(Circulation. 1999;99:384-391.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Increased Protein Kinase C Activity and Expression of Ca2+-Sensitive Isoforms in the Failing Human Heart
From Cardiovascular Research (N.B., T.E., T.P., J.L.M., G.G., C.J.V.) and Research Technologies and Product Development (G.E.S., R.L.F., K.M.), Eli Lilly and Co, Indianapolis, Ind; Division of Cardiology (R.A.W., G.S.), University of Cincinnati College of Medicine, Ohio; Division of Cardiology (R.R., M.R.B.), University of Colorado Health Sciences Center, Denver; Cardiovascular Research (H.N.S.), Henry Ford Hospital, Detroit, Mich; and Joslin Diabetes Center (G.L.K.), Harvard Medical School, Boston, Mass.
Correspondence to Chris J. Vlahos, PhD, Cardiovascular Research, Eli Lilly and Co, Indianapolis, IN 46285-0520. E-mail Vlahos_Chris_J{at}Lilly.Com
Background—Increased expression
of Ca2+-sensitive protein kinase C (PKC) isoforms may be
important markers of heart failure. Our aim was to determine the
relative expression of PKC-ß1, -ß2, and -
in failed and
nonfailed myocardium.
Methods and Results—Explanted hearts of patients in whom dilated
cardiomyopathy or ischemic
cardiomyopathy was diagnosed were examined for PKC
isoform content by Western blot, immunohistochemistry, enzymatic
activity, and in situ hybridization and compared with nonfailed left
ventricle. Quantitative immunoblotting revealed
significant increases of >40% in PKC-ß1 (P<0.05)
and -ß2 (P<0.04) membrane expression in failed hearts
compared with nonfailed; PKC- expression was significantly elevated
by 70% in membrane fractions (P<0.03). PKC-
expression was not significantly changed. In failed left ventricle,
PKC-ß1 and -ß2 immunostaining was intense
throughout myocytes, compared with slight, scattered staining in
nonfailed myocytes. PKC- immunostaining was also
more evident in cardiomyocytes from failed hearts with
staining primarily localized to intercalated disks. In situ
hybridization revealed increased PKC-ß1 and -ß2 mRNA expression in
cardiomyocytes of failed heart tissue. PKC activity was
significantly increased in membrane fractions from failed hearts
compared with nonfailed (1021±189 versus 261±89
pmol · mg-1 · min-1,
P<0.01). LY333531, a selective PKC-ß
inhibitor, significantly decreased PKC activity in membrane
fractions from failed hearts by 209
pmol · min-1 · mg-1 (versus 42.5
pmol · min-1 · mg-1 in nonfailed,
P<0.04), indicating a greater contribution of PKC-ß
to total PKC activity in failed hearts.
Conclusions—In failed human heart, PKC-ß1 and -ß2 expression and contribution to total PKC activity are significantly increased. This may signal a role for Ca2+-sensitive PKC isoforms in cardiac mechanisms involved in heart failure.
Key Words: cardiomyopathy • heart failure • hypertrophy • myocytes • signal transduction
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P. Rafiee, Y. Shi, X. Kong, K. A. Pritchard Jr, J. S. Tweddell, S. B. Litwin, K. Mussatto, R. D. Jaquiss, J. Su, and J. E. Baker Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts: Role in Cardioprotection Circulation, July 9, 2002; 106(2): 239 - 245. [Abstract] [Full Text] [PDF]
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D. E. Montgomery, B. M. Wolska, W. G. Pyle, B. B. Roman, J. C. Dowell, P. M. Buttrick, A. P. Koretsky, P. Del Nido, and R. J. Solaro alpha -Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2397 - H2405. [Abstract] [Full Text] [PDF]
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X. P. Yi, A. M. Gerdes, and F. Li Myocyte Redistribution of GRK2 and GRK5 in Hypertensive, Heart-Failure-Prone Rats Hypertension, June 1, 2002; 39(6): 1058 - 1063. [Abstract] [Full Text] [PDF]
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Y. Takeishi, Q. Huang, J.-i. Abe, W. Che, J.-D. Lee, H. Kawakatsu, B. D Hoit, Bradford.C Berk, and R. A Walsh Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy Cardiovasc Res, January 1, 2002; 53(1): 131 - 137. [Abstract] [Full Text] [PDF]
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J. M. Pass, J. Gao, W. K. Jones, W. B. Wead, X. Wu, J. Zhang, C. P. Baines, R. Bolli, Y.-T. Zheng, I. G. Joshua, et al. Enhanced PKCbeta II translocation and PKCbeta II-RACK1 interactions in PKCepsilon -induced heart failure: a role for RACK1 Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2500 - H2510. [Abstract] [Full Text] [PDF]
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K. L. Schreiber, L. Paquet, B. G. Allen, and H. Rindt Protein kinase C isoform expression and activity in the mouse heart Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2062 - H2071. [Abstract] [Full Text] [PDF]
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T. Noguchi, Z. Chen, S. P. Bell, L. Nyland, and M. M. LeWinter Activation of PKC decreases myocardial O2 consumption and increases contractile efficiency in rats Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2191 - H2197. [Abstract] [Full Text] [PDF]
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 L. Chen, H. Hahn, G. Wu, C.-H. Chen, T. Liron, D. Schechtman, G. Cavallaro, L. Banci, Y. Guo, R. Bolli, et al. Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and varepsilon PKC PNAS, September 5, 2001; (2001) 191369098. [Abstract] [Full Text] [PDF]
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L. Huang, B. M. Wolska, D. E. Montgomery, E. M. Burkart, P. M. Buttrick, and R. J. Solaro Increased contractility and altered Ca2+ transients of mouse heart myocytes conditionally expressing PKC{beta} Am J Physiol Cell Physiol, May 1, 2001; 280(5): C1114 - C1120. [Abstract] [Full Text] [PDF]
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B. B. Roman, D. L. Geenen, M. Leitges, and P. M. Buttrick PKC-{beta} is not necessary for cardiac hypertrophy Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2264 - H2270. [Abstract] [Full Text] [PDF]
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S. Ghosh, N. B. Standen, and M. Galinanes Failure to precondition pathological human myocardium J. Am. Coll. Cardiol., March 1, 2001; 37(3): 711 - 718. [Abstract] [Full Text] [PDF]
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D. E. Montgomery, M. Chandra, Q.-Q. Huang, J.-P. Jin, and R. J. Solaro Transgenic incorporation of skeletal TnT into cardiac myofilaments blunts PKC-mediated depression of force Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1011 - H1018. [Abstract] [Full Text] [PDF]
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S. Haq, G. Choukroun, H. Lim, K. M. Tymitz, F. del Monte, J. Gwathmey, L. Grazette, A. Michael, R. Hajjar, T. Force, et al. Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart Failure Circulation, February 6, 2001; 103(5): 670 - 677. [Abstract] [Full Text] [PDF]
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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]
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Y. G. Wang, W. J. Benedict, J. Huser, A. M. Samarel, L. A. Blatter, and S. L. Lipsius Brief rapid pacing depresses contractile function via Ca2+/PKC-dependent signaling in cat ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H90 - H98. [Abstract] [Full Text] [PDF]
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L. C. Hool Hypoxia Increases the Sensitivity of the L-Type Ca2+ Current to {beta}-Adrenergic Receptor Stimulation via a C2 Region-Containing Protein Kinase C Isoform Circ. Res., December 8, 2000; 87(12): 1164 - 1171. [Abstract] [Full Text] [PDF]
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H.-G. Shin, J. V. Barnett, P. Chang, S. Reddy, D. C. Drinkwater, R. N. Pierson, R. G. Wiley, and K. T. Murray Molecular heterogeneity of protein kinase C expression in human ventricle Cardiovasc Res, November 1, 2000; 48(2): 285 - 299. [Abstract] [Full Text] [PDF]
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H. Yokoyama, S. Gunasegaram, S. E. Harding, and M. Avkiran Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium J. Am. Coll. Cardiol., August 1, 2000; 36(2): 534 - 540. [Abstract] [Full Text] [PDF]
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 M. Meier and G. L King Protein kinase C activation and its pharmacological inhibition in vascular disease Vascular Medicine, August 1, 2000; 5(3): 173 - 185. [Abstract] [PDF]
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Y. Pi and J. W. Walker Diacylglycerol and fatty acids synergistically increase cardiomyocyte contraction via activation of PKC Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H26 - H34. [Abstract] [Full Text] [PDF]
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Y. Takeishi, P. Ping, R. Bolli, D. L. Kirkpatrick, B. D. Hoit, and R. A. Walsh Transgenic Overexpression of Constitutively Active Protein Kinase C {epsilon} Causes Concentric Cardiac Hypertrophy Circ. Res., June 23, 2000; 86(12): 1218 - 1223. [Abstract] [Full Text] [PDF]
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K. Naruse and G. L. King Protein Kinase C and Myocardial Biology and Function Circ. Res., June 9, 2000; 86(11): 1104 - 1106. [Full Text] [PDF]
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D. Mochly-Rosen, G. Wu, H. Hahn, H. Osinska, T. Liron, J. N. Lorenz, A. Yatani, J. Robbins, and G. W. Dorn II Cardiotrophic Effects of Protein Kinase C {epsilon} : Analysis by In Vivo Modulation of PKC{epsilon} Translocation Circ. Res., June 9, 2000; 86(11): 1173 - 1179. [Abstract] [Full Text] [PDF]
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J. van der Velden, J.W. de Jong, V.J. Owen, P.B.J. Burton, and G.J.M. Stienen Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes Cardiovasc Res, June 1, 2000; 46(3): 487 - 495. [Abstract] [Full Text] [PDF]
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L. J. De Windt, H. W. Lim, S. Haq, T. Force, and J. D. Molkentin Calcineurin Promotes Protein Kinase C and c-Jun NH2-terminal Kinase Activation in the Heart. CROSS-TALK BETWEEN CARDIAC HYPERTROPHIC SIGNALING PATHWAYS J. Biol. Chem., April 28, 2000; 275(18): 13571 - 13579. [Abstract] [Full Text] [PDF]
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S. J. Matkovich and E. A. Woodcock Ca2+-activated but Not G Protein-mediated Inositol Phosphate Responses in Rat Neonatal Cardiomyocytes Involve Inositol 1,4,5-Trisphosphate Generation J. Biol. Chem., April 6, 2000; 275(15): 10845 - 10850. [Abstract] [Full Text] [PDF]
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T. Matsumoto, R. Ozono, T. Oshima, H. Matsuura, T. Sueda, G. Kajiyama, and M. Kambe Type 2 angiotensin II receptor is downregulated in cardiomyocytes of patients with heart failure Cardiovasc Res, April 1, 2000; 46(1): 73 - 81. [Abstract] [Full Text] [PDF]
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Y. Takeishi, T. Jalili, B. D. Hoit, D. L. Kirkpatrick, L. E. Wagoner, W. T. Abraham, and R. A. Walsh Alterations in Ca2+ cycling proteins and G{alpha}q signaling after left ventricular assist device support in failing human hearts Cardiovasc Res, March 1, 2000; 45(4): 883 - 888. [Abstract] [Full Text] [PDF]
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Q. He and M. C. LaPointe Interleukin-1{beta} Regulates the Human Brain Natriuretic Peptide Promoter via Ca2+-Dependent Protein Kinase Pathways Hypertension, January 1, 2000; 35(1): 292 - 296. [Abstract] [Full Text] [PDF]
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T. Jalili, Y. Takeishi, G. Song, N. A. Ball, G. Howles, and R. A. Walsh PKC translocation without changes in Galpha q and PLC-beta protein abundance in cardiac hypertrophy and failure Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2298 - H2304. [Abstract] [Full Text] [PDF]
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 M. A. Sussman, S. Welch, N. Gude, P. R. Khoury, S. R. Daniels, D. Kirkpatrick, R. A. Walsh, R. L. Price, H. W. Lim, and J. D. Molkentin Pathogenesis of Dilated Cardiomyopathy : Molecular, Structural, and Population Analyses inTropomodulin-Overexpressing Transgenic Mice Am. J. Pathol., December 1, 1999; 155(6): 2101 - 2113. [Abstract] [Full Text] [PDF]
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T. Jalili, Y. Takeishi, and R. A Walsh Signal transduction during cardiac hypertrophy: the role of G{alpha}q, PLC {beta}I, and PKC Cardiovasc Res, October 1, 1999; 44(1): 5 - 9. [Full Text] [PDF]
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