Removal of FKBP12/12.6 from endothelial ryanodine receptors leads to an intracellular calcium leak and endothelial dysfunction.
OBJECTIVE
FK506 Binding Protein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca2+ release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca2+ levels. The immunosuppressive drugs rapamycin and FK506 bind and displace FKBP12/12.6 from RyRs, and can also cause endothelial dysfunction and hypertension. We tested whether rapamycin and FK506 cause an intracellular Ca2+ leak in endothelial cells and whether this affects endothelial function and blood pressure regulation.


RESULTS
Rapamycin or FK506 concentration-dependently caused a Ca2+ leak in isolated endothelial cells, decreased aortic NO production and endothelium-dependent dilation, and increased systolic blood pressure in control mice. Rapamycin or FK506 at 10 micromol/L abolished aortic NO production and endothelium-dependent dilation. Similar results were obtained in isolated endothelial cells and aortas from FKBP12.6-/- mice after displacement of FKBP12 with 1 micromol/L rapamycin or FK506. In hypertensive FKBP12.6-/- mice, systolic blood pressures were further elevated after treatment with either rapamycin or FK506. Blockade of the Ca2+ leak with ryanodine normalized NO production and endothelium-dependent dilation.


CONCLUSIONS
Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca2+ leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.
Long
Cheng
C
Dept. of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cook
Leslie G
LG
Wu
Gang-Yi
GY
Mitchell
Brett M
BM
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D020013:Calcium Signaling; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D017353:Gene Deletion; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D009569:Nitric Oxide; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus; D016559:Tacrolimus