The nuclear factor of activated T cells (NFAT) is a family of transcription factors that regulate immune responses and adaptive response in skeletal and cardiac muscle. NFAT inhibitor (VIVIT peptide) is a cell-permeable peptide that selectively inhibits calcineurin-mediated dephosphorylation of NFAT[1]. In peripheral blood CD14+ monocytes isolated from rheumatoid arthritis patients, treatment with 10μM of NFAT inhibitor plus 100ng/mL of recombinant human RANKL and 50ng/mL of M‐CSF for 24h significantly inhibited nuclear translocation of NFATc1, but not that of peroxisome proliferator-activated receptor γ coactivator 1β. Long-term (21 days) treatment with NFAT inhibitor in combination with M‐CSF and RANKL significantly inhibited the cytoplasmic levels of cathepsin K, tartrate‐resistant acid phosphatase, and matrix metalloproteinase 9[2]. Intraperitoneal administration of NFAT (10mg/kg) once daily for 2 days prevented T-cell activation and proliferation in C3H/HeN mice[3].
作用机制
NFAT inhibitor potently and selectively inhibits the NFAT-calcineurin interaction without affecting calcineurin phosphatase activity. It was developed based on the conserved calcineurin docking site of NFAT[1].
NFAT Inhibitor-1 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Bone marrow-derived macrophages (BMMs)
5 µM
1 hour
Inhibited LPS-induced expression of TNF, MIP-1α and IL-1β
Cell Signal. 2011 Nov;23(11):1785-93.
Primary murine microglia
10 µM
24 hours
To assess the effect of NFAT inhibitors on cytokine and neurotoxin secretion by Aβ-stimulated microglia. Results showed that tat-VIVIT and FK506 significantly attenuated Aβ- and LPS-stimulated secretion of TNFα and IL-6.
J Neuroinflammation. 2015 Mar 4;12:42.
LN229 cells
500 µM
24 hours and 48 hours
To evaluate the effect of Sim2-VIVIT on NFAT signaling, results showed Sim2-VIVIT did not affect the pattern of NFATc1 bands or NFAT-dependent promoter activity
Molecules. 2021 Aug 7;26(16):4785.
U87 cells
20 µM
25 hours
To evaluate the effect of 11R-VIVIT on NFAT activity, results showed 11R-VIVIT at 20 µM upregulated NFAT-dependent promoter activity, but the increase was not statistically significant
Molecules. 2021 Aug 7;26(16):4785.
LN229 cells
20 µM
25 hours
To evaluate the effect of 11R-VIVIT on NFAT activity, results showed 11R-VIVIT at 10 µM and 20 µM activated NFAT-dependent promoter activity
Molecules. 2021 Aug 7;26(16):4785.
ARPE-19 cells
10 µM
4 hours pretreatment followed by 24 hours LPS treatment
To evaluate the effect of VIVIT on LPS-induced NFAT luciferase activity, results showed that VIVIT significantly reduced LPS-induced luciferase activity.
Int J Mol Sci. 2021 Aug 12;22(16):8684.
Bone marrow macrophages
1 µM
48 hours
Inhibited NFATc1 expression and significantly downregulated Nod1 mRNA expression
PLoS Pathog. 2013 Jan;9(1):e1003152.
HPV E6/E7 immortalized mouse RPE cells
20 µM
48 hours
To study the effect of VIVIT on starvation-induced TFEB nuclear localization, results showed that VIVIT caused TFEB retention in the cytoplasm.
Int J Mol Sci. 2021 Aug 12;22(16):8684.
ARPE-19 cells
20 µM
48 hours
To investigate the effect of NFAT inhibition on TFEB expression, results showed that VIVIT treatment did not significantly alter TFEB expression levels.
Int J Mol Sci. 2021 Aug 12;22(16):8684.
Mouse bone marrow macrophages (BMMs)
2.0 µM
96 hours
To investigate the effect of VIVIT peptide on wear particle-induced osteoclastogenesis from BMMs. Results showed that VIVIT significantly inhibited wear particle (Ti and PMMA)-induced osteoclast formation and bone resorption activity.
Acta Pharmacol Sin. 2013 Nov;34(11):1457-66.
NFAT Inhibitor-1 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
APP/PS1 transgenic mice
Alzheimer's disease model
Subcutaneous injection
0.5 mg/kg/day
Continuous for 28 days
To evaluate the effect of NFAT inhibitors on microglial activation, Aβ plaque load, and memory in APP/PS1 mice. Results showed that FK506 and tat-VIVIT significantly attenuated microgliosis and Aβ plaque load but did not significantly affect memory performance.
J Neuroinflammation. 2015 Mar 4;12:42.
Mice
Renal retrograde infection model
Intraperitoneal injection
10 mg/kg
Once daily for 48 hours
11R-VIVIT significantly impaired neutrophil bacterial phagocytic killing capacity and increased renal susceptibility to UPEC
PLoS Pathog. 2013 Jan;9(1):e1003152.
Mice
Aortic banding (AB)-induced cardiac hypertrophy model
Subcutaneous injection
10 mg/kg
Every 2 days for 4 weeks
Inhibition of NFAT activity, alleviating the aggravated cardiac hypertrophy pathology caused by Nulp1 deficiency
J Am Heart Assoc. 2020 Aug 18;9(16):e016419
Mice
Aortic banding (AB)-induced cardiac hypertrophy model
Subcutaneous osmotic pump
10 mg/kg/day
Once daily for 2 weeks
Pre-treatment with VIVIT significantly attenuated AB-induced cardiac remodeling abnormalities in IRF8/C0//C0 mice, as evidenced by reduced ratios of HW/BW, LW/BW and HW/TL, and decreased cardiomyocyte cross-sectional area and collagen volume.
Nat Commun. 2014;5:3303
Rat
Regenerating and adult rat muscles
Intramuscular injection
50 μg
7 days
The VIVIT peptide blocked Cn-mediated NFAT activation, inhibited the expression of slow myosin heavy chain (MyHC-slow), and upregulated the expression of fast myosin heavy chains (MyHC-2X and MyHC-2B).
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10590-5
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