Published Online
on April 22, 2002

A more recent version of this article appeared on May 14, 2002

This Article Full Text (PDF) All Versions of this Article: 105/19/2265    most recent 01.CIR.0000016044.19527.96v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ritter, O. Articles by Neyses, L. Search for Related Content PubMed Articles by Ritter, O. Articles by Neyses, L. Related Collections Myocardial cardiomyopathy disease Remodeling

Submitted on December 11, 2001
Revised on March 6, 2002
Accepted on March 6, 2002

Calcineurin in Human Heart Hypertrophy

Oliver Ritter MD, Susanne Hack MS, Kai Schuh PhD, Nicola Röthlein BA, Andreas Perrot PhD, Karl J. Osterziel MD, Hagen D. Schulte MD, and Ludwig Neyses MD^*

From the Department of Medicine (O.R., S.H., K.S., N.R.), University of Wuerzburg, Germany; Franz Volhard Clinic at the Max Delbrueck Center (A.P., K.J.O.), Charité, Humboldt University of Berlin, Germany; Department of Thoracic Surgery (H.D.S.), Heinrich Heine University Duesseldorf, Germany; and University Department of Medicine (L.N.), Manchester, UK.

^* To whom correspondence should be addressed. E-mail: ludwig.neyses{at}mhc.cmht.nwest.nhs.uk.

Background—In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure.

Methods and Results—We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue.

Conclusions—Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.

Key words: hypertrophy • cardiomyopathy • signal transduction

This article has been cited by other articles:

				J. A. Hill and E. N. Olson Cardiac Plasticity N. Engl. J. Med., March 27, 2008; 358(13): 1370 - 1380. [Full Text] [PDF]

				D. Frank, C. Kuhn, M. van Eickels, D. Gehring, C. Hanselmann, S. Lippl, R. Will, H. A. Katus, and N. Frey Calsarcin-1 Protects Against Angiotensin-II Induced Cardiac Hypertrophy Circulation, November 27, 2007; 116(22): 2587 - 2596. [Abstract] [Full Text] [PDF]

				B. D. Hand, M. C. Kostek, R. E. Ferrell, M. J. Delmonico, L. W. Douglass, S. M. Roth, J. M. Hagberg, and B. F. Hurley Influence of promoter region variants of insulin-like growth factor pathway genes on the strength-training response of muscle phenotypes in older adults J Appl Physiol, November 1, 2007; 103(5): 1678 - 1687. [Abstract] [Full Text] [PDF]

				M. Hallhuber, N. Burkard, R. Wu, M. H. Buch, S. Engelhardt, L. Hein, L. Neyses, K. Schuh, and O. Ritter Inhibition of Nuclear Import of Calcineurin Prevents Myocardial Hypertrophy Circ. Res., September 15, 2006; 99(6): 626 - 635. [Abstract] [Full Text] [PDF]

				K. Obasanjo-Blackshire, R. Mesquita, R. I. Jabr, J. D. Molkentin, S. L. Hart, M. S. Marber, Y. Xia, and R. J. Heads Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: Co-operation with Src tyrosine kinase Cardiovasc Res, September 1, 2006; 71(4): 672 - 683. [Abstract] [Full Text] [PDF]

				Y. D. Barac, N. Zeevi-Levin, G. Yaniv, I. Reiter, F. Milman, M. Shilkrut, R. Coleman, Z. Abassi, and O. Binah The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes Cardiovasc Res, October 1, 2005; 68(1): 75 - 86. [Abstract] [Full Text] [PDF]

				L. Lipskaia, F. del Monte, T. Capiod, S. Yacoubi, L. Hadri, M. Hours, R. J. Hajjar, and A.-M. Lompre Sarco/Endoplasmic Reticulum Ca2+-ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat Circ. Res., September 2, 2005; 97(5): 488 - 495. [Abstract] [Full Text] [PDF]

				K. Berenji, M. H. Drazner, B. A. Rothermel, and J. A. Hill Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H8 - H16. [Abstract] [Full Text] [PDF]

				C. Woischwill, P. Karczewski, H. Bartsch, H.-P. Luther, M. Kott, H. Haase, and I. Morano Regulation of the human atrial myosin light chain 1 promoter by Ca2+-calmodulin-dependent signaling pathways FASEB J, April 1, 2005; 19(6): 503 - 511. [Abstract] [Full Text] [PDF]

				N. Burkard, J. Becher, C. Heindl, L. Neyses, K. Schuh, and O. Ritter Targeted Proteolysis Sustains Calcineurin Activation Circulation, March 1, 2005; 111(8): 1045 - 1053. [Abstract] [Full Text] [PDF]

				C.-C. Lin, J.-L. Lin, C.-S. Lin, M.-C. Tsai, M.-J. Su, L.-P. Lai, and S. K. S. Huang Activation of the Calcineurin-Nuclear Factor of Activated T-Cell Signal Transduction Pathway in Atrial Fibrillation Chest, December 1, 2004; 126(6): 1926 - 1932. [Abstract] [Full Text] [PDF]

				J. Nordmeyer, S. Eder, S. Mahmoodzadeh, P. Martus, J. Fielitz, J. Bass, N. Bethke, H. R. Zurbrugg, R. Pregla, R. Hetzer, et al. Upregulation of Myocardial Estrogen Receptors in Human Aortic Stenosis Circulation, November 16, 2004; 110(20): 3270 - 3275. [Abstract] [Full Text] [PDF]

				J. D Molkentin Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs Cardiovasc Res, August 15, 2004; 63(3): 467 - 475. [Abstract] [Full Text] [PDF]

				P. Tavi, S. Pikkarainen, J. Ronkainen, P. Niemela, M. Ilves, M. Weckstrom, O. Vuolteenaho, J. Bruton, H. Westerblad, and H. Ruskoaho Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression J. Physiol., January 15, 2004; 554(2): 309 - 320. [Abstract] [Full Text] [PDF]

				B. J. Wilkins, Y.-S. Dai, O. F. Bueno, S. A. Parsons, J. Xu, D. M. Plank, F. Jones, T. R. Kimball, and J. D. Molkentin Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy Circ. Res., January 9, 2004; 94(1): 110 - 118. [Abstract] [Full Text] [PDF]

				M. U Braun, P. LaRosee, S. Schon, M. M Borst, and R. H Strasser Differential regulation of cardiac protein kinase C isozyme expression after aortic banding in rat Cardiovasc Res, October 1, 2002; 56(1): 52 - 63. [Abstract] [Full Text] [PDF]

				R. S. Williams Calcineurin Signaling in Human Cardiac Hypertrophy Circulation, May 14, 2002; 105(19): 2242 - 2243. [Full Text] [PDF]