期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 27, 期 7, 页码 1580-1586出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.144808
关键词
endothelium; hypertension; experimental; nitric oxide; ryanodine receptors
资金
- NIAMS NIH HHS [AR050503, AR41802] Funding Source: Medline
Objectives - 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. Methods and 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 mu mol/ 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 mu mol/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.
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