Circulation Research. 2003
Published online before print March 6, 2003, doi: 10.1161/01.RES.0000065442.64694.9F
Published online before print March 6, 2003, doi: 10.1161/01.RES.0000065442.64694.9F
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 21, 2002
Revised on February 20, 2003
Accepted on February 26, 2003
Reengineering Inducible Cardiac-Specific Transgenesis With an Attenuated Myosin Heavy Chain Promoter
Atsushi Sanbe ;
From the Department of Pediatrics, Division of Molecular Cardiovascular Biology (A.S., J.G., Q.L., H.O., J.R.), The Children's Hospital Research Foundation, Cincinnati, Ohio, and Procter and Gamble Pharmaceuticals (M.C.H.), Health Care Research Center-Discovery, Mason, Ohio.
* To whom correspondence should be addressed. E-mail: jeff.robbins{at}chmcc.org.
Despite the advantages of reversibly altering cardiac transgene expression, the number of successful studies with inducible cardiac-specific transgene expression remains limited. The utility of the current system is hampered by the large number of lines needed before a nonleaky inducible line is isolated and by the use of a heterologous virus-based minimal promoter in the responder line. We developed an efficient, experimentally flexible system that enables us to reversibly affect both abundant and nonabundant cardiomyocyte proteins. The use of bacterial-codon-based transactivators led to aberrant splicing, whereas other more efficient transactivators, by themselves, caused disease when expressed in the heart. The redesign of the system focused on developing stable transactivator-expressing lines in which expression was driven by the mouse 
-myosin heavy chain promoter. A minimal responder locus was derived from the same promoter, in which the GATA sites and thyroid responsive elements responsible for robust cardiac specific expression were ablated, leading to an attenuated promoter that could be inducibly controlled. In all cases, whether activated or not, expression mimicked that of the parental promoter. By use of this system, an inducible expression of an abundant contractile protein, the atrial isoform of essential myosin light chain 1, and a powerful biological effector, glycogen synthase kinase-3
(GSK-3), were obtained. Subsequently, we tested the hypothesis that GSK-3 expression could reverse a preexisting hypertrophy. Inducible expression of GSK-3 could both attenuate a hypertrophic response and partially reverse a pressure-overload-induced hypertrophy. The system appears to be robust and can be used to temporally control high levels of cardiac-specific transgene expression.
Key words: transgene • myosin • cardiac disease • muscle • mice
This article has been cited by other articles:
 |
|
 |
|
  F.-L. Xiang, X. Lu, L. Hammoud, P. Zhu, P. Chidiac, J. Robbins, and Q. Feng Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice Circulation, September 22, 2009; 120(12): 1065 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wang, T. O. Chan, X.-Q. Zhang, E. Gao, J. Song, W. J. Koch, A. M. Feldman, and J. Y. Cheung Induced overexpression of Na+/Ca2+ exchanger transgene: altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H590 - H601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Y. Oudit and J. M. Penninger Cardiac regulation by phosphoinositide 3-kinases and PTEN Cardiovasc Res, May 1, 2009; 82(2): 250 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsuda, P. Zhai, Y. Maejima, C. Hong, S. Gao, B. Tian, K. Goto, H. Takagi, M. Tamamori-Adachi, S. Kitajima, et al. Distinct roles of GSK-3{alpha} and GSK-3{beta} phosphorylation in the heart under pressure overload PNAS, December 30, 2008; 105(52): 20900 - 20905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Jaleel, H. Nakayama, X. Chen, H. Kubo, S. MacDonnell, H. Zhang, R. Berretta, J. Robbins, L. Cribbs, J. D. Molkentin, et al. Ca2+ Influx Through T- and L-Type Ca2+ Channels Have Different Effects on Myocyte Contractility and Induce Unique Cardiac Phenotypes Circ. Res., November 7, 2008; 103(10): 1109 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yano, A. Tseng, T. C. Zhao, J. Robbins, J. F. Padbury, and Y.-T. Tseng Temporally controlled overexpression of cardiac-specific PI3K{alpha} induces enhanced myocardial contractility--a new transgenic model Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1690 - H1694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Vinet, P. Rouet-Benzineb, X. Marniquet, N. Pellegrin, L. Mangin, L. Louedec, J.-L. Samuel, and J.-J. Mercadier Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H352 - H360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Jacobshagen, M. Gruber, N. Teucher, A. G. Schmidt, B. W. Unsold, K. Toischer, P. Nguyen Van, L. S. Maier, H. Kogler, and G. Hasenfuss Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction Eur J Heart Fail, April 1, 2008; 10(4): 334 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. DeGeorge Jr, E. Gao, M. Boucher, L. E. Vinge, J. S. Martini, P. W. Raake, J. K. Chuprun, D. M. Harris, G. W. Kim, S. Soltys, et al. Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress Circulation, March 18, 2008; 117(11): 1378 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Wolf, M. Arad, F. Ahmad, A. Sanbe, S. A. Bernstein, O. Toka, T. Konno, G. Morley, J. Robbins, J.G. Seidman, et al. Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations Circulation, January 15, 2008; 117(2): 144 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hambleton, A. York, M. A. Sargent, R. A. Kaiser, J. N. Lorenz, J. Robbins, and J. D. Molkentin Inducible and myocyte-specific inhibition of PKC{alpha} enhances cardiac contractility and protects against infarction-induced heart failure Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3768 - H3771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hirotani, P. Zhai, H. Tomita, J. Galeotti, J. P. Marquez, S. Gao, C. Hong, A. Yatani, J. Avila, and J. Sadoshima Inhibition of Glycogen Synthase Kinase 3{beta} During Heart Failure Is Protective Circ. Res., November 26, 2007; 101(11): 1164 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Zhai, S. Gao, E. Holle, X. Yu, A. Yatani, T. Wagner, and J. Sadoshima Glycogen Synthase Kinase-3{alpha} Reduces Cardiac Growth and Pressure Overload-induced Cardiac Hypertrophy by Inhibition of Extracellular Signal-regulated Kinases J. Biol. Chem., November 9, 2007; 282(45): 33181 - 33191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang Mitogen-Activated Protein Kinases in Heart Development and Diseases Circulation, September 18, 2007; 116(12): 1413 - 1423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. H. Purcell, B. J. Wilkins, A. York, M. K. Saba-El-Leil, S. Meloche, J. Robbins, and J. D. Molkentin Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo PNAS, August 28, 2007; 104(35): 14074 - 14079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Oka, J. Xu, R. A. Kaiser, J. Melendez, M. Hambleton, M. A. Sargent, A. Lorts, E. W. Brunskill, G. W. Dorn II, S. J. Conway, et al. Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular Remodeling Circ. Res., August 3, 2007; 101(3): 313 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Reudelhuber, K. E. Bernstein, and P. Delafontaine Is Angiotensin II a Direct Mediator of Left Ventricular Hypertrophy?: Time for Another Look Hypertension, June 1, 2007; 49(6): 1196 - 1201. [Full Text] [PDF]
|
|
|
|
|
|
A. S. Galvez, A. Diwan, A. M. Odley, H. S. Hahn, H. Osinska, J. G. Melendez, J. Robbins, R. A. Lynch, Y. Marreez, and G. W. Dorn II Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis Circ. Res., April 13, 2007; 100(7): 1071 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Burkard, A. G. Rokita, S. G. Kaufmann, M. Hallhuber, R. Wu, K. Hu, U. Hofmann, A. Bonz, S. Frantz, E. J. Cartwright, et al. Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility Circ. Res., February 16, 2007; 100(3): e32 - e44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Yutzey and J. Robbins Principles of Genetic Murine Models for Cardiac Disease Circulation, February 13, 2007; 115(6): 792 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sanbe, J. Yamauchi, Y. Miyamoto, Y. Fujiwara, M. Murabe, and A. Tanoue Interruption of CryAB-Amyloid Oligomer Formation by HSP22 J. Biol. Chem., January 5, 2007; 282(1): 555 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Kotlikoff Genetically encoded Ca2+ indicators: using genetics and molecular design to understand complex physiology J. Physiol., January 1, 2007; 578(1): 55 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Funakoshi, T. O. Chan, J. C. Good, J. R. Libonati, J. Piuhola, X. Chen, S. M. MacDonnell, L. L. Lee, D. E. Herrmann, J. Zhang, et al. Regulated Overexpression of the A1-Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function Circulation, November 21, 2006; 114(21): 2240 - 2250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Trivieri, G. Y. Oudit, R. Sah, B.-G. Kerfant, H. Sun, A. O. Gramolini, Y. Pan, A. D. Wickenden, W. Croteau, G. Morreale de Escobar, et al. Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction PNAS, April 11, 2006; 103(15): 6043 - 6048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. N. Tallini, M. Ohkura, B.-R. Choi, G. Ji, K. Imoto, R. Doran, J. Lee, P. Plan, J. Wilson, H.-B. Xin, et al. Imaging cellular signals in the heart in vivo: Cardiac expression of the high-signal Ca2+ indicator GCaMP2 PNAS, March 21, 2006; 103(12): 4753 - 4758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Turnbull, H.-Z. Zhou, P. M. Swigart, S. Turcato, J. S. Karliner, B. R. Conklin, P. C. Simpson, and A. J. Baker Sustained preconditioning induced by cardiac transgenesis with the tetracycline transactivator Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1103 - H1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Handa, M. A. Momen, A.-M. Sadi, T. Afroze, C. Wang, and M. Husain Troubles With a Transgene: Experiences With SM22{alpha}-tTA Mice Circ. Res., October 14, 2005; 97(8): e85 - e87. [Full Text] [PDF]
|
|
|
|
|
|
A. Sanbe, H. Osinska, C. Villa, J. Gulick, R. Klevitsky, C. G. Glabe, R. Kayed, and J. Robbins Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy PNAS, September 20, 2005; 102(38): 13592 - 13597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Barandon, P. Dufourcq, P. Costet, C. Moreau, C. Allieres, D. Daret, P. D. Santos, J.-M. D. Lamaziere, T. Couffinhal, and C. Duplaa Involvement of FrzA/sFRP-1 and the Wnt/Frizzled Pathway in Ischemic Preconditioning Circ. Res., June 24, 2005; 96(12): 1299 - 1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. McCloskey, L. Turnbull, P. M. Swigart, A. C. Zambon, S. Turcato, S. Joho, W. Grossman, B. R. Conklin, P. C. Simpson, and A. J. Baker Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression Physiol Genomics, June 16, 2005; 22(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sanbe, J. James, V. Tuzcu, S. Nas, L. Martin, J. Gulick, H. Osinska, S. Sakthivel, R. Klevitsky, K. S. Ginsburg, et al. Transgenic Rabbit Model for Human Troponin I-Based Hypertrophic Cardiomyopathy Circulation, May 10, 2005; 111(18): 2330 - 2338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Syed, A. Odley, H. S. Hahn, E. W. Brunskill, R. A. Lynch, Y. Marreez, A. Sanbe, J. Robbins, and G. W. Dorn II Physiological Growth Synergizes With Pathological Genes in Experimental Cardiomyopathy Circ. Res., December 10, 2004; 95(12): 1200 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D Molkentin Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs Cardiovasc Res, August 15, 2004; 63(3): 467 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E Hardt and J. Sadoshima Negative regulators of cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 500 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Hardt, H. Tomita, H. A. Katus, and J. Sadoshima Phosphorylation of Eukaryotic Translation Initiation Factor 2B{epsilon} by Glycogen Synthase Kinase-3{beta} Regulates {beta}-Adrenergic Cardiac Myocyte Hypertrophy Circ. Res., April 16, 2004; 94(7): 926 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gupta, V. Sueblinvong, J. Raman, V. Jeevanandam, and M. P. Gupta Single-stranded DNA-binding Proteins PUR{alpha} and PUR{beta} Bind to a Purine-rich Negative Regulatory Element of the {alpha}-Myosin Heavy Chain Gene and Control Transcriptional and Translational Regulation of the Gene Expression: IMPLICATIONS IN THE REPRESSION OF {alpha}-MYOSIN HEAVY CHAIN DURING HEART FAILURE J. Biol. Chem., November 7, 2003; 278(45): 44935 - 44948. [Abstract] [Full Text] [PDF]
|
|