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(Hypertension. 2007;49:569.)
© 2007 American Heart Association, Inc.

Original Articles

FK506 Binding Protein 12/12.6 Depletion Increases Endothelial Nitric Oxide Synthase Threonine 495 Phosphorylation and Blood Pressure

Cheng Long; Leslie G. Cook; Susan L. Hamilton; Gang-Yi Wu; Brett M. Mitchell

From the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Tex.

Correspondence to Brett M. Mitchell, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail brettm{at}bcm.tmc.edu

Chronic treatment with the immunosuppressive drug rapamycin leads to hypertension; however, the mechanisms are unknown. Rapamycin binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and displaces them from intracellular Ca²⁺ release channels (ryanodine receptors) eliciting a Ca²⁺ leak from the endoplasmic/sarcoplasmic reticulum. We tested whether this Ca²⁺ leak promotes conventional protein kinase C–mediated endothelial NO synthase phosphorylation at Thr495, which reduces production of the vasodilator NO. Rapamycin treatment of control mice for 7 days, as well as genetic deletion of FKBP12.6, increased systolic arterial pressure significantly compared with controls. Untreated aortas from FKBP12.6^–/– mice and in vitro rapamycin-treated control aortas had similarly decreased endothelium-dependent relaxation responses and NO production and increased endothelial NO synthase Thr495 phosphorylation and protein kinase C activity. Inhibition of either conventional protein kinase C or ryanodine receptor restored endothelial NO synthase Thr495 phosphorylation and endothelial function to control levels. Rapamycin induced a small increase in basal intracellular Ca²⁺ levels in isolated endothelial cells, and rapamycin or FKBP12.6 gene deletion decreased acetylcholine-induced intracellular Ca²⁺ release, all of which were reversed by ryanodine. These data demonstrate that displacement of FKBP12/12.6 from ryanodine receptors induces an endothelial intracellular Ca²⁺ leak and increases conventional protein kinase C–mediated endothelial NO synthase Thr495 phosphorylation leading to decreased NO production and endothelial dysfunction. This molecular mechanism may, in part, explain rapamycin-induced hypertension.

Key Words: endothelium • hypertension • experimental • NO • NO synthase • protein kinases • vasorelaxation

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