Removal of Fkbp12/12.6 from endothelial ryanodine receptors leads to an intracellular calcium leak and endothelial dysfunction

Cheng Long, Leslie G. Cook, Gang Yi Wu, Brett M. Mitchell

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

OBJECTIVES - FK506 Binding Protein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca 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 Ca leak in endothelial cells and whether this affects endothelial function and blood pressure regulation. METHODS AND RESULTS - Rapamycin or FK506 concentration-dependently caused a Ca 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 μmol/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 μmol/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 Ca leak with ryanodine normalized NO production and endothelium-dependent dilation. CONCLUSIONS - Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.

Original languageEnglish (US)
Pages (from-to)1580-1586
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume27
Issue number7
DOIs
StatePublished - Jul 1 2007

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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