© 1999 American Heart Association, Inc.
Original Contribution |
Apoptosis of Cardiac Myocytes in Gs
Transgenic Mice
From the Cardiovascular and Pulmonary Research Institute (Y-J.G., Y.I., D.E.V., S.F.V.), Allegheny University of the Health Sciences, Pittsburgh, Pa; Departments of Molecular and Cellular Biology and Oncology Research (T.E.W.), The Greenville Hospital System, Greenville, SC; Department of Microbiology and Molecular Medicine (T.E.W.), Clemson University, Clemson, SC; Department of Pathology (S.P.B.), University of Alabama at Birmingham; and COR Therapeutics, Inc (C.J.H.), South San Francisco, Calif.
Correspondence to Stephen F. Vatner, MD, George J. Magovern Professor and Director, Cardiovascular Research Institute, Allegheny University of Health Sciences, 320 East North Avenue, Pittsburgh, PA 15212.
Abstract—The stimulatory
GTP-binding protein Gs
transmits signals from
catecholamine receptors to activate adenylyl
cyclase and thereby initiate a cascade leading to cardiac chronotropy
and inotropy. Transgenic mice overexpressing the Gs subunit (Gs)
selectively in their hearts exhibit increased cardiac
contractility in response to ß-adrenergic receptor
stimulation. However, with aging, these mice develop a
cardiomyopathy. This study sought morphological and
biochemical evidence that overexpression of Gs is associated with
increased myocyte apoptosis in the older animals and to
determine whether such overexpression can promote apoptosis of
isolated neonatal cardiac myocytes exposed to ß-adrenergic receptor
agonists. In the hearts of 15- to 18-month-old Gs transgenic mice,
histochemistry and electron microscopy illustrated the existence of
numerous myocytes with abnormal nuclei embedded in collagen-rich
connective tissue. Terminal deoxyribonucleotide
transferase-mediated dUTP nick-end labeling (TUNEL, for in situ
labeling of DNA breaks) demonstrated that 
0.6% of myocyte
nuclei contained fragmented DNA. Agarose gel electrophoresis provided
further biochemical evidence of apoptosis by showing
internucleosomal DNA fragmentation. Cultured cardiac myocytes from
newborn Gs transgenic mice showed increased TUNEL staining and
internucleosomal DNA fragmentation compared with wild-type controls
when treated with the ß-agonist isoproterenol. Thus, enhanced
activation of ß-adrenergic signaling by overexpression of Gs in
the hearts of transgenic mice induces apoptosis of cardiac
myocytes. This represents a potential mechanism that may
contribute to the development of cardiomyopathy in
this model.
Key Words: adenylyl cyclase • ß-adrenergic receptor • catecholamine • programmed cell death • cardiomyopathy
This article has been cited by other articles:
 |
|
 |
|
  S. Choudhury, S. Bae, S. R. Kumar, Q. Ke, B. Yalamarti, J. H. Choi, L. A. Kirshenbaum, and P. M. Kang Role of AIF in cardiac apoptosis in hypertrophic cardiomyocytes from Dahl salt-sensitive rats Cardiovasc Res, January 1, 2010; 85(1): 28 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Liu, B. Ramani, D. Soto, V. De Arcangelis, and Y. Xiang Agonist Dose-dependent Phosphorylation by Protein Kinase A and G Protein-coupled Receptor Kinase Regulates {beta}2 Adrenoceptor Coupling to Gi Proteins in Cardiomyocytes J. Biol. Chem., November 20, 2009; 284(47): 32279 - 32287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Chu, B.-S. Tzang, L.-M. Chen, C.-J. Liu, F.-J. Tsai, C.-H. Tsai, J. A. Lin, W.-W. Kuo, D.-T. Bau, C.-H. Yao, et al. Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through G{alpha}q and Downstream Calcineurin Signaling in Myocardial Cells Endocrinology, June 1, 2009; 150(6): 2723 - 2731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Lewin, M. Matus, A. Basu, K. Frebel, S. P. Rohsbach, A. Safronenko, M. D. Seidl, F. Stumpel, I. Buchwalow, S. Konig, et al. Critical Role of Transcription Factor Cyclic AMP Response Element Modulator in {beta}1-Adrenoceptor-Mediated Cardiac Dysfunction Circulation, January 6, 2009; 119(1): 79 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hedhli, P. Lizano, C. Hong, L. F. Fritzky, S. K. Dhar, H. Liu, Y. Tian, S. Gao, K. Madura, S. F. Vatner, et al. Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1385 - H1393. [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]
|
|
|
|
 |
|
 G. S. Lynch and J. G. Ryall Role of {beta}-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease Physiol Rev, April 1, 2008; 88(2): 729 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ulucan, X. Wang, E. Baljinnyam, Y. Bai, S. Okumura, M. Sato, S. Minamisawa, S. Hirotani, and Y. Ishikawa Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1662 - H1672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Malhotra, R. Begley, B. P. S. Kang, I. Rana, J. Liu, G. Yang, D. Mochly-Rosen, and L. G. Meggs PKC-{varepsilon}-dependent survival signals in diabetic hearts Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1343 - H1350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. V. Y. Raju, L. A. Barouch, and J. M. Hare Nitric Oxide and Oxidative Stress in Cardiovascular Aging Sci. Aging Knowl. Environ., May 25, 2005; 2005(21): re4 - re4. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhang Prenatal Hypoxia and Cardiac Programming Reproductive Sciences, January 1, 2005; 12(1): 2 - 13. [Abstract] [PDF]
|
|
|
|
|
|
K. Iwatsubo, S. Minamisawa, T. Tsunematsu, M. Nakagome, Y. Toya, J. E. Tomlinson, S. Umemura, R. M. Scarborough, D. E. Levy, and Y. Ishikawa Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration J. Biol. Chem., September 24, 2004; 279(39): 40938 - 40945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Depre, S.-J. Kim, A. S. John, Y. Huang, O. E. Rimoldi, J. R. Pepper, G. D. Dreyfus, V. Gaussin, D. J. Pennell, D. E. Vatner, et al. Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium Circ. Res., August 20, 2004; 95(4): 433 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kang, P. Yue, Z. Liu, O. Tarnavski, N. Bodyak, and S. Izumo Alterations in apoptosis regulatory factors during hypertrophy and heart failure Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H72 - H80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Hayakawa, M. Chandra, W. Miao, J. Shirani, J. H. Brown, G. W. Dorn II, R. C. Armstrong, and R. N. Kitsis Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of G{alpha}q Transgenic Mice Circulation, December 16, 2003; 108(24): 3036 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Gaussin, J. E. Tomlinson, C. Depre, S. Engelhardt, C. L. Antos, G. Takagi, L. Hein, J. N. Topper, S. B. Liggett, E. N. Olson, et al. Common Genomic Response in Different Mouse Models of {beta}-Adrenergic-Induced Cardiomyopathy Circulation, December 9, 2003; 108(23): 2926 - 2933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Li, Y. Xiao, J. L. Estrella, C. A. Ducsay, R. D. Gilbert, and L. Zhang Effect of Fetal Hypoxia on Heart Susceptibility to Ischemia and Reperfusion Injury in the Adult Rat Reproductive Sciences, July 1, 2003; 10(5): 265 - 274. [Abstract] [PDF]
|
|
|
|
|
|
M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF]
|
|
|
|
|
|
C. Depre, M. Hase, V. Gaussin, A. Zajac, L. Wang, L. Hittinger, B. Ghaleh, X. Yu, R. K. Kudej, T. Wagner, et al. H11 Kinase Is a Novel Mediator of Myocardial Hypertrophy In Vivo Circ. Res., November 29, 2002; 91(11): 1007 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-P. Huang, X. Song, H.-Y. Wang, and C. C. Malbon Targeted expression of activated Q227L Galpha s in vivo Am J Physiol Cell Physiol, August 1, 2002; 283(2): C386 - C395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Park, S. E. Woodman, W. Schubert, A. W. Cohen, P. G. Frank, M. Chandra, J. Shirani, B. Razani, B. Tang, L. A. Jelicks, et al. Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype Am. J. Pathol., June 1, 2002; 160(6): 2207 - 2217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Hardt, Y.-J. Geng, O. Montagne, K. Asai, C. Hong, G. P. Yang, S. P. Bishop, S.-J. Kim, D. E. Vatner, C. E. Seidman, et al. Accelerated Cardiomyopathy in Mice With Overexpression of Cardiac Gs{alpha} and a Missense Mutation in the {alpha}-Myosin Heavy Chain Circulation, February 5, 2002; 105(5): 614 - 620. [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]
|
|
|
|
 |
|
 F. Mehraban and J. E. Tomlinson Application of industrial scale genomics to discovery of therapeutic targets in heart failure Eur J Heart Fail, December 1, 2001; 3(6): 641 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Mallat, P. Fornes, R. Costagliola, B. Esposito, J. Belmin, D. Lecomte, and A. Tedgui Age and Gender Effects on Cardiomyocyte Apoptosis in the Normal Human Heart J Gerontol A Biol Sci Med Sci, November 1, 2001; 56(11): M719 - M723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice Cardiovasc Res, June 1, 2001; 50(3): 443 - 453. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Henaff, S. N. Hatem, and J.-J. Mercadier Low Catecholamine Concentrations Protect Adult Rat Ventricular Myocytes against Apoptosis through cAMP-Dependent Extracellular Signal-Regulated Kinase Activation Mol. Pharmacol., April 13, 2001; 58(6): 1546 - 1553. [Abstract] [Full Text]
|
|
|
|
 |
|
 W.-Z. Zhu, M. Zheng, W. J. Koch, R. J. Lefkowitz, B. K. Kobilka, and R.-P. Xiao Dual modulation of cell survival and cell death by beta 2-adrenergic signaling in adult mouse cardiac myocytes PNAS, February 13, 2001; 98(4): 1607 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Muth, I. Bodi, W. Lewis, G. Varadi, and A. Schwartz A Ca2+-Dependent Transgenic Model of Cardiac Hypertrophy : A Role for Protein Kinase C{{alpha}} Circulation, January 2, 2001; 103(1): 140 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du, X.-M. Gao, B. Wang, G. L Jennings, E. A Woodcock, and A. M Dart Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing {beta}2-adrenergic receptors in the heart Cardiovasc Res, December 1, 2000; 48(3): 448 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zaugg, W. Xu, E. Lucchinetti, S. A. Shafiq, N. Z. Jamali, and M. A. Q. Siddiqui {beta}-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes Circulation, July 18, 2000; 102(3): 344 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ding, R. L. Price, E. C. Goldsmith, T. K. Borg, X. Yan, P. S. Douglas, E. O. Weinberg, J. Bartunek, T. Thielen, V. V. Didenko, et al. Left Ventricular Hypertrophy in Ascending Aortic Stenosis Mice : Anoikis and the Progression to Early Failure Circulation, June 20, 2000; 101(24): 2854 - 2862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kang and S. Izumo Apoptosis and Heart Failure : A Critical Review of the Literature Circ. Res., June 9, 2000; 86(11): 1107 - 1113. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Asai, R. K. Kudej, Y.-T. Shen, G.-P. Yang, G. Takagi, A. B. Kudej, Y.-J. Geng, N. Sato, J. B. Nazareno, D. E. Vatner, et al. Peripheral Vascular Endothelial Dysfunction and Apoptosis in Old Monkeys Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1493 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Vatner, D. E. Vatner, and C. J. Homcy {beta}-Adrenergic Receptor Signaling: An Acute Compensatory Adjustment--Inappropriate for the Chronic Stress of Heart Failure? : Insights from Gs{alpha} Overexpression and Other Genetically Engineered Animal Models Circ. Res., March 17, 2000; 86(5): 502 - 506. [Full Text] [PDF]
|
|
|
|
|
|
A. Haunstetter and S. Izumo Toward Antiapoptosis as a New Treatment Modality Circ. Res., March 3, 2000; 86(4): 371 - 376. [Full Text] [PDF]
|
|
|
|
|
|
L. J. De Windt, H. W. Lim, T. Taigen, D. Wencker, G. Condorelli, G. W. Dorn II, R. N. Kitsis, and J. D. Molkentin Calcineurin-Mediated Hypertrophy Protects Cardiomyocytes From Apoptosis In Vitro and In Vivo : An Apoptosis-Independent Model of Dilated Heart Failure Circ. Res., February 18, 2000; 86(3): 255 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-C. Tsai, K. B. S. Pasumarthi, L. Pajak, M. Franklin, B. Patton, H. Wang, W. J. Henzel, J. T. Stults, and L. J. Field Simian Virus 40 Large T Antigen Binds a Novel Bcl-2 Homology Domain 3-containing Proapoptosis Protein in the Cytoplasm J. Biol. Chem., February 4, 2000; 275(5): 3239 - 3246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Singh, C. Communal, D. B. Sawyer, and W. S. Colucci Adrenergic regulation of myocardial apoptosis Cardiovasc Res, February 1, 2000; 45(3): 713 - 719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Communal, K. Singh, D. B. Sawyer, and W. S. Colucci Opposing Effects of {beta}1- and {beta}2-Adrenergic Receptors on Cardiac Myocyte Apoptosis : Role of a Pertussis Toxin-Sensitive G Protein Circulation, November 30, 1999; 100(22): 2210 - 2212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Gu, Y.-C. Ma, J. Benjamin, D. Littman, M. V. Chao, and X.-Y. Huang Apoptotic Signaling through the beta -Adrenergic Receptor. A NEW Gs EFFECTOR PATHWAY J. Biol. Chem., June 30, 2000; 275(27): 20726 - 20733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Saito, Y. Hiroi, Y. Zou, R. Aikawa, H. Toko, F. Shibasaki, Y. Yazaki, R. Nagai, and I. Komuro beta -Adrenergic Pathway Induces Apoptosis through Calcineurin Activation in Cardiac Myocytes J. Biol. Chem., October 27, 2000; 275(44): 34528 - 34533. [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]
|
|
|
|
|
|
G. Condorelli, R. Roncarati, J. Ross Jr., A. Pisani, G. Stassi, M. Todaro, S. Trocha, A. Drusco, Y. Gu, M. A. Russo, et al. Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function PNAS, August 14, 2001; 98(17): 9977 - 9982. [Abstract] [Full Text] [PDF]
|
|