Tacrolimus reduces nitric oxide synthase function by binding to FKBP rather than by its calcineurin effect

Leslie G. Cook, Valorie L. Chiasson, Cheng Long, Gangyi Wu, Brett M. Mitchell

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Hypertension develops in many patients receiving the immunosuppressive drug tacrolimus (FK506). One possible mechanism for hypertension is a reduction in vasodilatory nitric oxide. We found that tacrolimus and a calcineurin autoinhibitory peptide significantly decreased vascular calcineurin activity; however, only tacrolimus altered intracellular calcium release in mouse aortic endothelial cells. In mouse aortas, incubation with tacrolimus increased protein kinase C activity and basal endothelial nitric oxide synthase phosphorylation at threonine 495 but reduced basal and agonist-induced endothelial nitric oxide synthase phosphorylation at serine 1177, a mechanism known to inhibit synthase activity. While this decreased nitric oxide production and endothelial function, the calcineurin autoinhibitory peptide had no such effects. Inhibition of ryanodine receptor opening or protein kinase C blocked the effects of tacrolimus. Since it is known that the FK506 binding protein (FKBP12/12.6) interacts with the ryanodine receptor to regulate calcium release, we propose this as the mechanism by which tacrolimus alters intracellular calcium and endothelial nitric oxide synthase rather than by its effect on calcineurin. Our study shows that prevention of the tacrolimus-induced intracellular calcium leak may attenuate endothelial dysfunction and the consequent hypertension.

Original languageEnglish (US)
Pages (from-to)719-726
Number of pages8
JournalKidney International
Volume75
Issue number7
DOIs
StatePublished - Apr 1 2009

Fingerprint

Tacrolimus Binding Proteins
Calcineurin
Tacrolimus
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Calcium
Ryanodine Receptor Calcium Release Channel
Hypertension
Protein Kinase C
Nitric Oxide
Tacrolimus Binding Protein 1A
Phosphorylation
Peptides
Threonine
Immunosuppressive Agents
Serine
Blood Vessels
Aorta
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Cook, Leslie G. ; Chiasson, Valorie L. ; Long, Cheng ; Wu, Gangyi ; Mitchell, Brett M. / Tacrolimus reduces nitric oxide synthase function by binding to FKBP rather than by its calcineurin effect. In: Kidney International. 2009 ; Vol. 75, No. 7. pp. 719-726.
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Tacrolimus reduces nitric oxide synthase function by binding to FKBP rather than by its calcineurin effect. / Cook, Leslie G.; Chiasson, Valorie L.; Long, Cheng; Wu, Gangyi; Mitchell, Brett M.

In: Kidney International, Vol. 75, No. 7, 01.04.2009, p. 719-726.

Research output: Contribution to journalArticle

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