Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Hong-Bo Xin, Takaaki Senbonmatsu, Dong-Sheng Cheng, Yong-Xiao Wang, Julio A. Copello, Guang-Ju Ji, Mei Lin Collier, Ke-Yu Deng, Loice H. Jeyakumar, Mark A. Magnuson, Tadashi Inagami, Michael I. Kotlikoff () and Sidney Fleischer ()
Additional contact information
Hong-Bo Xin: Vanderbilt University
Takaaki Senbonmatsu: Vanderbilt University
Dong-Sheng Cheng: Vanderbilt University
Yong-Xiao Wang: Cornell University
Julio A. Copello: Vanderbilt University
Guang-Ju Ji: Cornell University
Mei Lin Collier: University of Pennsylvania
Ke-Yu Deng: Cornell University
Loice H. Jeyakumar: Vanderbilt University
Mark A. Magnuson: Vanderbilt University
Tadashi Inagami: Vanderbilt University
Michael I. Kotlikoff: Cornell University
Sidney Fleischer: Vanderbilt University

Nature, 2002, vol. 416, issue 6878, 334-337

Abstract: 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.

Date: 2002
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DOI: 10.1038/416334a

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