| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 1999;99:505-510.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Protein Kinase A (PKA)-Dependent Troponin-I Phosphorylation and PKA Regulatory Subunits Are Decreased in Human Dilated Cardiomyopathy
From the Department of Physiology and Biophysics (D.R.Z., C.S.M., M.B.), Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Molecular Cardiology (D.R.Z., M.B.), Lerner Research Institute and Department of Thoracic and Cardiovascular Surgery (R.W.S.) and Center for Anesthesiology Research (C.S.M.), Cleveland Clinic Foundation, Cleveland, Ohio. The current affiliation for Dr Stewart is the University Hospitals of Cleveland, Ohio.
Correspondence to Meredith Bond, PhD, Department of Molecular Cardiology FF10, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail bondm{at}cesmtp.ccf.org
Background—Most studies indicate that failing human hearts have greater baseline myofibrillar Ca2+ sensitivity of tension development than nonfailing hearts. Phosphorylation of cardiac troponin I (TnI) by cAMP-dependent protein kinase (PKA) decreases the affinity of the troponin complex for Ca2+, thus altering the Ca2+ sensitivity of force production. We tested the hypothesis that PKA-dependent TnI phosphorylation is altered in the failing human heart and investigated changes in PKA regulatory subunits as a potential mechanism.
Methods and Results—Using in vitro
back-phosphorylation with [
-32P]ATP,
we demonstrated a significant (P<0.05) 
25%
reduction in baseline PKA-dependent TnI phosphorylation
in human hearts with dilated cardiomyopathy (DCM)
compared with nonfailing (NF) human hearts. There was no significant
difference in cAMP content or maximal PKA activity between DCM and NF
hearts, but expression of the regulatory subunits of PKA-I (RI) and
PKA-II (RII) was significantly decreased in DCM versus NF hearts (RI by
40%, P<0.05; RII by 30%,
P<0.01).
Conclusions—PKA activity is regulated at the substrate level through interactions of PKA regulatory subunits with A-kinase anchoring proteins. The reduced baseline PKA-dependent phosphorylation of TnI in DCM may be due to decreased expression of RI and RII and consequently reduced anchoring of PKA holoenzyme. These findings provide new evidence of deficiencies in downstream regulation of the ß-adrenergic pathway in the failing human heart and may account for increased baseline myofibrillar Ca2+ sensitivity.
Key Words: cardiomyopathy • troponin • enzymes • proteins • receptors, adrenergic, beta
This article has been cited by other articles:
 |
|
 |
|
  L. M. Hanft and K. S. McDonald Sarcomere length dependence of power output is increased after PKA treatment in rat cardiac myocytes Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1524 - H1531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, T. Ramjiganesh, Y.-H. Chen, S. W. Chung, S. R. Hall, S. L. Schissel, R. F. Padera Jr, R. Liao, K. G. Ackerman, J. Kajstura, et al. Disruption of Striated Preferentially Expressed Gene Locus Leads to Dilated Cardiomyopathy in Mice Circulation, January 20, 2009; 119(2): 261 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. McConnell, Z. Popovic, N. Mal, K. Lee, J. Bautista, F. Forudi, R. Schwartzman, J.-P. Jin, M. Penn, and M. Bond Disruption of Protein Kinase A Interaction with A-kinase-anchoring Proteins in the Heart in Vivo: EFFECTS ON CARDIAC CONTRACTILITY, PROTEIN KINASE A PHOSPHORYLATION, AND TROPONIN I PROTEOLYSIS J. Biol. Chem., January 16, 2009; 284(3): 1583 - 1592. [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]
|
|
|
|
 |
|
 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. A. Ramirez-Correa and A. M. Murphy Is Phospholamban or Troponin I the "Prima Donna" in -Adrenergic Induced Lusitropy? Circ. Res., August 17, 2007; 101(4): 326 - 327. [Full Text] [PDF]
|
|
|
|
|
|
B. J. Biesiadecki, T. Kobayashi, J. S. Walker, R. John Solaro, and P. P. de Tombe The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation Circ. Res., May 25, 2007; 100(10): 1486 - 1493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Jweied, R. D. McKinney, L. A. Walker, I. Brodsky, A. S. Geha, M. G. Massad, P. M. Buttrick, and P. P. de Tombe Depressed cardiac myofilament function in human diabetes mellitus Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2478 - H2483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Layland, R. J. Solaro, and A. M. Shah Regulation of cardiac contractile function by troponin I phosphorylation Cardiovasc Res, April 1, 2005; 66(1): 12 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. S. Korte, E. A. Mokelke, M. Sturek, and K. S. McDonald Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs J Appl Physiol, February 1, 2005; 98(2): 461 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Murphy Another New Kinase Targets Troponin I Circ. Res., November 26, 2004; 95(11): 1043 - 1045. [Full Text] [PDF]
|
|
|
|
|
|
U. Gergs, P. Boknik, I. Buchwalow, L. Fabritz, M. Matus, I. Justus, G. Hanske, W. Schmitz, and J. Neumann Overexpression of the Catalytic Subunit of Protein Phosphatase 2A Impairs Cardiac Function J. Biol. Chem., September 24, 2004; 279(39): 40827 - 40834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Takimoto, D. G. Soergel, P. M.L. Janssen, L. B. Stull, D. A. Kass, and A. M. Murphy Frequency- and Afterload-Dependent Cardiac Modulation In Vivo by Troponin I With Constitutively Active Protein Kinase A Phosphorylation Sites Circ. Res., March 5, 2004; 94(4): 496 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. El-Armouche, T. Pamminger, D. Ditz, O. Zolk, and T. Eschenhagen Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts Cardiovasc Res, January 1, 2004; 61(1): 87 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mishra, H. N. Sabbah, J. C. Jain, and R. C. Gupta Reduced Ca2+-calmodulin-dependent protein kinase activity and expression in LV myocardium of dogs with heart failure Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H876 - H883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Murphy Troponin I: In Sickness and In Health--and Normal Development Circ. Res., September 20, 2002; 91(6): 449 - 450. [Full Text] [PDF]
|
|
|
|
|
|
A. V. Gomes, G. Guzman, J. Zhao, and J. D. Potter Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity and Inhibition of Force Development. INSIGHTS INTO THE ROLE OF TROPONIN T ISOFORMS IN THE HEART J. Biol. Chem., September 13, 2002; 277(38): 35341 - 35349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Pyle, M. P. Sumandea, R. J. Solaro, and P. P. De Tombe Troponin I serines 43/45 and regulation of cardiac myofilament function Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1215 - H1224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F.-L. Tan, C. S. Moravec, J. Li, C. Apperson-Hansen, P. M. McCarthy, J. B. Young, and M. Bond The gene expression fingerprint of human heart failure PNAS, August 20, 2002; 99(17): 11387 - 11392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, M. X. Li, and B. D. Sykes Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin I147-163 and Bepridil J. Biol. Chem., August 16, 2002; 277(34): 31124 - 31133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Armoundas, G. F. Tomaselli, and H. D. Esperer Pathophysiological basis and clinical application of T-wave alternans J. Am. Coll. Cardiol., July 17, 2002; 40(2): 207 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Carr, A. G. Schmidt, Y. Suzuki, F. del Monte, Y. Sato, C. Lanner, K. Breeden, S.-L. Jing, P. B. Allen, P. Greengard, et al. Type 1 Phosphatase, a Negative Regulator of Cardiac Function Mol. Cell. Biol., June 15, 2002; 22(12): 4124 - 4135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B Sande, I. Sjaastad, I. B Hoen, J. Bokenes, T. Tonnessen, E. Holt, P. K Lunde, and G. Christensen Reduced level of serine16 phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity Cardiovasc Res, February 1, 2002; 53(2): 382 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Westfall and J. M. Metzger Troponin I Isoforms and Chimeras: Tuning the Molecular Switch of Cardiac Contraction Physiology, December 1, 2001; 16(6): 278 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Boknik, I. Heinroth-Hoffmann, U. Kirchhefer, J. Knapp, B. Linck, H. Luss, T. Muller, W. Schmitz, O.-E. Brodde, and J. Neumann Enhanced protein phosphorylation in hypertensive hypertrophy Cardiovasc Res, September 1, 2001; 51(4): 717 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-Y. Hwang, B. S. Schwartz, B.-K. Lee, P. T. Strickland, A. C. Todd, and J. P. Bressler Associations of Lead Exposure and Dose Measures with Erythrocyte Protein Kinase C Activity in 212 Current Korean Lead Workers Toxicol. Sci., August 1, 2001; 62(2): 280 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang, T. E. Hewett, R. Klevitsky, A. Sanbe, X. Wang, and J. Robbins PKA-dependent phosphorylation of cardiac myosin binding protein C in transgenic mice Cardiovasc Res, July 1, 2001; 51(1): 80 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yang, C. S. Moravec, M. A. Sussman, N. R. DiPaola, D. Fu, L. Hawthorn, C. A. Mitchell, J. B. Young, G. S. Francis, P. M. McCarthy, et al. Decreased SLIM1 Expression and Increased Gelsolin Expression in Failing Human Hearts Measured by High-Density Oligonucleotide Arrays Circulation, December 19, 2000; 102(25): 3046 - 3052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dorigo, M. Floreani, G. Santostasi, I. Maragno, D. Danieli-Betto, E. Germinario, S. M. Magno, G. Primofiore, A. M. Marini, and F. Da Settimo Pharmacological Characterization of a New Ca2+ Sensitizer J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 994 - 1004. [Abstract] [Full Text]
|
|
|
|
|
|
A. Sanbe, J. Gulick, E. Hayes, D. Warshaw, H. Osinska, C.-B. Chan, R. Klevitsky, and J. Robbins Myosin light chain replacement in the heart Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1355 - H1364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Zakhary, C. S. Moravec, and M. Bond Regulation of PKA Binding to AKAPs in the Heart : Alterations in Human Heart Failure Circulation, March 28, 2000; 101(12): 1459 - 1464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Ruehr, D. R. Zakhary, D. S. Damron, and M. Bond Cyclic AMP-dependent Protein Kinase Binding to A-kinase Anchoring Proteins in Living Cells by Fluorescence Resonance Energy Transfer of Green Fluorescent Protein Fusion Proteins J. Biol. Chem., November 12, 1999; 274(46): 33092 - 33096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Zakhary, M. A. Fink, M. L. Ruehr, and M. Bond Selectivity and Regulation of A-kinase Anchoring Proteins in the Heart. THE ROLE OF AUTOPHOSPHORYLATION OF THE TYPE II REGULATORY SUBUNIT OF cAMP-DEPENDENT PROTEIN KINASE J. Biol. Chem., December 22, 2000; 275(52): 41389 - 41395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-B. Yu, L.-F. Zhang, and J.-P. Jin A Proteolytic NH2-terminal Truncation of Cardiac Troponin I That Is Up-regulated in Simulated Microgravity J. Biol. Chem., May 4, 2001; 276(19): 15753 - 15760. [Abstract] [Full Text] [PDF]
|
|