CN107569495A - Inhibitory action of the eplerenone to Patients with Chronic Heart Failure helper T lymphocyte activation/propagation - Google Patents
Inhibitory action of the eplerenone to Patients with Chronic Heart Failure helper T lymphocyte activation/propagation Download PDFInfo
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Abstract
The present invention has inquired into eplerenone (EPL) to chronic heart failure (CHF) patient CD4+The mRNA and protein expression of the passages such as T lymphocytes Kv1.3 influence, find eplerenone to Patients with Chronic Heart Failure CD4+Activation/propagation of T lymphocytes is inhibited.Result of study confirmation of the present invention, chronic heart failure CD4+The mRNA of Kv1.3, KCa3.1 and CRAC passage of T lymphocytes expression dramatically increases compared with normal group, after giving 30 μM of eplerenones, its expression is suppressed significantly, and wherein Kv1.3 passages suppress the most obvious, and inhibiting rate is about 64.8% (P ＜ 0.01).Therefore the detection to Kv1.3 channel proteins is more significant.The Kv1.3 albumen of CHF groups adds 120.8%, adds 30 μM of eplerenones and inhibits 39.6% (P ＜ 0.01).
Description
Technical field
Inhibitory action the present invention relates to eplerenone to Patients with Chronic Heart Failure helper T lymphocyte activation/propagation.
Background technology
Chronic heart failure (chronic heart failure, CHF) is extracellular Matrix (fibroblast, glue
Original, matrix metalloproteinase etc.) long-term accumulated and cause that ventricle is stiff and diastole is full impaired.Machine is occurred to chronic heart failure at present
The research of system relates generally to neuroendocrine system and immune system RAAS activation.RAAS excessive activations are to cause cardiac muscle fibre
The main reason for change, therefore ACEI classes and beta-blocker are used for prevention and reverse myocardial fibrosis, numerous studies table by classics
Bright aldosterone (ALD) is risen by its signal transduction pathway in the occurrence and development of coronary heart disease, acute myocardial infarction, myocardial ischemia and heart failure
Key effect.ACEI classes and beta-blocker can reduce releases of the ALD in heart failure, but ACEI prolonged application can go out
Existing " ALD escapes " phenomenon.In recent years, evidence-based medicine EBM shows that aldosterone (ALD) receptor antagonist can further reduce heart failure
Mortality, therefore ALD receptor antagonists are used in combination in heart failure modern treatment scheme and have great importance.Eplerenone
(Eplerenone, EPL) is second generation ALD receptor antagonists, and compared to first generation ALD receptor antagonists, it has selectivity
Height, the small advantage of toxic side effect.
In recent years, the inflammation of heart failure is widely approved, it thinks that immune activation can make immunocyte produce inflammation
The factor, and promote it to be in progress and deteriorate.The signal path network regulation pattern of received T cell activation is at present：T lymphs are thin
After born of the same parents' activation, promote calcium release activation Ca2+(Ca2+-release activating Ca2+, CRAC) and passage opening, raises endoplasm
The calcium storehouse release Ca of net2+Amount, Ca2+Interior stream increase can start various cell factors by the protein kinase pathways of Ca-dependent
Transcription, make its play immunologic function.KCa3.1 passages can make film potential hyperpolarization as calcium ion activated potassium-channel,
So that Ca2+Flowed in continuing, Kv1.3 passages then maintain the resting potential of T lymphocytes, T cell is in activable state.
Selective exclusion/gene knocks out Kv1.3 passages by the activation of depression effect T lymphocytes and function.Due to Kv1.3 potassium channels
T lymphocytes are distributed mainly on, with TEMCell is in the majority, and specific inhibition Kv1.3 passages do not influence other cell functions and just then
Normal T cell immunity, therefore Kv1.3 passages are considered as the new target drone of various immunity disease treatments.
Initial CD4+After T cell receives antigenic stimulus, the T cell of different subtype can be divided under different conditions, is held
The different function of row.The many factors such as hormone and cell factor of its differentiation direction in by the property of antigen, local environment are adjusted
Control, wherein differentiation of the balance between the species and cell factor of cell factor to Th cells have important adjustment effect.Just
Beginning CD4+T cell is divided into Th1 cells under the induction of IL-12 and interferon (interferon-g, IFN-γ), secretion
IFN-γ, participate in cell-mediated immune response；Th2 cells are divided under IL-4 induction, secrete IL-4, IL-5 and IL-
13, participate in humoral immune response；It is single in transforming growth factor β (Transforming growth factor beta, TGF-β)
Treg cells solely are divided under induction, secrete TGF-β, participate in immunological regulation；It is divided under TGF-β and IL-6 common induction
Th17, IL-6 and IL-17 is secreted, participate in inflammatory reaction and autoimmune disease.
The content of the invention
Animal experiment research display early stage of the applicant：Eplerenone can suppress normal rat Treg cells
The Kv1.3 electric currents of (Regulatory T lymphocytes, Autoimmune disease), illustrate that eplerenone can suppress
The activation of Treg cells.Induction type Treg cells (induced Tregs, iTregs) are by CD4+T lymphocyte differentiations and
Come, whether eplerenone has now not clear to suppress its differentiation to Treg cells by suppressing its activity.
The applicant has found that eplerenone is to Patients with Chronic Heart Failure CD4 by further experiment+T lymphocytes
The expression of the passage mRNA and Kv1.3 such as Kv1.3 channel protein has obvious inhibiting effect.
Suppression of the claimed eplerenone to Patients with Chronic Heart Failure helper T lymphocyte activation/propagation is made
With.
Preferably, eplerenone is to Patients with Chronic Heart Failure CD4+T cell Kv1.3, KCa3.1 and CRAC passage
The inhibitory action of mRNA expression.
Preferably, eplerenone is to Patients with Chronic Heart Failure CD4+The suppression of T cell Kv1.3 passages mRNA expression
Rate is 64.8%.
Preferably, eplerenone is to Patients with Chronic Heart Failure CD4+The suppression of T cell KCa3.1 passages mRNA expression
Rate is 19.2%.
Preferably, eplerenone is to Patients with Chronic Heart Failure CD4+The inhibiting rate of T cell CRAC passages mRNA expression
For 37.3%.
Preferably, eplerenone is to Patients with Chronic Heart Failure CD4+The suppression of T cell Kv1.3 channel proteins expression
Effect.
Preferably, after giving eplerenone, chronic heart failure CD4+T cell Kv1.3 channel proteins expression quantity declines
39.6%.
The present invention is also claimed eplerenone and suppresses CD4+The differentiation of T lymphocytes downstream immunocyte.
Result of study confirmation of the present invention, chronic heart failure CD4+Kv1.3, KCa3.1 and CRAC passage of T lymphocytes
MRNA expression dramatically increased compared with normal group, after giving 30 μM of EPL, its expression is suppressed significantly, and wherein Kv1.3 leads to
Road suppresses the most obvious, and inhibiting rate is about 64.8% (P ＜ 0.01).Therefore the detection to Kv1.3 channel proteins is more significant.
The Kv1.3 albumen of CHF groups adds 120.8%, adds 30 μM of EPL and inhibits 39.6% (P ＜ 0.01).
2nd, the chronic heart failure peripheral blood CD4 of 3 phases+The activation of the passages such as T lymphocytes Kv1.3 promote its activation/
Propagation, its downstream immunocyte (such as Th17 cells and Treg cells) differentiation provide possibility, and eplerenone is to chronic heart failure
Peripheral blood in patients CD4+The passages such as the Kv1.3 on T Lymphocyte Membranes have obvious inhibiting effect, illustrate that eplerenone inhibits
CD4+The differentiation of T lymphocytes downstream immunocyte.
Due to the CD4 of Patients with Chronic Heart Failure+The mRNA and/or protein of three kinds of ion channels of T lymphocytes are equal
Height expression, and eplerenone can substantially lower the mRNA and/or protein expression of three kinds of ion channels, wherein leading to Kv1.3
The downward effect in road is especially prominent, therefore prompts eplerenone in vitro can be by suppressing CD4+Kv1.3 on T Lymphocyte Membranes
The activation of T lymphocytes is reduced Deng the activity of passage.
The present invention subsidizes (bullets for state natural sciences fund regional science fund project：81360491).
Brief description of the drawings
Accompanying drawing is used for providing a further understanding of the present invention, and a part for constitution instruction, the reality with the present invention
Apply example to be used to explain the present invention together, be not construed as limiting the invention.In the accompanying drawings：
Fig. 1 is flow cytometer detection CD4+The purity of T lymphocytes；
Fig. 2 is the EPL of various concentrations to CD4+The lymphopoietic inhibiting rate curves of T；
Fig. 3 is that RT-qPCR methods detect CD4+The gene expression of relevant ions passage on T Lymphocyte Membranes；
Fig. 4 is CD4+The expression of T lymphocyte Kv1.3 channel proteins.
Embodiment
Following embodiment facilitates a better understanding of the present invention, but does not limit the present invention.Experiment in following embodiments
Method, it is conventional method unless otherwise specified.Test material used, is city unless otherwise specified in following embodiments
Sell.
Embodiment 1
1. materials and methods
1.1 material
1.1.1 experimental subjects and case screening conditions experimental group：30, be No.1 Hospital Attached to Xinjiang Medical Univ.'s heart
Decline the inpatient of section, wherein man 18, female 12, the age 32~69 (48.34 ± 4.86) year.Inclusion criteria：(a) make a definite diagnosis
For CHF at least three moons；(b) NYHA cardiac functional gradings are 2~3 grades；Exclusion standard：(a) acute and chronic infection, diseases associated with inflammation；
(b) autoimmune disease；(c) recent unstable angina pectoris and acute myocardial infarction AMI (in 3 months)；(d) rheumatic disease
There is active rheumatism (in 3 months) in the recent period；(e) diabetes, hyperthyroidism or other endocrine system diseases；(f) use in the recent period
Influence immune response medicine (such as corticosteroid)；(g) serious Liver and kidney function is not complete；(h) tumour；(i) it is pregnant.Control group：20
Example, is selected from outpatient service physical examination of healthy population, man 10, female 10, the age 25~69 (50.11 ± 14.73) year.Two groups of ages and property
It is not statistically significant Gou Cheng difference not compared.
1.1.2 key instrument and reagent C T15RE type low-temperature and high-speeds centrifuge (Hitachi, Japan), Midi types magnetic force point
Select device (MACS, Germany), 25LS types sorting post (MACS, Germany), HF240 types CO2Cell incubation case (OlyPus, Japan) is exempted from
Epidemic disease magnetic bead sorting device (Germany U.S. day Ni), 0.5-10 μ L, 20-200 μ L and 100-1000 μ L-types liquid-transfering gun (Ependorf, moral
State), CD4+T cell isolation kit, Human, FACS Calibur flow cytometers (U.S. company BD), people's lymph
Cell separating liquid (LTS1077, Sigma), hyclone, RPMI1640 nutrient solutions (Hyclone), sybr kits (Life),
KCNN1.3 mouse anti humans (abcom, ab105595), β-actin ab8226 (Abcam),800CW Goat anti-
Mouse (LI-COR) etc..
1.2 method
1.2.1 immuno magnetic cell separation CD4+T proliferation assays group and control group venous blood sampling 10mL, with PBS and periphery
Blood 1:Dilution is obtained after 1 dilution, is slowly laid in separating liquid, 2000rpm centrifugation 20min, collects mononuclearcell
Layer, adjustment cell concentration are 1010·L-1.Positive sorting obtains CD4+T lymphocytes, with EDTA containing 2mM, 0.5wt%BSA's
Buffer adds CD4 after cell is resuspended+T cell Biotin-Antibody Cooktial are incubated 5min, washing after 4 DEG C
3 times, abandon supernatant；Anti-Biotin MicroBeads are added after cell is resuspended with buffer to mix in 4 DEG C of incubation 10min；From
It is resuspended, is washed 3 times with buffer after the heart；Cell is resuspended with 0.5mL buffer, LS sorting posts are placed in magnetic field, the positive point
Cell is collected in choosing.
1.2.2 CD4+The packet of T lymphocytes and the culture above-mentioned cell of complete medium suspension, are seeded in after counting
3 10cm culture dish (is used and contains 10 μ gmL-1Anti-CD3,10 μ gmL-1HSP60 bags ware) in, cell quantity 105It is individual,
Wherein, every kind of experimental group cell is inoculated in CHF groups respectively and (CHF+EPL) is organized in two groups of culture dishes, cellular control unit is connect
Kind is in control group culture dishes, then by the CD4 of control groups, CHF groups and (CHF+EPL) group+T lymphocytes, in
37 DEG C, 5%CO2Incubator in be incubated 12h after, CHF groups and (CHF+EPL) are organized and give physiological saline and 30 μM respectively
EPL.Three groups of cells are placed in 37 DEG C, 5%CO2Incubator in be incubated 48h, it is to be measured.
1.2.3 flow cytomery CD4+The purity of T cell collects the CD4 that each group is incubated+T lymphocytes, add 1mL
RPMI-1640 (10% hyclone, 50ngmL-1Cell stimulatory agents PMA, 1 μ gmL-1Ionomycin, 0.7 μ LmL-1It is high
That base blocking agent), adjustment cell concentration to 106·mL-1；Take out the cell suspension 1mL after above-mentioned adjustment concentration, be placed in 15mL from
In heart pipe, 1500rpm centrifugation 10min, supernatant is abandoned, adds RPMI-1640, is mixed；It is placed in 5%CO2, in 37 DEG C of incubator,
4h is incubated, does Nature enemy；1500rpm centrifugations 10min abandons supernatant, adds each 10 μ L of CD3-PC7, CD8-PC5 respectively, according to thin
Cellular surface antigen colouring method marks surface antigen, and CD4 is marked with CD3-PC7, CD8-PC5；Washed in room temperature lucifuge 20min, PBS
Wash cell one time；250 μ L cells are added to fix/rupture of membranes agent (Fixation/Permeabilization solution), lucifuge, 4
DEG C be incubated 20min；Cleaned with 1 times of washing lotion of 1mL (Perm/wash buffer), centrifuge 10min in 1500rpm, abandon supernatant；Weight
Clean 2 times, detected through flow cytometer again, lymphocyte populations are selected on FSC-SSC scatter diagrams, by different cell marks
The note cell subsets different with gated detection, data analysis is carried out to the cell of all dyeing by Cell Quest softwares, and
Record the percentage of positive cell.
1.2.4RT-qPCR CD is detected+The mRNA of Kv1.3, KCa3.1, CARC path on T Lymphocyte Membranes collects each
The CD4 of group+T lymphocytes, it is 10 in concentration7·mL-1In cell plus 1mL Trizol are mixed in being stored at room temperature 5min, add 1/
The chloroform of 5Trizol volumes, fully vibrates 15s, and in being stored at room temperature 5min, in 4 DEG C, 15000 rpm centrifugations 10min is (fast to rise soon
Drop), collect supernatant liquor.1 is pressed in the EP pipes without RNase:1 plus isopropanol, be stored at room temperature 25min, 4 DEG C, 12000rpm from
Heart 10min, abandons supernatant.Now cleaned with absolute ethyl alcohol with 75% ethanol solution, 4 DEG C, 10000rpm centrifugation 5min, be repeated 3 times, dry in the air
To RNA surfaces no liquid.Detection and Extraction RNA concentration and purity.Reverse transcription is carried out immediately to crack to prevent RNA.With without RNase water
Purpose RNA to 11 μ L is diluted, adds 1 μ L rander Primer to set 65 DEG C in PCR amplification instrument, system is added after 5min
(Thermo) (the μ L of 5 × Reaction Buffer, 4 μ L, RNase inhibitor (R1), 1 μ L, DNTP mix 2) then in
(1) 65 DEG C of Cycle2,5min are carried out in PCR amplification instrument；25 DEG C, 5min；42 DEG C, 60min；70 DEG C, 5min；Cycle3(1)4
DEG C, ∞.PCR is expanded, in matching somebody with somebody amplification system (H on ice2O, 6.4 μ L, SYBR, 10 μ L, Primer, 0.8 μ L) sample-adding product 1.8 μ L.
Set (1) 50.0 DEG C of amplification program Cycle1,2min；(1) 95.0 DEG C of Cycle2,2min；(40) 95.0 DEG C, 15s of Cycle3,
60 DEG C, 15s；(1) 60 DEG C of Cycle4,15s；(1) 95 DEG C of Cycle5,15s.Table 1 is used upstream and downstream primer.
The upstream and downstream primer of table 1
1.2.5 In-Cell Western Blotting detect CD4+Each group CD4 is collected in the expression of T lymphocyte proteins+
T lymphocytes, it is suspended, is distributed in respectively in the U-shaped orifice plate of black wall 96 with above-mentioned 1640 culture medium, adds 100 μ L suspensions i.e. 10 per hole4It is individual
Cell, 37 DEG C of incubation 15min；50 μ L fixatives (4% paraformaldehyde) are added to be placed in 30rpm jogs on shaking table at room temperature per hole
20min；Supernatant is gently sucked, adds 100 μ L confining liquids (configuration of 5% skimmed milk power) to be placed in 30rpm on shaking table at room temperature per hole light
Shake 1h；Supernatant is gently sucked, adding 50 μ L primary antibodies (KCNN1.3 mouse anti humans) per hole, 30rpm jogs are stayed overnight in 4 DEG C on shaking table,
Primary antibody is eluted with TBST 5 times, dilutes secondary antibody (1 with 2.5% skimmed milk power solution:1000), 50 μ L secondary antibodies are added per hole, on shaking table
30r lucifuges are incubated 1h, are eluted 5 times with TBST, eluent are abandoned, with Odyssey 700 and 800 Channel scan orifice plates, medium scanning
Quality, 169 μm of resolution ratio, 3.0mm focal lengths, brightness 5.
1.2.6 data statistic analysis is analyzed data with the softwares of SPSS 22.0, is compared between group using single factor test side
Difference is analysed, and P ＜ 0.05 think there is significant difference, have statistical significance.
2. experimental result
2.1 flow cytometer detection CD4+The purity of T lymphocytes：CD4+The purity of T lymphocytes is 98.7%, more than 80%
It is therefore representative with research.The CD4 sorted with flow cytometer detection immunological magnetic bead sorting method+The purity of T lymphocytes, streaming result
See Fig. 1.
2.2 CCK-8 methods detect various concentrations EPL to CD4+The lymphopoietic suppression situations of T：CD4+T lymphs are thin
Born of the same parents be administered be incubated 48h after, give CCK-8 reagents be incubated (37 DEG C, 5%CO2) 4h, in being detected on ultraviolet specrophotometer, obtain
Fig. 2 curve.Fig. 2 is EPL to CD4+T lymphocyte inhibiting rates curve (the OD values of CCK-8 dyeing), inhibiting rate formula：N=1,2,3....CD4+The inhibiting rate of T cell propagation (R after Hill equation models
=0.9995) IC, is obtained50=2.4 μM.As seen from Figure 2：30 μM of EPL about suppresses CD4+T lymphopoiesis reaches
83.4%, close to maximal percentage inhibition, therefore subsequent experimental is intervened using 30 μM of EPL as experimental concentration.It is shown in Table 2 and Fig. 2.
The EPL of the various concentrations of table 2 is to CD4+The lymphopoietic inhibiting rates of T
2.3 RT-qPCR detection each groups CD4+The mRNA expression of T lymphocyte Kv1.3, KCa3.1 and CRAC passages：
The mRNA expression of Kv1.3, KCa3.1, CRAC passage of CHF groups is 974.1%, 373.3% and compared with the growth rate of control groups
276.8% (P ＜ 0.01), the inhibiting rate that CHF+EPL groups are expressed compared with the mRNA of three groups of ion channels of CHF groups for 64.8%,
19.2% and 37.3% (P ＜ 0.01).By control group result marks, CHF groups are main to see compared with control groups
Examine the CD4 of chronic heart failure+Kv1.3, KCa3.1, CRAC passage mRNA are expressed on T Lymphocyte Membranes, and are given
The change of each related gene expression, is shown in Table 3 and Fig. 3 after EPL cultures.
The CD4 of table 3+Relevant ions passage on T Lymphocyte Membranes mRNA expression (N=8)
**P ＜ 0.01 are CHF group vs control groups,##P ＜ 0.01 are CHF+EPL group vs CHF groups
2.4 In-cell western blotting detect CD4+The expression of T lymphocyte Kv1.3 channel proteins：Slowly
The CD4 of property patients with heart failure+The expression of T lymphocyte Kv1.3 channel proteins is compared with normal person CD4+T lymphocyte Kv1.3 passage eggs
120.8% (P ＜ 0.01) of white up-regulated expression.CD4 in chronic heart failure peripheral blood+T lymphocytes give EPL
Afterwards, the expression of Kv1.3 channel proteins have dropped 39.6% (P ＜ 0.01).The A figures and B figures seen in Fig. 4.Fig. 4 is CD4+T lymphs
Cell Kv1.3 channel proteins expression (N=8), wherein,**P ＜ 0.01 are CHF group vs control groups,##P ＜
0.01 is CHF+EPL group vs CHF groups.
3. discuss：
The confirmation of this result of study, chronic heart failure CD4+Kv1.3, KCa3.1 and CRAC passage of T lymphocytes
MRNA expression is dramatically increased compared with normal group, and after giving 30 μM of EPL, its expression is suppressed significantly, wherein Kv1.3 passages
Suppress the most obvious, inhibiting rate is about 64.8% (P ＜ 0.01).Therefore the detection to Kv1.3 channel proteins is more significant.
The Kv1.3 albumen of CHF groups adds 120.8%, and 30 μM of EPL inhibit 39.6% (P ＜ 0.01).
2nd, the chronic heart failure peripheral blood CD4 of 3 phases+The activation of the passages such as T lymphocytes Kv1.3 promote its activation/
Propagation, its downstream immunocyte (such as Th17 cells and Treg cells) differentiation provide possibility, and eplerenone is to chronic heart failure
Peripheral blood in patients CD4+The passages such as the Kv1.3 on T Lymphocyte Membranes have obvious inhibiting effect, illustrate that eplerenone inhibits
CD4+The differentiation of T lymphocytes downstream immunocyte.
Finally it should be noted that：The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention,
Although the present invention is described in detail with reference to the foregoing embodiments, for those skilled in the art, it still may be used
To be modified to the technical scheme described in foregoing embodiments, or equivalent substitution is carried out to which part technical characteristic.
Within the spirit and principles of the invention, any modification, equivalent substitution and improvements made etc., it should be included in the present invention's
Within protection domain.
Claims (8)
1. eplerenone is to the inhibitory action of Patients with Chronic Heart Failure helper T lymphocyte activation/propagation.
2. inhibitory action according to claim 1, it is characterised in that：Eplerenone is to Patients with Chronic Heart Failure CD4+T is thin
The inhibitory action of born of the same parents' Kv1.3, KCa3.1 and CRAC passage mRNA expression.
3. inhibitory action according to claim 2, it is characterised in that：When the concentration of eplerenone is 30 μM, according to Puli
Ketone is to Patients with Chronic Heart Failure CD4+The inhibiting rate of T cell Kv1.3 passages mRNA expression is 64.8%.
4. inhibitory action according to claim 2, it is characterised in that：When the concentration of eplerenone is 30 μM, according to Puli
Ketone is to Patients with Chronic Heart Failure CD4+The inhibiting rate of T cell KCa3.1 passages mRNA expression is 19.2%.
5. inhibitory action according to claim 2, it is characterised in that：When the concentration of eplerenone is 30 μM, according to Puli
Ketone is to Patients with Chronic Heart Failure CD4+The inhibiting rate of T cell CRAC passages mRNA expression is 37.3%.
6. inhibitory action according to claim 1, it is characterised in that：Eplerenone is to Patients with Chronic Heart Failure CD4+T is thin
The inhibitory action of born of the same parents Kv1.3 channel proteins expression.
7. inhibitory action according to claim 6, it is characterised in that：After giving 30 μM of eplerenones, chronic heart failure
CD4+T cell Kv1.3 channel proteins expression quantity declines 39.6%.
8. eplerenone suppresses CD4+The differentiation of T lymphocytes downstream immunocyte.
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Cited By (1)
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| CN110592013A (en) * | 2019-04-22 | 2019-12-20 | 新疆医科大学 | EPL blockade of Treg cell Kv1.3 channels reduces exosome-mediated cardiofibrosis |
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