This Article Full Text Full Text (PDF) All Versions of this Article: 105/16/1989    most recent 01.CIR.0000014968.54967.D3v1 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 Roth, D. M. Articles by Hammond, H. K. Search for Related Content PubMed PubMed Citation Articles by Roth, D. M. Articles by Hammond, H. K. Related Collections Animal models of human disease Gene therapy

(Circulation. 2002;105:1989.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Adenylyl Cyclase Increases Survival in Cardiomyopathy

David M. Roth, PhD MD; Hamed Bayat, MD; Jeffrey D. Drumm, BS; Mei Hua Gao, PhD; James S. Swaney, MS; Aziz Ander, BS; H. Kirk Hammond, MD

From the VA San Diego Healthcare System (D.M.R., H.B., J.S.S., A.A., H.K.H.); Departments of Anesthesiology (D.M.R.) and Medicine (H.B., H.K.H.), University of California, San Diego; and Collateral Therapeutics Incorporated (J.D.D., H.M.G.), San Diego, Calif.

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

Background— To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC_VI) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC_VI. We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC_VI.

Methods and Results— Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC_VI (P<0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC_VI, as documented by the ratio of ventricular weight to tibial length (Gq, 11.93±0.99 mg/mm, n=11; Gq/AC, 8.00±0.73 mg/mm, n=9; P<0.01) and by left ventricular cardiac myocyte size (Gq, 2800±254 µm², n=4; Gq/AC, 1721±166 µm², n=5; P<0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20±0.15 mm, n=12; Gq/AC, 3.68±0.12 mm, n=7; P<0.05) and increased fractional shortening (Gq, 32±1%, n=12; Gq/AC, 41±2%, n=7; P<0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8±1.3 fmol/cell, n=5; Gq/AC, 10.7±2.6 fmol/cell, n=6; P<0.02), documenting increased AC function.

Conclusions— Cardiac-directed expression of AC_VI restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.

Key Words: receptors, adrenergic, beta • heart failure • myocytes

This article has been cited by other articles:

				A. El-Armouche, K. Wittkopper, F. Degenhardt, F. Weinberger, M. Didie, I. Melnychenko, M. Grimm, M. Peeck, W. H. Zimmermann, B. Unsold, et al. Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy Cardiovasc Res, December 1, 2008; 80(3): 396 - 406. [Abstract] [Full Text] [PDF]

				M. H. Gao, T. Tang, T. Guo, A. Miyanohara, T. Yajima, K. Pestonjamasp, J. R. Feramisco, and H. K. Hammond Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes J. Biol. Chem., November 28, 2008; 283(48): 33527 - 33535. [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]

				N. C. Lai, T. Tang, M. H. Gao, M. Saito, T. Takahashi, D. M. Roth, and H. K. Hammond Activation of Cardiac Adenylyl Cyclase Expression Increases Function of the Failing Ischemic Heart in Mice J. Am. Coll. Cardiol., April 15, 2008; 51(15): 1490 - 1497. [Abstract] [Full Text] [PDF]

				R. Gros, S. Van Uum, A. Hutchinson-Jaffe, Q. Ding, J. G. Pickering, R. A. Hegele, and R. D. Feldman Increased Enzyme Activity and -Adrenergic Mediated Vasodilation in Subjects Expressing a Single-Nucleotide Variant of Human Adenylyl Cyclase 6 Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2657 - 2663. [Abstract] [Full Text] [PDF]

				J. S. Swaney, H. H. Patel, U. Yokoyama, N. C. Lai, M. Spellman, P. A. Insel, and D. M. Roth Adenylyl cyclase activity and function are decreased in rat cardiac fibroblasts after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3216 - H3220. [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. Colombo, S. Gatti, F. Turcatti, A. Sordi, L. R. Fassati, F. Bonino, J. M. Lipton, and A. Catania Gene Expression Profiling Reveals Multiple Protective Influences of the Peptide {alpha}-Melanocyte-Stimulating Hormone in Experimental Heart Transplantation J. Immunol., September 1, 2005; 175(5): 3391 - 3401. [Abstract] [Full Text] [PDF]

				B. Ding, J.-i. Abe, H. Wei, Q. Huang, R. A. Walsh, C. A. Molina, A. Zhao, J. Sadoshima, B. C. Blaxall, B. C. Berk, et al. Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis: Implication in Heart Failure Circulation, May 17, 2005; 111(19): 2469 - 2476. [Abstract] [Full Text] [PDF]

				T. Tang, M. H. Gao, D. M. Roth, T. Guo, and H. K. Hammond Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1906 - H1912. [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]

				C. Sesti and R. A. Kloner Gene Therapy in Congestive Heart Failure Circulation, July 20, 2004; 110(3): 242 - 243. [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]

				M. A Movsesian Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy Cardiovasc Res, June 1, 2004; 62(3): 450 - 459. [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]

				A. El-Armouche, O. Zolk, T. Rau, and T. Eschenhagen Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure Cardiovasc Res, December 1, 2003; 60(3): 478 - 487. [Abstract] [Full Text] [PDF]

				S. Okumura, G. Takagi, J.-i. Kawabe, G. Yang, M.-C. Lee, C. Hong, J. Liu, D. E. Vatner, J. Sadoshima, S. F. Vatner, et al. Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload PNAS, August 19, 2003; 100(17): 9986 - 9990. [Abstract] [Full Text] [PDF]

				H. Tomita, M. Nazmy, K. Kajimoto, G. Yehia, C. A. Molina, and J. Sadoshima Inducible cAMP Early Repressor (ICER) Is a Negative-Feedback Regulator of Cardiac Hypertrophy and an Important Mediator of Cardiac Myocyte Apoptosis in Response to {beta}-Adrenergic Receptor Stimulation Circ. Res., July 11, 2003; 93(1): 12 - 22. [Abstract] [Full Text] [PDF]

				I. Sjaastad, J A. Wasserstrom, and O. M Sejersted Heart failure - a challenge to our current concepts of excitation-contraction coupling J. Physiol., January 1, 2003; 546(1): 33 - 47. [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]