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

被引:47
作者
Cook, Leslie G. [2 ]
Chiasson, Valorie L. [1 ]
Long, Cheng [2 ]
Wu, Gang-Yi [2 ]
Mitchell, Brett M. [1 ,2 ]
机构
[1] Texas A&M Hlth Sci Ctr Coll Med, Dept Internal Med, Temple, TX 76504 USA
[2] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA
关键词
endothelium; hypertension; nitric oxide synthase; protein kinase C; CALCIUM-RELEASE CHANNEL; PROTEIN-KINASE-C; CYCLOSPORINE-A; CYCLOPHILIN-A; PHOSPHORYLATION; FK506; HYPERTENSION; MECHANISMS; CELLS; GENE;
D O I
10.1038/ki.2008.697
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:719 / 726
页数:8
相关论文
共 33 条
[1]   SINGLE-CHANNEL ACTIVITY OF THE RYANODINE RECEPTOR CALCIUM-RELEASE CHANNEL IS MODULATED BY FK-506 [J].
AHERN, GP ;
JUNANKAR, PR ;
DULHUNTY, AF .
FEBS LETTERS, 1994, 352 (03) :369-374
[2]   Cyclophilin-mediated pathways in the effect of cyclosporin A on endothelial cells -: Role of vascular endothelial growth factor [J].
Alvarez-Arroyo, MV ;
Yagüe, S ;
Wenger, RM ;
Pereira, DS ;
Jiménez, S ;
González-Pacheco, FR ;
Castilla, MA ;
Deudero, JJP ;
Caramelo, C .
CIRCULATION RESEARCH, 2002, 91 (03) :202-209
[3]   STABILIZATION OF CALCIUM-RELEASE CHANNEL (RYANODINE RECEPTOR) FUNCTION BY FK506-BINDING PROTEIN [J].
BRILLANTES, AMB ;
ONDRIAS, K ;
SCOTT, A ;
KOBRINSKY, E ;
ONDRIASOVA, E ;
MOSCHELLA, MC ;
JAYARAMAN, T ;
LANDERS, M ;
EHRLICH, BE ;
MARKS, AR .
CELL, 1994, 77 (04) :513-523
[4]   Impaired cardiac hypertrophic response in calcineurin Aβ-deficient mice [J].
Bueno, OF ;
Wilkins, BJ ;
Tymitz, KM ;
Glascock, BJ ;
Kimball, TF ;
Lorenz, JN ;
Molkentin, JD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (07) :4586-4591
[5]  
BUSUTTIL RW, 1994, NEW ENGL J MED, V331, P1110
[6]   Effects of FK506 in rat and human resistance arteries [J].
De Lima, JJG ;
Xue, H ;
Coburn, L ;
Andoh, TF ;
McCarron, DA ;
Bennett, WM ;
Roullet, JB .
KIDNEY INTERNATIONAL, 1999, 55 (04) :1518-1527
[7]  
Fulton D, 2001, J PHARMACOL EXP THER, V299, P818
[8]   Mechanisms of soluble β-amyloid impairment of endothelial function [J].
Gentile, MT ;
Vecchione, C ;
Maffei, A ;
Aretini, A ;
Marino, G ;
Poulet, R ;
Capobianco, L ;
Selvetella, G ;
Lembo, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (46) :48135-48142
[9]   Site-specific dephosphorylation of endothelial nitric oxide synthase by protein phosphatase 2A: Evidence for crosstalk between phosphorylation sites [J].
Greif, DM ;
Kou, RQ ;
Michel, T .
BIOCHEMISTRY, 2002, 41 (52) :15845-15853
[10]   Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation [J].
Harris, MB ;
Ju, H ;
Venema, VJ ;
Liang, HY ;
Zou, R ;
Michell, BJ ;
Chen, ZP ;
Kemp, BE ;
Venema, RC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (19) :16587-16591