Circulation Research. 2001;89:997-1004
Published online before print October 11, 2001, doi: 10.1161/hh2301.100003
Published online before print October 11, 2001, doi: 10.1161/hh2301.100003
© 2001 American Heart Association, Inc.
Integrative Physiology |
Dilated Cardiomyopathy and Sudden Death Resulting From Constitutive Activation of Protein Kinase A
From the Departments of Molecular Biology (C.L.A., N.F., E.N.O.) and Pathology (J.A.R.), University of Texas, Southwestern Medical Center at Dallas, Tex; and the Center for Molecular Cardiology (S.O.M., S.R., M.G., A.R.M.), Columbia University College of Physicians & Surgeons, New York, NY.
Correspondence to Eric N. Olson, Department of Molecular Biology, University of Texas, Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd, Dallas, TX 75390-9148. E-mail eolson{at}hamon.swmed.edu
ß-Adrenergic receptor (ßAR) signaling, which elevates intracellular cAMP and enhances cardiac contractility, is severely impaired in the failing heart. Protein kinase A (PKA) is activated by cAMP, but the long-term physiological effect of PKA activation on cardiac function is unclear. To investigate the consequences of chronic cardiac PKA activation in the absence of upstream events associated with ßAR signaling, we generated transgenic mice that expressed the catalytic subunit of PKA in the heart. These mice developed dilated cardiomyopathy with reduced cardiac contractility, arrhythmias, and susceptibility to sudden death. As seen in human heart failure, these abnormalities correlated with PKA-mediated hyperphosphorylation of the cardiac ryanodine receptor/Ca2+-release channel, which enhances Ca2+ release from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca2+-ATPase. These findings demonstrate a specific role for PKA in the pathogenesis of heart failure, independent of more proximal events in ßAR signaling, and support the notion that PKA activity is involved in the adverse effects of chronic ßAR signaling.
Key Words: protein kinase A • transgenic mice • dilated cardiomyopathy
This article has been cited by other articles:
 |
|
 |
|
  A. Abi-Gerges, W. Richter, F. Lefebvre, P. Mateo, A. Varin, C. Heymes, J.-L. Samuel, C. Lugnier, M. Conti, R. Fischmeister, et al. Decreased Expression and Activity of cAMP Phosphodiesterases in Cardiac Hypertrophy and Its Impact on {beta}-Adrenergic cAMP Signals Circ. Res., October 9, 2009; 105(8): 784 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S Kirschner, Z. Yin, G. N Jones, and E. Mahoney Mouse models of altered protein kinase A signaling Endocr. Relat. Cancer, September 1, 2009; 16(3): 773 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Lin, I. Murtaza, K. Wang, J. Jiao, J. Gao, and P.-F. Li miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy PNAS, July 21, 2009; 106(29): 12103 - 12108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Gordon, C. Pagiatakis, J. Salma, M. Du, J. J. Andreucci, J. Zhao, G. Hou, R. L. Perry, Q. Dan, D. Courtman, et al. Protein Kinase A-regulated Assembly of a MEF2{middle dot}HDAC4 Repressor Complex Controls c-Jun Expression in Vascular Smooth Muscle Cells J. Biol. Chem., July 10, 2009; 284(28): 19027 - 19042. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
H.-Z. Feng, M. Chen, L. S. Weinstein, and J.-P. Jin Removal of the N-terminal Extension of Cardiac Troponin I as a Functional Compensation for Impaired Myocardial {beta}-Adrenergic Signaling J. Biol. Chem., November 28, 2008; 283(48): 33384 - 33393. [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]
|
|
|
|
|
|
P. W. Raake, L. E. Vinge, E. Gao, M. Boucher, G. Rengo, X. Chen, B. R. DeGeorge Jr, S. Matkovich, S. R. Houser, P. Most, et al. G Protein-Coupled Receptor Kinase 2 Ablation in Cardiac Myocytes Before or After Myocardial Infarction Prevents Heart Failure Circ. Res., August 15, 2008; 103(4): 413 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, B. Burstein, and D. Dobrev Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications Circ Arrhythm Electrophysiol, April 1, 2008; 1(1): 62 - 73. [Full Text] [PDF]
|
|
|
|
|
|
Z. Yin, G. N. Jones, W. H. Towns II, X. Zhang, E. D. Abel, P. F. Binkley, D. Jarjoura, and L. S. Kirschner Heart-Specific Ablation of Prkar1a Causes Failure of Heart Development and Myxomagenesis Circulation, March 18, 2008; 117(11): 1414 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Most, A. Remppis, S. T. Pleger, H. A. Katus, and W. J. Koch S100A1: a novel inotropic regulator of cardiac performance. Transition from molecular physiology to pathophysiological relevance Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R568 - R577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Anderson Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus Cardiovasc Res, March 1, 2007; 73(4): 657 - 666. [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. El-Armouche, P. Boknik, T. Eschenhagen, L. Carrier, M. Knaut, U. Ravens, and D. Dobrev Molecular Determinants of Altered Ca2+ Handling in Human Chronic Atrial Fibrillation Circulation, August 15, 2006; 114(7): 670 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamada, Y. Ikeda, M. Yano, K. Yoshimura, S. Nishino, H. Aoyama, L. Wang, H. Aoki, and M. Matsuzaki Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy FASEB J, June 1, 2006; 20(8): 1197 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Penela, C. Murga, C. Ribas, A. S. Tutor, S. Peregrin, and F. Mayor Jr. Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease Cardiovasc Res, January 1, 2006; 69(1): 46 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Morel, A. Marcantoni, M. Gastineau, R. Birkedal, F. Rochais, A. Garnier, A.-M. Lompre, G. Vandecasteele, and F. Lezoualc'h cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy Circ. Res., December 9, 2005; 97(12): 1296 - 1304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ding, J.-i. Abe, H. Wei, H. Xu, W. Che, T. Aizawa, W. Liu, C. A. Molina, J. Sadoshima, B. C. Blaxall, et al. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis PNAS, October 11, 2005; 102(41): 14771 - 14776. [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. Veugelers, D. Wilkes, K. Burton, D. A. McDermott, Y. Song, M. M. Goldstein, K. La Perle, C. J. Vaughan, A. O'Hagan, K. R. Bennett, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice PNAS, September 28, 2004; 101(39): 14222 - 14227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Selvetella, E. Hirsch, A. Notte, G. Tarone, and G. Lembo Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence Cardiovasc Res, August 15, 2004; 63(3): 373 - 380. [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]
|
|
|
|
|
|
G.-C. Fan, G. Chu, B. Mitton, Q. Song, Q. Yuan, and E. G. Kranias Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits {beta}-Agonist-Induced Cardiac Apoptosis Circ. Res., June 11, 2004; 94(11): 1474 - 1482. [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]
|
|
|
|
|
|
C. F. Rossow, E. Minami, E. G. Chase, C. E. Murry, and L.F. Santana NFATc3-Induced Reductions in Voltage-Gated K+ Currents After Myocardial Infarction Circ. Res., May 28, 2004; 94(10): 1340 - 1350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Toyo-Oka, T. Kawada, J. Nakata, H. Xie, M. Urabe, F. Masui, T. Ebisawa, A. Tezuka, K. Iwasawa, T. Nakajima, et al. Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure: A scheme for the progression of cardiac dysfunction PNAS, May 11, 2004; 101(19): 7381 - 7385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Onishi, V. A. Browne, S. Kono, V. M. Stiffel, and R. D. Gilbert Effects of Long-Term High-Altitude Hypoxia and Troponin I Phosphorylation on Cardiac Myofilament Calcium Responses in Fetal and Nonpregnant Sheep Reproductive Sciences, January 1, 2004; 11(1): 1 - 8. [Abstract] [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]
|
|
|
|
 |
|
 X.-M. Gao, A. Agrotis, D. J. Autelitano, E. Percy, E. A. Woodcock, G. L. Jennings, A. M. Dart, and X.-J. Du Sex Hormones and Cardiomyopathic Phenotype Induced by Cardiac {beta}2-Adrenergic Receptor Overexpression Endocrinology, September 1, 2003; 144(9): 4097 - 4105. [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]
|
|
|
|
 |
|
 Genetically Modified Animals in Endocrinology Endocr. Rev., August 1, 2003; 24(4): 554 - 555. [Full Text] [PDF]
|
|
|
|
|
|
G. Takagi, K. Asai, S. F. Vatner, R. K. Kudej, F. Rossi, A. Peppas, I. Takagi, R. R. G. Resuello, F. Natividad, Y.-T. Shen, et al. Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H527 - H534. [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]
|
|
|
|
|
|
D. M. Plank, A. Yatani, H. Ritsu, S. Witt, B. Glascock, M. J. Lalli, M. Periasamy, C. Fiset, N. Benkusky, H. H. Valdivia, et al. Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H305 - H315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Zhang, L. S. Maier, N. D. Dalton, S. Miyamoto, J. Ross Jr, D. M. Bers, and J. H. Brown The {delta}C Isoform of CaMKII Is Activated in Cardiac Hypertrophy and Induces Dilated Cardiomyopathy and Heart Failure Circ. Res., May 2, 2003; 92(8): 912 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Onishi, M. Kamitomo, V. M. Stiffel, and R. D. Gilbert Effects of Long-Term High-Altitude Hypoxia on Myocardial Protein Kinase A Activity and Troponin I Isoforms in Fetal and Nonpregnant Sheep Reproductive Sciences, May 1, 2003; 10(4): 189 - 193. [Abstract] [PDF]
|
|
|
|
|
|
S. Kammerer, L. L. Burns-Hamuro, Y. Ma, S. C. Hamon, J. M. Canaves, M. M. Shi, M. R. Nelson, C. F. Sing, C. R. Cantor, S. S. Taylor, et al. Amino acid variant in the kinase binding domain of dual-specific A kinase-anchoring protein 2: A disease susceptibility polymorphism PNAS, April 1, 2003; 100(7): 4066 - 4071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Marks A Guide for the Perplexed: Towards an Understanding of the Molecular Basis of Heart Failure Circulation, March 25, 2003; 107(11): 1456 - 1459. [Full Text] [PDF]
|
|
|
|
|
|
S. Reiken, M. Gaburjakova, S. Guatimosim, A. M. Gomez, J. D'Armiento, D. Burkhoff, J. Wang, G. Vassort, W. J. Lederer, and A. R. Marks Protein Kinase A Phosphorylation of the Cardiac Calcium Release Channel (Ryanodine Receptor) in Normal and Failing Hearts. ROLE OF PHOSPHATASES AND RESPONSE TO ISOPROTERENOL J. Biol. Chem., January 3, 2003; 278(1): 444 - 453. [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]
|
|
|
|
 |
|
 L F Santana, E G Chase, V S Votaw, M. T Nelson, and R Greven Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytes J. Physiol., October 1, 2002; 544(1): 57 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Kapiloff Contributions of Protein Kinase A Anchoring Proteins to Compartmentation of cAMP Signaling in the Heart Mol. Pharmacol., August 1, 2002; 62(2): 193 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. HOSHIJIMA, M. PASHMFOROUSH, R. KNOLL, and K.R. CHIEN The MLP Family of Cytoskeletal Z Disc Proteins and Dilated Cardiomyopathy: A Stress Pathway Model for Heart Failure Progression Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 399 - 408. [Abstract] [PDF]
|
|
|
|
|
|
M. J. Lohse and S. Engelhardt Protein Kinase A Transgenes: The Many Faces of cAMP Circ. Res., November 23, 2001; 89(11): 938 - 940. [Full Text] [PDF]
|
|