J. A. Fallavollita, and J. M. Canty Jr Adenoviral Gene Transfer of FGF-5 to Hibernating Myocardium Improves Function and Stimulates Myocytes to Hypertrophy and Reenter the Cell Cycle Circ. Res., April 15, 2005; 96(7): 767 - 775. [Abstract] [Full Text] [PDF]

				M. H. Gao, T. Tang, T. Guo, S. Q. Sun, J. R. Feramisco, and H. K. Hammond Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3 J. Biol. Chem., September 10, 2004; 279(37): 38797 - 38802. [Abstract] [Full Text] [PDF]

				N. C. Lai, D. M. Roth, M. H. Gao, T. Tang, N. Dalton, Y. Y. Lai, M. Spellman, P. Clopton, and H. K. Hammond Intracoronary Adenovirus Encoding Adenylyl Cyclase VI Increases Left Ventricular Function in Heart Failure Circulation, July 20, 2004; 110(3): 330 - 336. [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]

				F. del Monte and R. J Hajjar Targeting calcium cycling proteins in heart failure through gene transfer J. Physiol., January 1, 2003; 546(1): 49 - 61. [Abstract] [Full Text] [PDF]

				P. Most, A. Remppis, and H. A Katus Conditional AC type VI expression in the heart: relevant insights into function of inducible target gene expression Cardiovasc Res, November 1, 2002; 56(2): 181 - 183. [Full Text] [PDF]

				M. H. Gao, H. Bayat, D. M Roth, J. Yao Zhou, J. Drumm, J. Burhan, and H Kirk Hammond Controlled expression of cardiac-directed adenylylcyclase type VI provides increased contractile function Cardiovasc Res, November 1, 2002; 56(2): 197 - 204. [Abstract] [Full Text] [PDF]

				A. M. Feldman Adenylyl Cyclase: A New Target for Heart Failure Therapeutics Circulation, April 23, 2002; 105(16): 1876 - 1878. [Full Text] [PDF]

				D. M. Roth, H. Bayat, J. D. Drumm, M. H. Gao, J. S. Swaney, A. Ander, and H. K. Hammond Adenylyl Cyclase Increases Survival in Cardiomyopathy Circulation, April 23, 2002; 105(16): 1989 - 1994. [Abstract] [Full Text] [PDF]