Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Calmodulin kinase II inhibition protects against structural heart disease

Nature Medicine volume 11, pages 409–417 (2005)Cite this article

Abstract

β-Adrenergic receptor (βAR) stimulation increases cytosolic Ca2+ to physiologically augment cardiac contraction, whereas excessive βAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca2+-calmodulin–dependent protein kinase II (CaMKII) is a recently identified downstream element of the βAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in βAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive βAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and βAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to βAR signaling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A genetic model of cardiac CaMKII inhibition.
Figure 2: CaMKII inhibition improves adverse ventricular remodeling after myocardial infarction.
Figure 3: CaMKII inhibition protects cellular mechanical function and preserves [Ca2+]i homeostasis after myocardial infarction.
Figure 4: CaMKII is a downstream element in the βAR signaling cascade.
Figure 5: Cellular mechanical responses to βAR stimulation are preserved during CaMKII inhibition.
Figure 6: The effects of CaMKII inhibition on ICa.

Similar content being viewed by others

References

  1. Jessup, M. & Brozena, S. Heart failure. N. Engl. J. Med. 348, 2007–2018 (2003).

    Article  Google Scholar 

  2. Doughty, R.N., Whalley, G.A., Gamble, G., MacMahon, S. & Sharpe, N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. J. Am. Coll. Cardiol. 29, 1060–1066 (1997).

    Article  CAS  Google Scholar 

  3. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353, 2001–2007 (1999).

  4. Chu, G. et al. A single site (Ser16) phosphorylation in phospholamban is sufficient in mediating its maximal cardiac responses to beta -agonists. J. Biol. Chem. 275, 38938–38943 (2000).

    Article  CAS  Google Scholar 

  5. Zhu, W.Z. et al. Linkage of beta(1)-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. J. Clin. Invest. 111, 617–625 (2003).

    Article  CAS  Google Scholar 

  6. Hoch, B., Meyer, R., Hetzer, R., Krause, E.G. & Karczewski, P. Identification and expression of delta-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. Circ. Res. 84, 713–721 (1999).

    Article  CAS  Google Scholar 

  7. Zhang, T. et al. The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ. Res. 92, 912–919 (2003).

    Article  CAS  Google Scholar 

  8. Maier, L.S. et al. Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release. Circ. Res. 92, 904–911 (2003).

    Article  CAS  Google Scholar 

  9. Gwathmey, J.K. et al. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ. Res. 61, 70–76 (1987).

    Article  CAS  Google Scholar 

  10. Gomez, A.M. et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276, 800–806 (1997).

    Article  CAS  Google Scholar 

  11. Hudmon, A. & Schulman, H. Structure/function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem. J. 364, 593–611 (2002).

    Article  CAS  Google Scholar 

  12. Braun, A.P. & Schulman, H. A non-selective cation current activated via the multi-functional Ca(2+)-calmodulin-dependent protein kinase in human epithelial cells. J. Physiol. 488, 37–55 (1995).

    Article  CAS  Google Scholar 

  13. Huang, W., Aramburu, J., Douglas, P.S. & Izumo, S. Transgenic expression of green fluorescence protein can cause dilated cardiomyopathy. Nat. Med. 6, 482–483 (2000).

    Article  CAS  Google Scholar 

  14. Wu, Y. et al. Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation 106, 1288–1293 (2002).

    Article  CAS  Google Scholar 

  15. Benedict, C.R. et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation 94, 690–697 (1996).

    Article  CAS  Google Scholar 

  16. Vinogradova, T.M. et al. Sinoatrial node pacemaker activity requires Ca2+/calmodulin- dependent protein kinase II activation. Circ. Res. 87, 760–767 (2000).

    Article  CAS  Google Scholar 

  17. Bauman, A.L. & Scott, J.D. Kinase- and phosphatase-anchoring proteins: harnessing the dynamic duo. Nat. Cell Biol. 4, E203–E206 (2002).

    Article  CAS  Google Scholar 

  18. Hagemann, D. et al. Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes. J. Biol. Chem. 275, 2532–22536 (2000).

    Article  Google Scholar 

  19. Drago, G.A. & Colyer, J. Discrimination between two sites of phosphorylation on adjacent amino acids by phosphorylation site-specific antibodies to phospholamban. J. Biol. Chem. 269, 25073–25077 (1994).

    CAS  Google Scholar 

  20. Benjamin, I.J. et al. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ. Res. 65, 657–670 (1989).

    Article  CAS  Google Scholar 

  21. Ramirez, M.T., Zhao, X.L., Schulman, H. & Brown, J.H. The nuclear deltaB isoform of Ca2+/calmodulin-dependent protein kinase II regulates atrial natriuretic factor gene expression in ventricular myocytes. J. Biol. Chem. 272, 31203–31208 (1997).

    Article  CAS  Google Scholar 

  22. Kudej, R.K. et al. Effects of chronic beta-adrenergic receptor stimulation in mice. J. Mol. Cell Cardiol. 29, 2735–2746 (1997).

    Article  CAS  Google Scholar 

  23. Dzhura, I., Wu, Y., Colbran, R.J., Balser, J.R. & Anderson, M.E. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels. Nat. Cell Biol. 2, 173–177 (2000).

    Article  CAS  Google Scholar 

  24. Yue, D.T., Herzig, S. & Marban, E. Beta-adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. Proc. Nat. Acad. Sci. USA 87, 753–757 (1990).

    Article  CAS  Google Scholar 

  25. Currie, S., Loughrey, C.M., Craig, M.A. & Smith, G.L. Calcium/calmodulin-dependent protein kinase IIdelta associates with the ryanodine receptor complex and regulates channel function in rabbit heart. Biochem. J. 377, 357–366 (2004).

    Article  CAS  Google Scholar 

  26. Marx, S.O. et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365–376 (2000).

    Article  CAS  Google Scholar 

  27. Cannon, W.P. & de la Paz, D. Emotional stimulation of adrenal secretion. Am. J. Physiol. 28, 64–70 (1911).

    Article  CAS  Google Scholar 

  28. Fabiato, A. & Fabiato, F. Contractions induced by a calcium-triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells. J. Physiol. 249, 469–495 (1975).

    Article  CAS  Google Scholar 

  29. Wehrens, X.H., Lehnart, S.E., Reiken, S.R. & Marks, A.R. Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ. Res. 94, e61–e70 (2004).

    Article  CAS  Google Scholar 

  30. Rodriguez, P., Bhogal, M.S. & Colyer, J. Stoichiometric phosphorylation of cardiac ryanodine receptor on serine 2809 by calmodulin-dependent kinase II and protein kinase A. J. Biol. Chem. 278, 38593–38600 (2003).

    Article  CAS  Google Scholar 

  31. Cheng, H., Lederer, W.J. & Cannell, M.B. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262, 740–744 (1993).

    Article  CAS  Google Scholar 

  32. Sah, R., Ramirez, R.J., Kaprielian, R. & Backx, P.H. Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes. J. Physiol. 533, 201–214 (2001).

    Article  CAS  Google Scholar 

  33. Alseikhan, B.A., DeMaria, C.D., Colecraft, H.M. & Yue, D.T. Engineered calmodulins reveal the unexpected eminence of Ca2+ channel inactivation in controlling heart excitation. Proc. Natl. Acad. Sci. USA 99, 17185–17190 (2002).

    Article  CAS  Google Scholar 

  34. Chao, S.H., Suzuki, Y., Zysk, J.R. & Cheung, W.Y. Activation of calmodulin by various metal cations as a function of ionic radius. Mol. Pharmacol. 26, 75–82 (1984).

    CAS  Google Scholar 

  35. Gao, T. et al. cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits. Neuron 19, 185–196 (1997).

    Article  CAS  Google Scholar 

  36. Anderson, M.E., Braun, A.P., Schulman, H. & Premack, B.A. Multifunctional Ca2+/calmodulin-dependent protein kinase mediates Ca(2+)-induced enhancement of the L-type Ca2+ current in rabbit ventricular myocytes. Circ. Res. 75, 854–861 (1994).

    Article  CAS  Google Scholar 

  37. Xiao, R.P., Cheng, H., Lederer, W.J., Suzuki, T. & Lakatta, E.G. Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx. Proc. Natl. Acad. Sci. USA 91, 9659–9663 (1994).

    Article  CAS  Google Scholar 

  38. Yuan, W. & Bers, D.M. Ca-dependent facilitation of cardiac Ca current is due to Ca-calmodulin-dependent protein kinase. Am. J. Physiol. 267, H982–H993 (1994).

    CAS  Google Scholar 

  39. Cohen, P. Protein kinases--the major drug targets of the twenty-first century? Nat. Rev. Drug Discov. 1, 309–315 (2002).

    Article  CAS  Google Scholar 

  40. Bers, D.M. Cardiac excitation-contraction coupling. Nature 415, 198–205 (2002).

    Article  CAS  Google Scholar 

  41. Patberg, K.W. et al. Cardiac memory is associated with decreased levels of the transcriptional factor CREB modulated by angiotensin II and calcium. Circ. Res. 93, 472–478 (2003).

    Article  CAS  Google Scholar 

  42. Benitah, J.P. & Vassort, G. Aldosterone upregulates Ca(2+) current in adult rat cardio-myocytes. Circ. Res. 85, 1139–1145 (1999).

    Article  CAS  Google Scholar 

  43. Chu, L. et al. Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium. Circ. Res. 92, 1024–1032 (2003).

    Article  CAS  Google Scholar 

  44. Muth, J.N., Bodi, I., Lewis, W., Varadi, G. & Schwartz, A. A Ca(2+)-dependent transgenic model of cardiac hypertrophy: A role for protein kinase Calpha. Circulation 103, 140–147 (2001).

    Article  CAS  Google Scholar 

  45. Pan, L., Gurevich, E.V. & Gurevich, V.V. The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor. J. Biol. Chem. 278, 11623–11632 (2003).

    Article  CAS  Google Scholar 

  46. Wu, Y., Colbran, R.J. & Anderson, M.E. Calmodulin kinase is a molecular switch for cardiac excitation - contraction coupling. Proc. Natl. Acad. Sci. USA 98, 2877–2881 (2001).

    Article  CAS  Google Scholar 

  47. Hadley, R.W. & Lederer, W.J. Properties of L-type calcium channel gating current in isolated guinea pig ventricular myocytes. J. Gen. Physiol. 98, 265–285 (1991).

    Article  CAS  Google Scholar 

  48. Rottman, J.N. et al. Temporal changes in ventricular function assessed echocardiographically in conscious and anesthetized mice. J. Am. Soc. Echocardiogr. 16, 1150–1157 (2003).

    Article  Google Scholar 

  49. Ichihara, S. et al. Targeted deletion of angiotensin II type 2 receptor caused cardiac rupture after acute myocardial infarction. Circulation 106, 2244–2249 (2002).

    Article  CAS  Google Scholar 

  50. Choi, B.R. & Salama, G. Optical mapping of atrioventricular node reveals a conduction barrier between atrial and nodal cells. Am. J. Physiol. 274, H829–H845 (1998).

    CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the US National Institutes of Health (HL070250 and HL046681 to M.E.A., MH63232 to R.J.C., EY11500 and GM63097 to G.S. and HL25675, HL36974, HL70709, HL67849 to W.J.L.) and a US National Institutes of Health training grant (HL70511) for C.E.G., and an American Heart Association postdoctoral fellowship (M.S.C.K.). Mark E. Anderson is an Established Investigator of the American Heart Association. J. Yang, M. Bass, Y. Hou, L. Gleaves, C. Perlroth and R. Towne provided technical assistance. J. Robbins provided the αMHC cDNA for creating the transgenic mice. J. Corbin, A. George, J.T. Kimbrough, D.E. Vaughan and D.M. Roden provided criticisms. Echocardiograms and surgery were performed in the Vanderbilt Mouse Metabolic Core Facility and transgenic mice were engineered in the Vanderbilt Mouse Transgenic Core Facility, both supported by the US National Institutes of Health.

Author information

Author notes

  1. Rong Zhang, Michelle S C Khoo, Yuejin Wu and Yingbo Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, 37232-6300, Tennessee, USA

    Rong Zhang, Michelle S C Khoo, Yuejin Wu, Yingbo Yang, Gemin Ni, Ernest C Madu & Mark E Anderson

  2. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, 37232-6300, Tennessee, USA

    Chad E Grueter, Edward E Price Jr. & Roger J Colbran

  3. Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, 37232-6300, Tennessee, USA

    William Thiel, Tatiana A Vishnivetskaya, Vsevolod V Gurevich & Mark E Anderson

  4. Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, 21021, Maryland, USA

    Silvia Guatimosim, Long-Sheng Song & W J Lederer

  5. Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, 31270-901, Brazil

    Silvia Guatimosim

  6. Department of Cell Biology, University of Pittsburgh School of Medicine, S362 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, 15261, Pennsylvania, USA

    Anisha N Shah & Guy Salama

  7. Department of Pathology, Vanderbilt University School of Medicine, Medical Center North C3320, Nashville, 37232-2561, Tennessee, USA

    James B Atkinson

Authors
  1. Rong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michelle S C Khoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuejin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingbo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chad E Grueter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gemin Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward E Price Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William Thiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Silvia Guatimosim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Long-Sheng Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ernest C Madu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anisha N Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tatiana A Vishnivetskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. James B Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Vsevolod V Gurevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Guy Salama
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. W J Lederer
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Roger J Colbran
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Mark E Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark E Anderson.

Ethics declarations

Competing interests

Mark Anderson is a named incentor on a patent for using calmodulin kinase II inhibitors to treat arrhythmias. He is also a named inventor on a patent application to use calmodulin kinase II inhibition as a therapy for structural heart disease.

Supplementary information

Supplementary Fig. 1

Similar heart weights (wt) and left ventricular (LV) chamber dimensions in AC3-I(I), wild type (WT) and AC3-C (C) hearts. (PDF 51 kb)

Supplementary Fig. 2

Similar protein phosphatase expression in AC3-I, WT and AC3-C hearts. (PDF 93 kb)

Supplementary Fig. 3

Quantification of surgical myocardial infarctions. (PDF 43 kb)

Supplementary Fig. 4

Quantification of interventricular septal thickness after myocardial infarction surgery. (PDF 85 kb)

Supplementary Fig. 5

Heart rates in wild type mice 24 hours after injection with KN-93 or KN-92, at baseline or up to three weeks after myocardial infarction. (PDF 126 kb)

Supplementary Fig. 6

Excitation-contraction coupling protein expression in AC3-I, AC3-C and wild type hearts. (PDF 147 kb)

Supplementary Fig. 7

Ryanodine receptor Ca2+ spark properties are not different between AC3-I and AC3-C cardiomyocytes. (PDF 178 kb)

Supplementary Methods (PDF 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, R., Khoo, M., Wu, Y. et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med 11, 409–417 (2005). https://doi.org/10.1038/nm1215

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1215

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing