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 muscle and developmental cardiac defects have been reported in FKBP12-deficient mice, 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.
Xin
Hong-Bo
HB
Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, USA.
Senbonmatsu
Takaaki
T
Cheng
Dong-Sheng
DS
Wang
Yong-Xiao
YX
Copello
Julio A
JA
Ji
Guang-Ju
GJ
Collier
Mei Lin
ML
Deng
Ke-Yu
KY
Jeyakumar
Loice H
LH
Magnuson
Mark A
MA
Inagami
Tadashi
T
Kotlikoff
Michael I
MI
Fleischer
Sidney
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology*; D004452:Echocardiography; D004965:Estrogen Antagonists / Q000008:administration & dosage; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D015183:Restriction Mapping; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012727:Sex Characteristics; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000008:administration & dosage
D004965:Estrogen Antagonists; D004967:Estrogens; D019837:Ryanodine Receptor Calcium Release Channel; D013629:Tamoxifen; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium