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Displacement of FKBP12 and 12.6 from ryanodine receptors abolishes endothelial nitric oxide production and augments blood pressure
Author(s) -
Mitchell Brett M.,
Cook Leslie G.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a862-d
Subject(s) - fkbp , ryanodine receptor , calcineurin , nitric oxide , medicine , vasodilation , endothelium , endocrinology , blood pressure , sirolimus , chemistry , calcium , pharmacology , transplantation , biochemistry
Organ transplant recipients treated with both rapamycin and FK506 have significantly higher blood pressures than when treated with these drugs alone. Rapamycin and FK506 both bind FKBP12/12.6 and displace them from intracellular ryanodine receptors (RyRs), but rapamycin/FKBP inhibits mTOR whereas FK506/FKBP inhibits calcineurin. It is unknown if the combined therapy augments blood pressure by redundant effects on FKBP12/12.6. Rapamycin or FK506 caused a concentration‐dependent endothelial cell calcium leak, decrease in aortic NO production, decrease in endothelium‐dependent dilation, and increase in blood pressure. Rapamycin or FK506 at 10 uM completely abolished NO production and endothelium‐dependent dilation in control aortas. In vessels from FKBP12.6 −/− mice, displacement of FKBP12 from endothelial RyRs exacerbated the calcium leak and endothelial dysfunction. Rapamycin or FK506 treatment of FKBP12.6 −/− mice augmented systolic blood pressures compared to hypertensive rapamycin‐treated, FK506‐treated, or FKBP12.6 −/− mice. The effects of FKBP12/12.6 depletion on calcium leakage, NO production, and vasodilation were normalized following inhibition of RyR opening. These data may explain the hypertension in patients treated with both rapamycin and FK506. Supported by an American Heart Association Scientist Development Grant (BMM).