(Circulation. 2001;103:140.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
A Ca2+-Dependent Transgenic Model of Cardiac Hypertrophy
A Role for Protein Kinase C
From the Institute of Molecular Pharmacology and Biophysics (J.N.M., I.B., G.V., A.S.) and the Department of Cell Biology, Neurobiology, and Anatomy (J.N.M., G.V.), University of Cincinnati Medical Center, Cincinnati, Ohio; and the Department of Pathology (W.L.), Emory University, School of Medicine, Atlanta, Ga.
Correspondence to Arnold Schwartz, Institute of Molecular Pharmacology and Biophysics, University of Cincinnati Medical Center, 231 Bethesda Ave, Mail Location 0828, Cincinnati, OH 45267-0828. E-mail schwara{at}email.uc.edu
Background—Calcium imbalances have been implicated as an underlying mechanism of human cardiac dysfunction. The voltage-dependent calcium channel plays a critical role in calcium regulation in the heart. Thus, aberrant calcium signaling arising from this channel could initiate the calcium imbalances observed in heart failure. In the present study, we used a transgenic mouse with an increased number of L-type calcium channels to identify the role of an increased, sustained ingress of calcium as an initiator of hypertrophy.
Methods and
Results—Whole-heart histology and
electrophysiology in isolated cardiomyocytes identified calcium-channel
overexpression in the hearts of transgenic mice. Calcium-channel
density was increased in 2-, 4-, and 8-month-old transgenic
cardiomyocytes. Ventricular fibrosis, damage, and remodeling became
more pronounced as the transgenic mice aged. Apoptosis was also present
in transgenic hearts at 8 months of age. Increased protein kinase C
activation was elevated before the development of hypertrophy and
failure.
Conclusions—Transgenic
mice developed hypertrophy and severe cardiomyopathy as a function of
age, thus confirming that changes in channel density are sufficient to
induce disease. The small, sustained increase in the ingress of
Ca2+ through the calcium channel elevated
protein kinase C before the development of hypertrophy, suggesting
that protein kinase C plays an important role in triggering
hypertrophy.
Key Words: calcium • ion channels • heart failure
This article has been cited by other articles:
 |
|
 |
|
  S. R. Houser and J. D. Molkentin Does Contractile Ca2+ Control Calcineurin-NFAT Signaling and Pathological Hypertrophy in Cardiac Myocytes? Sci. Signal., June 24, 2008; 1(25): pe31 - pe31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Sun, B.-G. Kerfant, D. Zhao, M. G. Trivieri, G. Y. Oudit, J. M. Penninger, and P. H. Backx Insulin-Like Growth Factor-1 and PTEN Deletion Enhance Cardiac L-Type Ca2+ Currents via Increased PI3K{alpha}/PKB Signaling Circ. Res., June 9, 2006; 98(11): 1390 - 1397. [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]
|
|
|
|
|
|
X. Chen, X. Zhang, H. Kubo, D. M. Harris, G. D. Mills, J. Moyer, R. Berretta, S. T. Potts, J. D. Marsh, and S. R. Houser Ca2+ Influx-Induced Sarcoplasmic Reticulum Ca2+ Overload Causes Mitochondrial-Dependent Apoptosis in Ventricular Myocytes Circ. Res., November 11, 2005; 97(10): 1009 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rubio, I. Bodi, G. A. Fuller-Bicer, H. S. Hahn, M. Periasamy, and A. Schwartz Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4): 235 - 249. [Abstract] [PDF]
|
|
|
|
|
|
W. Zhu, X. Zeng, M. Zheng, and R.-P. Xiao The Enigma of {beta}2-Adrenergic Receptor Gi Signaling in the Heart: The Good, the Bad, and the Ugly Circ. Res., September 16, 2005; 97(6): 507 - 509. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Lebeche, R. Kaprielian, F. del Monte, G. Tomaselli, J. K. Gwathmey, A. Schwartz, and R. J. Hajjar In Vivo Cardiac Gene Transfer of Kv4.3 Abrogates the Hypertrophic Response in Rats After Aortic Stenosis Circulation, November 30, 2004; 110(22): 3435 - 3443. [Abstract] [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]
|
|
|
|
 |
|
 R. B. Vega, B. C. Harrison, E. Meadows, C. R. Roberts, P. J. Papst, E. N. Olson, and T. A. McKinsey Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5 Mol. Cell. Biol., October 1, 2004; 24(19): 8374 - 8385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Perrier, B.-G. Kerfant, N. Lalevee, P. Bideaux, M. F. Rossier, S. Richard, A. M. Gomez, and J.-P. Benitah Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction Circulation, August 17, 2004; 110(7): 776 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Fiedler and K. C Wollert Interference of antihypertrophic molecules and signaling pathways with the Ca2+-calcineurin-NFAT cascade in cardiac myocytes Cardiovasc Res, August 15, 2004; 63(3): 450 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N Petrashevskaya, I. Bodi, S. E Koch, S. A Akhter, and A. Schwartz Effects of {alpha}1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression Cardiovasc Res, August 15, 2004; 63(3): 561 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. MORAD and M. CHAU Learning about Cardiac Calcium Signaling from Genetic Engineering Ann. N.Y. Acad. Sci., May 1, 2004; 1015(1): 1 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. LAMMERDING, R. D. KAMM, and R. T. LEE Mechanotransduction in Cardiac Myocytes Ann. N.Y. Acad. Sci., May 1, 2004; 1015(1): 53 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. Flagg, F. Charpentier, J. Manning-Fox, M. S. Remedi, D. Enkvetchakul, A. Lopatin, J. Koster, and C. Nichols Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1361 - H1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. B. Walsh and Q. Cheng Intracellular Ca2+ regulates responsiveness of cardiac L-type Ca2+ current to protein kinase A: role of calmodulin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H186 - H194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Most, A. Remppis, S. T. Pleger, E. Loffler, P. Ehlermann, J. Bernotat, C. Kleuss, J. Heierhorst, P. Ruiz, H. Witt, et al. Transgenic Overexpression of the Ca2+-binding Protein S100A1 in the Heart Leads to Increased in Vivo Myocardial Contractile Performance J. Biol. Chem., September 5, 2003; 278(36): 33809 - 33817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Henning and Y. Li Cocaine Produces Cardiac Hypertrophy by Protein Kinase C Dependent Mechanisms Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2003; 8(2): 149 - 160. [Abstract] [PDF]
|
|
|
|
 |
|
 I. Bodi, J. N. Muth, H. S. Hahn, N. N. Petrashevskaya, M. Rubio, S. E. Koch, G. Varadi, and A. Schwartz Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure: Complex nature of k+ current changes and action potential duration J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1611 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Jalili, J. Manning, and S. Kim Increased Translocation of Cardiac Protein Kinase C {beta}2 Accompanies Mild Cardiac Hypertrophy in Rats Fed Saturated Fat J. Nutr., February 1, 2003; 133(2): 358 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Sussman, A. McCulloch, and T. K. Borg Dance Band on the Titanic: Biomechanical Signaling in Cardiac Hypertrophy Circ. Res., November 15, 2002; 91(10): 888 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zobel, Z. Kassiri, T.-T. T. Nguyen, Y. Meng, and P. H. Backx Prevention of Hypertrophy by Overexpression of Kv4.2 in Cultured Neonatal Cardiomyocytes Circulation, October 29, 2002; 106(18): 2385 - 2391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Way, K. Isshiki, K. Suzuma, T. Yokota, D. Zvagelsky, F. J. Schoen, G. E. Sandusky, P. A. Pechous, C. J. Vlahos, H. Wakasaki, et al. Expression of Connective Tissue Growth Factor Is Increased in Injured Myocardium Associated With Protein Kinase C {beta}2 Activation and Diabetes Diabetes, September 1, 2002; 51(9): 2709 - 2718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N Petrashevskaya, I. Bodi, M. Rubio, J. D Molkentin, and A. Schwartz Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse Cardiovasc Res, April 1, 2002; 54(1): 117 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-S. Song, A. Guia, J. N. Muth, M. Rubio, S.-Q. Wang, R.-P. Xiao, I. R. Josephson, E. G. Lakatta, A. Schwartz, and H. Cheng Ca2+ Signaling in Cardiac Myocytes Overexpressing the {alpha}1 Subunit of L-Type Ca2+ Channel Circ. Res., February 8, 2002; 90(2): 174 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schwartz and N. N Petrashevskaya The importance of calcium in interpretation of NaK-ATPase isoform function in the mouse heart Cardiovasc Res, July 1, 2001; 51(1): 9 - 12. [Full Text] [PDF]
|
|
|
|
|
|
L.-S. Song, A. Guia, J. N. Muth, M. Rubio, S.-Q. Wang, R.-P. Xiao, I. R. Josephson, E. G. Lakatta, A. Schwartz, and H. Cheng Ca2+ Signaling in Cardiac Myocytes Overexpressing the {alpha}1 Subunit of L-Type Ca2+ Channel Circ. Res., February 8, 2002; 90(2): 174 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sah, G. Y. Oudit, T.-T. T. Nguyen, H. W. Lim, A. D. Wickenden, G. J. Wilson, J. D. Molkentin, and P. H. Backx Inhibition of Calcineurin and Sarcolemmal Ca2+ Influx Protects Cardiac Morphology and Ventricular Function in Kv4.2N Transgenic Mice Circulation, April 16, 2002; 105(15): 1850 - 1856. [Abstract] [Full Text] [PDF]
|
|