Circulation Research. 2003;93:1111-1119
Published online before print November 6, 2003, doi: 10.1161/01.RES.0000105087.79373.17
Published online before print November 6, 2003, doi: 10.1161/01.RES.0000105087.79373.17
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Integrative Physiology |
Protein Kinase C
Negatively Regulates Systolic and Diastolic Function in Pathological Hypertrophy
From the Departments of Internal Medicine/Cardiology (H.S.H., Y.M., A.O., A.S., M.G.Y., K.C.H., G.W.D.), Institute of Molecular Pharmacology and Biophysics (I.B., A.S.), and Internal Medicine/Pulmonary (S.B.L.), University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to G.W. Dorn II, Division of Cardiology, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH 45267-0542. E-mail dorngw{at}ucmail.uc.edu
The protein kinase C (PKC) family is implicated in cardiac hypertrophy, contractile failure, and ß-adrenergic receptor (ßAR) dysfunction. Herein, we describe the effects of gain- and loss-of-PKC
function using transgenic expression of conventional PKC isoform translocation modifiers. In contrast to previously studied PKC isoforms, activation of PKC failed to induce cardiac hypertrophy, but instead caused ßAR insensitivity and ventricular dysfunction. PKC inhibition had opposite effects. Because PKC is upregulated in human and experimental cardiac hypertrophy and failure, its effects were also assessed in the context of the Gq overexpression model (in which PKC is transcriptionally upregulated). Normalization (inhibition) of PKC activity in Gq hearts improved systolic and diastolic function, whereas further activation of PKC caused a lethal restrictive cardiomyopathy with marked interstitial fibrosis. These results define pathological roles for PKC as a negative regulator of ventricular systolic and diastolic function.
Key Words: systolic and diastolic heart failure • protein kinase C • interstitial fibrosis • restrictive cardiomyopathy
This article has been cited by other articles:
 |
|
 |
|
  W. Soesanto, H.-y. Lin, E. Hu, S. Lefler, S. E. Litwin, S. Sena, E. D. Abel, J. D. Symons, and T. Jalili Mammalian Target of Rapamycin Is a Critical Regulator of Cardiac Hypertrophy in Spontaneously Hypertensive Rats Hypertension, December 1, 2009; 54(6): 1321 - 1327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Liu, X. Chen, S. M. MacDonnell, E. G. Kranias, J. N. Lorenz, M. Leitges, S. R. Houser, and J. D. Molkentin Protein Kinase C{alpha}, but Not PKC{beta} or PKC{gamma}, Regulates Contractility and Heart Failure Susceptibility: Implications for Ruboxistaurin as a Novel Therapeutic Approach Circ. Res., July 17, 2009; 105(2): 194 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Patten and M. R. Hall-Porter Small Animal Models of Heart Failure: Development of Novel Therapies, Past and Present Circ Heart Fail, March 1, 2009; 2(2): 138 - 144. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Niizeki, Y. Takeishi, T. Kitahara, T. Arimoto, M. Ishino, O. Bilim, S. Suzuki, T. Sasaki, O. Nakajima, R. A. Walsh, et al. Diacylglycerol kinase-{varepsilon} restores cardiac dysfunction under chronic pressure overload: a new specific regulator of G{alpha}q signaling cascade Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H245 - H255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. D'Souza, N. N. Petrashevskaya, W. H. Merrill, and S. A. Akhter Inhibition of protein kinase C{alpha} improves myocardial -adrenergic receptor signaling and ventricular function in a model of myocardial preservation J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 172 - 179. [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]
|
|
|
|
 |
|
 R. A. Bouwman, R. J. P. Musters, B. J. van Beek-Harmsen, J. J. de Lange, R. R. Lamberts, S. A. Loer, and C. Boer Sevoflurane-induced cardioprotection depends on PKC-{alpha} activation via production of reactive oxygen species Br. J. Anaesth., November 1, 2007; 99(5): 639 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Belin, M. P. Sumandea, E. J. Allen, K. Schoenfelt, H. Wang, R. J. Solaro, and P. P. de Tombe Augmented Protein Kinase C-{alpha}-Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure Circ. Res., July 20, 2007; 101(2): 195 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Dong, M. M. Taylor, W. K. Samson, and J. Ren Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes J Appl Physiol, September 1, 2006; 101(3): 778 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hambleton, H. Hahn, S. T. Pleger, M. C. Kuhn, R. Klevitsky, A. N. Carr, T. F. Kimball, T. E. Hewett, G. W. Dorn II, W. J. Koch, et al. Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase C{alpha}/{beta} Enhances Cardiac Contractility and Attenuates Heart Failure Circulation, August 8, 2006; 114(6): 574 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Dorn II Containing Hypertrophy With a PICOT Fence Circ. Res., August 4, 2006; 99(3): 228 - 230. [Full Text] [PDF]
|
|
|
|
|
|
D. Jeong, H. Cha, E. Kim, M. Kang, D. K. Yang, J. M. Kim, P. O. Yoon, J. G. Oh, O. Y. Bernecker, S. Sakata, et al. PICOT Inhibits Cardiac Hypertrophy and Enhances Ventricular Function and Cardiomyocyte Contractility Circ. Res., August 4, 2006; 99(3): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Menne, J.-K. Park, R. Agrawal, C. Lindschau, J. T. Kielstein, T. Kirsch, A. Marx, D. Muller, F. H. Bahlmann, M. Meier, et al. Cellular and molecular mechanisms of tissue protection by lipophilic calcium channel blockers FASEB J, May 1, 2006; 20(7): 994 - 996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Galvez, E. W. Brunskill, Y. Marreez, B. J. Benner, K. M. Regula, L. A. Kirschenbaum, and G. W. Dorn II Distinct Pathways Regulate Proapoptotic Nix and BNip3 in Cardiac Stress J. Biol. Chem., January 20, 2006; 281(3): 1442 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kenessey, E. A. Sullivan, and K. Ojamaa Nuclear localization of protein kinase C-{alpha} induces thyroid hormone receptor-{alpha}1 expression in the cardiomyocyte Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H381 - H389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sadayappan, J. Gulick, H. Osinska, L. A. Martin, H. S. Hahn, G. W. Dorn II, R. Klevitsky, C. E. Seidman, J. G. Seidman, and J. Robbins Cardiac Myosin-Binding Protein-C Phosphorylation and Cardiac Function Circ. Res., November 25, 2005; 97(11): 1156 - 1163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Takahashi, K. Okumura, T. Asai, T. Hirai, H. Murakami, R. Murakami, Y. Numaguchi, H. Matsui, M. Ito, and T. Murohara Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency Cardiovasc Res, November 1, 2005; 68(2): 213 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P D Wheeler-Jones Cell signalling in the cardiovascular system: an overview Heart, October 1, 2005; 91(10): 1366 - 1374. [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Korzick, J. C. Hunter, M. K. McDowell, M. D. Delp, M. M. Tickerhoof, and L. D. Carson Chronic Exercise Improves Myocardial Inotropic Reserve Capacity Through {alpha}1-Adrenergic and Protein Kinase C-Dependent Effects in Senescent Rats J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2004; 59(11): 1089 - 1098. [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]
|
|
|
|
 |
|
 A. Odley, H. S. Hahn, R. A. Lynch, Y. Marreez, H. Osinska, J. Robbins, and G. W. Dorn II Regulation of cardiac contractility by Rab4-modulated {beta}2-adrenergic receptor recycling PNAS, May 4, 2004; 101(18): 7082 - 7087. [Abstract] [Full Text] [PDF]
|
|