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Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/416334a

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