FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure.

FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Research Abstract Details 

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FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Abstract Text:

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

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.

FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Publishing Authors By Initials

C Long,LG Cook,SL Hamilton,GY Wu,BM Mitchell,

For similar amino acids, peptides, and proteins: amino acids: amino acids, essential: threonine research abstracts see: amino acids, peptides, and proteins: amino acids: amino acids, essential: threonine research

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FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Hypertension

VOLUME: 49

Page Numbers: 569-76

Journal Abbreviation: Hypertension

ISSN: 1524-4563

DAY: 29

MONTH: 01

YEAR: 2007

FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7906255

FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Keywords Mesh Terms:

KEYWORDS: Threonine

MESH TERMS: metabolism

Chemical & Substance for Abstract: FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Information

Substance Name: Tacrolimus Binding Proteins

Registry Number: EC 5.2.1.-

Grant and Affiliation Information for FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure.

AFFILIATION: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Tex 77030, USA.

Country: United States

AGENCY: United States NIAMS

GRANT: AR41802

ACRONYM: AR

MEDLINETA: Hypertension

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