Skip to main content

Advertisement

SpringerLink
Log in

Calcineurin and matrix protein expression in cardiac hypertrophy

Evidence for calcineurin B to control excessive hypertrophic signaling

  • ORIGINAL CONTRIBUTION
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

In the compensatory state of human left ventricular hypertrophy (LVH), the remodeling processes in the extracellular matrix and the role of calcineurin (Cn) are not completely understood. The present work aimed to analyze the expression and activity of matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), and of Cn in patients with compensated LVH. By semiquantitative RT-PCR, Western blotting, and gelatine zymography, we determined mRNA, protein, and/or enzyme activity levels of MMPs, TIMPs, atrial natriuretic peptide (ANP), Cn subunits, and of the modulatory calcineurin-interacting protein (MCIP) 1. Myocardial samples from patients showing severe aortic stenosis, normal ejection fraction, and compensated LVH were compared with autopsy samples from healthy hearts. LVH patients showed upregulation of CnA-β mRNA but downregulation of both CnB-α mRNA and protein. Total Cn activity (as determined through NF-AT phosphorylation and MCIP1 mRNA expression) was unchanged. There were no differences in gene expression and activities of MMP-2, MMP-9, and of TIMPs 1–4 between LVH patients and controls. As expected, ANP mRNA expression was high in LVH patients. We propose a prominent role for CnB in controlling Cn activity in compensated LVH. At this stage of the disease, MMP and TIMP activities are balanced.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Abbasi S, Lee JD, Su B, Chang X, Alcon J, Yang J, Kellems RE, Xia Y (2006) Protein kinase mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin interacting protein 1. J Biol Chem Jan 16; [Epub ahead of print]

  2. Bueno OF, Lips DJ, Kaiser RA, Wilkins BJ, Dai YS, Glascock BJ, Klevitsky R, Hewett TE, Kimball TR, Aronow BJ, Doevendans PA, Molkentin JD (2004) Calcineurin Aβ gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction. Circ Res 94:91–99

    Article  PubMed  CAS  Google Scholar 

  3. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, Molkentin JD (2002) Impaired cardiac hypertrophic response in Calcineurin Aβ -deficient mice. Proc Natl Acad Sci USA 99:4586–4591

    Article  PubMed  CAS  Google Scholar 

  4. Burkard N, Becher J, Heindl C, Neyses L, Schuh K, Ritter O (2005) Targeted proteolysis sustains calcineurin activation. Circulation 111:1045–1053

    Article  PubMed  CAS  Google Scholar 

  5. Diedrichs H, Chi M, Boelck B, Mehlhorn U, Schwinger RH (2004) Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure. Eur J Heart Fail 6:3–9

    Article  PubMed  CAS  Google Scholar 

  6. Grammer JB, Böhm J, Dufour A, Benz M, Lange R, Bauernschmitt R (2005) Atrial fibrosis in heart surgery patients. Decreased collagen III/I ratio in postoperative atrial fibrillation. Basic Res Cardiol 100:288–294

    Article  PubMed  CAS  Google Scholar 

  7. Grammer JB, Bosch RF, Kühlkamp V, Seipel L (2000) Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation. J Cardiovasc Electrophysiol 11:626–633

    PubMed  CAS  Google Scholar 

  8. Hannan RD, Jenkins A, Jenkins AK, Brandenburger Y (2003) Cardiac hypertrophy: a matter of translation. Clin Exp Pharmacol Physiol 30:517–527

    Article  PubMed  CAS  Google Scholar 

  9. Harris CD, Ermak G, Davies KJ (2005) Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product calcipressin 1 (or RCAN1) in disease. Cell Mol Life Sci 62:2477–2486

    Article  PubMed  CAS  Google Scholar 

  10. Hubbard MJ, Klee CB (1989) Functional domain structure of calcineurin A: mapping by limited proteolysis. Biochemistry 28:1868–1874

    Article  PubMed  CAS  Google Scholar 

  11. Iwanaga Y, Aoyama T, Kihara Y, Onozawa Y, Yoneda T, Sasayama S (2002) Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. J Am Coll Cardiol 39:1384–1391

    Article  PubMed  CAS  Google Scholar 

  12. Kupari M, Turto H, Lommi J (2005) Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure? Eur Heart J 26:1790–1796

    Article  PubMed  Google Scholar 

  13. Li YY, Feldman AM, Sun Y, McTiernan CF (1998) Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 98:1728–1734

    PubMed  CAS  Google Scholar 

  14. Li YY, McTiernan CF, Feldman AM (2000) Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res 46:214–224

    Article  PubMed  CAS  Google Scholar 

  15. Lips DJ, de Windt LJ, van Kraaij DJ, Doevendans PA (2003) Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy. Eur Heart J 24:883–896

    Article  PubMed  CAS  Google Scholar 

  16. Molkentin JD (2004) Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 63:467–475

    Article  PubMed  CAS  Google Scholar 

  17. Noji Y, Shimizu M, Ino H, Higashikata T, Yamaguchi M, Nohara A, Horita T, Shimizu K, Ito Y, Matsuda T, Namura M, Mabuchi H (2004) Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction. Circ J 68:355–360

    Article  PubMed  CAS  Google Scholar 

  18. Oka T, Dai YS, Molkentin JD (2005) Regulation of calcineurin through transcriptional induction of the calcineurin A beta promoter in vitro and in vivo. Mol Cell Biol 25:6649–6659

    Article  PubMed  CAS  Google Scholar 

  19. Polyakova V, Hein S, Kostin S, Ziegelhoeffer T, Schaper J (2004) Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression. J Am Coll Cardiol 44:1609–1618

    Article  PubMed  CAS  Google Scholar 

  20. Ritter O, Hack S, Schuh K, Röthlein N, Perrot A, Osterziel KJ, Schulte HD, Neyses L (2002) Calcineurin in human heart hypertrophy. Circulation 105:2265–2269

    Article  PubMed  CAS  Google Scholar 

  21. Rothermel BA, Vega RB, Williams RS (2003) The role of modulatory calcineurin-interacting proteins in calcineurin signaling. Trends Cardiovasc Med 13:15–21

    Article  PubMed  CAS  Google Scholar 

  22. Ruskoaho H (1992) Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol Rev 44:479–602

    PubMed  CAS  Google Scholar 

  23. Schubert A, Walther T, Falk V, Binner C, Löscher N, Kanev A, Bleiziffer S, Rauch T, Autschbach R, Mohr FW (2001) Extracellular matrix gene expression correlates to left ventricular mass index after surgical induction of left ventricular hypertrophy. Basic Res Cardiol 96:381–387

    Article  PubMed  CAS  Google Scholar 

  24. Schwartz K, de la Bastie D, Bouveret P, Oliviéro P, Alonso S, Buckingham M (1986) α-skeletal muscle actin mRNA’s accumulate in hypertrophied adult rat hearts. Circ Res 59:551–555

    PubMed  CAS  Google Scholar 

  25. Stemmer PM, Klee CB (1994) Dual calcium ion regulation of calcineurin by calmodulin and calcineurin B. Biochemistry 33:6859–6866

    Article  PubMed  CAS  Google Scholar 

  26. Taigen T, de Windt LJ, Lim HW, Molkentin JD (2000) Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci USA 97:1196–1201

    Article  PubMed  CAS  Google Scholar 

  27. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118

    Article  PubMed  CAS  Google Scholar 

  28. Wilkins BJ, de Windt LJ, Bueno OF, Braz JC, Glascock BJ, Kimball TF, Molkentin JD (2002) Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol 22:7603–7613

    Article  PubMed  CAS  Google Scholar 

  29. Wilkins BJ, Molkentin JD (2004) Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochem Biophys Res Commun 322:1178–1191

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work has been supported by the Commission for Clinical Research at the Technical University of Munich (KKF H 10-01), Munich, Germany. Expert technical assistance from Angelika Bernhard-Abt is kindly acknowledged.

Author information

Authors and Affiliations

  1. German Heart Center Munich, Department of Cardiac and Vascular Surgery, Technical University of Munich, Lazarettstrasse 36, 80636, Munich, Germany

    Joachim Burkhard Grammer PhD, Sabine Bleiziffer MD, Rüdiger Lange MD & Robert Bauernschmitt MD

  2. Institute of Forensic Medicine and Forensic Psychiatry, Salzburg University, Ignaz-Harrerstr. 79, 5020, Salzburg, Austria

    Fabio Monticelli MD

Authors
  1. Joachim Burkhard Grammer PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabine Bleiziffer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabio Monticelli MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rüdiger Lange MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Bauernschmitt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joachim Burkhard Grammer PhD.

Additional information

Drs. Grammer and Bleiziffer contributed equally to the study

Returned for 1st revision: 23 February 2006 1. revision received: 8 April 2006

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grammer, J.B., Bleiziffer, S., Monticelli, F. et al. Calcineurin and matrix protein expression in cardiac hypertrophy. Basic Res Cardiol 101, 292–300 (2006). https://doi.org/10.1007/s00395-006-0598-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-006-0598-z

Key words

Search

Navigation