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Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy


FK506 binding proteins 12 and 12.6 (FKBP12 and FKBP12.6) are intracellular receptors for the immunosuppressant drug FK506 (ref. 1). The skeletal muscle ryanodine receptor (RyR1) is isolated as a hetero-oligomer with FKBP12 (ref. 2), whereas the cardiac ryanodine receptor (RyR2) more selectively associates with FKBP12.6 (refs 3, 4, 5). FKBP12 modulates Ca2+ release from the sarcoplasmic reticulum in skeletal muscle6,7 and developmental cardiac defects have been reported in FKBP12-deficient mice8, but the role of FKBP12.6 in cardiac excitation–contraction coupling remains unclear. Here we show that disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy in male mice, but not in females. Female hearts are normal, despite the fact that male and female knockout mice display similar dysregulation of Ca2+ release, seen as increases in the amplitude and duration of Ca2+ sparks and calcium-induced calcium release gain. Female FKBP12.6-null mice treated with tamoxifen, an oestrogen receptor antagonist, develop cardiac hypertrophy similar to that of male mice. We conclude that FKBP12.6 modulates cardiac excitation–contraction coupling and that oestrogen plays a protective role in the hypertrophic response of the heart to Ca2+ dysregulation.

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Figure 1: Targeted disruption of FKBP12.6 gene in mice.
Figure 2: Increased CICR gain in FKBP12.6 knockout myocytes.
Figure 3: Altered Ca2+ sparks in FKBP12.6 knockout mice.
Figure 4: Sex-specific cardiac hypertrophy in male FKBP12.6 knockout mice and cardiac hypertrophy in female knockout mice treated with tamoxifen.


  1. Marks, A. R. Cellular functions of immunophilins. Physiol. Rev. 76, 631–649 (1996).

    CAS  Article  Google Scholar 

  2. Jayaraman, T. et al. FK506 binding protein associated with the calcium release channel (ryanodine receptor). J. Biol. Chem. 267, 9474–9477 (1992).

    CAS  PubMed  Google Scholar 

  3. Lam, E. et al. A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor. J. Biol. Chem. 270, 26511–26522 (1995).

    CAS  Article  Google Scholar 

  4. Timerman, A. P. et al. Selective binding of FKBP12.6 by the cardiac ryanodine receptor. J. Biol. Chem. 271, 20385–20391 (1996).

    CAS  Article  Google Scholar 

  5. Xin, H. B., Rogers, K., Qi, Y., Kanematsu, T. & Fleischer, S. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. J. Biol. Chem. 274, 15315–15319 (1999).

    CAS  Article  Google Scholar 

  6. Timerman, A. P. et al. The calcium release channel of sarcoplasmic reticulum is modulated by FK-506-binding protein. Dissociation and reconstitution of FKBP-12 to the calcium release channel of skeletal muscle sarcoplasmic reticulum. J. Biol. Chem. 268, 22992–22999 (1993).

    CAS  PubMed  Google Scholar 

  7. Brillantes, A. B. et al. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 77, 513–523 (1994).

    CAS  Article  Google Scholar 

  8. Shou, W. et al. Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12. Nature 391, 489–492 (1998).

    ADS  CAS  Article  Google Scholar 

  9. Fleischer, S. & Inui, M. Biochemistry and biophysics of excitation–contraction coupling. Annu. Rev. Biophys. Biophys. Chem. 18, 333–364 (1989).

    CAS  Article  Google Scholar 

  10. Meissner, G. Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu. Rev. Physiol. 56, 485–508 (1994).

    CAS  Article  Google Scholar 

  11. Timerman, A. P., Wiederrecht, G., Marcy, A. & Fleischer, S. Characterization of an exchange reaction between soluble FKBP-12 and the FKBP.ryanodine receptor complex. Modulation by FKBP mutants deficient in peptidyl-prolyl isomerase activity. J. Biol. Chem. 270, 2451–2459 (1995).

    CAS  Article  Google Scholar 

  12. Barg, S., Copello, J. A. & Fleischer, S. Different interactions of cardiac and skeletal muscle ryanodine receptors with FK-506 binding protein isoforms. Am. J. Physiol. 272, C1726–C1733 (1997).

    CAS  Article  Google Scholar 

  13. Van Duyne, G. D., Standaert, R. F., Karplus, P. A., Schreiber, S. L. & Clardy, J. Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex. Science 252, 839–842 (1991).

    ADS  CAS  Article  Google Scholar 

  14. Aldape, R. A. et al. Charged surface residues of FKBP12 participate in formation of the FKBP12-FK506-calcineurin complex. J. Biol. Chem. 267, 16029–16032 (1992).

    CAS  PubMed  Google Scholar 

  15. Wang, Y.-X. & Kotlikoff, M. I. Inactivation of calcium-activated chloride channels in smooth muscle by calcium/calmodulin dependent protein kinase. Proc. Natl Acad. Sci. USA 94, 14918–14923 (1997).

    ADS  CAS  Article  Google Scholar 

  16. Collier, M. L., Ji, G., Wang, Y. & Kotlikoff, M. I. Calcium-induced calcium release in smooth muscle: loose coupling between the action potential and calcium release. J. Gen. Physiol. 115, 653–662 (2000).

    CAS  Article  Google Scholar 

  17. Shorofsky, S. R. et al. Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks. Circ. Res. 84, 424–434 (1999).

    CAS  Article  Google Scholar 

  18. Fentzke, R. C. et al. Evaluation of ventricular and arterial hemodynamics in anesthetized closed-chest mice. J. Am. Soc. Echocardiogr. 10, 915–925 (1997).

    CAS  Article  Google Scholar 

  19. Louie, E. K. & Edwards, L. C. III Hypertrophic cardiomyopathy. Prog. Cardiovasc. Dis. 36, 275–308 (1994).

    CAS  Article  Google Scholar 

  20. Levy, D. et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann. Intern. Med. 108, 7–13 (1988).

    CAS  Article  Google Scholar 

  21. Lim, W. K., Wren, B., Jepson, N., Roy, S. & Caplan, G. Effect of hormone replacement therapy on left ventricular hypertrophy. Am. J. Cardiol. 83, 1132–1134 (1999).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  23. 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).

    CAS  Article  Google Scholar 

  24. Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    CAS  Article  Google Scholar 

  25. Falvo, J. V. et al. Stimulus-specific assembly of enhancer complexes on the tumor necrosis factor alpha gene promoter. Mol. Cell Biol. 20, 2239–2247 (2000).

    CAS  Article  Google Scholar 

  26. Kadokami, T., McTiernan, C. F., Kubota, T., Frye, C. S. & Feldman, A. M. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J. Clin. Invest. 106, 589–597 (2000).

    CAS  Article  Google Scholar 

  27. Pelzer, T., Shamim, A., Wolfges, S., Schumann, M. & Neyses, L. Modulation of cardiac hypertrophy by estrogens. Adv. Exp. Med. Biol. 432, 83–89 (1997).

    CAS  Article  Google Scholar 

  28. Hulley, S. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J. Am. Med. Assoc. 280, 605–613 (1998).

    CAS  Article  Google Scholar 

  29. Hayward, C. S., Kelly, R. P. & Collins, P. The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc. Res. 46, 28–49 (2000).

    CAS  Article  Google Scholar 

  30. Tybulewicz, V. L., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 (1991).

    CAS  Article  Google Scholar 

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Histology was carried out at the Vascular Histology and Imaging Core Vanderbilt Division of Cardiology. We thank J. V. Barnett and L. Gleaves for advice and help in preparing the histological sections, J. B. Atkinson for analysing the histological sections, and E. Price for blood-pressure measurements. The production of the FKBP12.6 knockout mouse was achieved with the aid of the Vanderbilt Transgenic/ES Cell Shared Resource Lab. We thank M. Sutherland for help in this regard. This work was supported by grants from the NIH to S.F., T.I., M.M., Y.-X.W. and M.I.K., and a Discovery Grant from Vanderbilt University (S.F.).

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Correspondence to Michael I. Kotlikoff or Sidney Fleischer.

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Xin, HB., Senbonmatsu, T., Cheng, DS. et al. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 416, 334–337 (2002).

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