CN104174010B - The function and application of SHPS1 in treatment angiostenosis after damage - Google Patents
The function and application of SHPS1 in treatment angiostenosis after damage Download PDFInfo
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Abstract
The invention discloses the function and application of a kind of SHPS1 in treatment angiostenosis after damage, belong to function and the application of gene.The present invention for experimental subject, by vascular injury model, has carried out the detection of mice neointima, the gentle smooth muscle cell phenotype conversion of cells of vascular wall proliferation water with SHPS1 knock out mice and wild-type mice.Result shows, SHPS1 gene knockout can obviously promote neointima and cell proliferation, promotes that smooth muscle cell is changed to synthesis type by shrinkage type.This shows the function of SHPS1 in angiostenosis after damage, is mainly reflected in SHPS1 and has the function suppressing neointima and cell proliferation and the conversion of suppression smooth muscle cell phenotype.For the above-mentioned functions of SHPS1, SHPS1 can be used for preparing prevention, alleviate and/treatment the medicine of angiostenosis after damage and arterial bracket.
Description
Technical field
The invention belongs to function and the application of gene, be specifically related to the function and application of a kind of SHPS1 in treatment angiostenosis after damage, specifically SHPS1 prevents in preparation, alleviates and/or treats in the medicine of angiostenosis after damage and applies.
Background technology
Along with the change of dietary structure and the aging process of population, atherosclerosis occlusive disease presents the trend that increases year by year and becomes one of main cause of death of our country.There is no radical cure way to this kind of disease at present, the treatment means of vascular surgery comprises balloon expandable, support is inserted and the mode such as tremulous pulse bypass, but after reconstructing blood vessel, restenosis has had a strong impact on therapeutic effect.There are some researches show, in the process that damage is formed, new intima and middle membrane tissue hyperplasia and simultaneously adjoint extracellular matrix are formed, and are the main pathological basis causing restenosis after reconstructing blood vessel.Vascular smooth muscle cell (vascularsmoothmusclecells, VSMCs) Phenotypic Change plays important role in Neointimal formation process.VSMCs has two kinds of different phenotypic status, i.e. differentiation/shrinkage type and dedifferente/synthesis type, and two kinds of phenotypes can transform under certain condition mutually.When VSMCs is transformed to synthesis type by shrinkage type, propagation, transfer ability strengthen and secrete, synthesize a large amount of extracellular matrixs, thus formation new intima, and then cause the generation of serious vascular proliferative disease.If can prevent even to reverse VSMCs Phenotypic Change, developing of above-mentioned disease can be contained in early days.
Tumor necrosis factor-alpha (tumornecrosisfactor-α, TNF-α) be a multifunctional cytokine, it is the main regulatory factors of apoptosis, inflammation and immunity, plays Promote cell's growth, differentiation, apoptosis and brings out the important function such as inflammation after the specific receptors bind on it and cell membrane.The imbalance of TNF-alpha signal and septicemia, diabetes, cancer, osteoporosis and atherosclerosis etc. closely related [1].By the relevant signal path of inflammation in active cell especially NF-κ B path, inducing cell expresses various marker of inflammation to TNF-α, at the inflammatory cell of blood vessel injury local infiltration, is induced VSMC Phenotypic Change and propagation by TNF secretion-α.Studies have reported that the process closely related [2,3] that the albumen of TNF-α self and abduction delivering thereof and VSMC breed and move.
Signal adjusting protein (signalregulatoryproteins, SIRPs) family's contactin member, first SIRP family member be found is SHPS1, namely containing Protein-tyrosine-phosphatase substrate 1(Srchomology2 (SH2) domain-containingproteintyrosinephosphatasesubstrate1 of Src homeodomain 2), be also called SIRP α (signalregulatoryprotein α), the neural adhesion molecule [4,5] of BIT, MFR or P84.SHPS1 is the transmembrane protein of an about 115kDa, is one of SIRP family member.SHPS1 mainly expresses in myocardial cell, dendritic cell, macrophage, leukocyte, neurocyte, secondly in fibroblast, also have expression, play negativity and regulate the phagocytosis of macrophage, the activation of mastocyte, the activation of dendritic cell and promote the effect of apoptosis.Recent studies have found that SHPS1 can negativity regulate the activation of NF-κ B signal to promote the apoptosis that TNF-α induces, thus play the effect [6,7] of cell growth inhibiting and propagation.Infer thus, SHPS1, as the Function protein of Tumor Necrosis Factor Receptors TNFR1, can regulate the expression of the downstream signaling pathway of TNF-α and relevant genes of interest, affect the function of blood vessel V SMC, thus play a role in vascular restenosis by negativity.
[list of references]
1、BarzilayJI1,AbrahamL,HeckbertSR,etal.Therelationofmarkersofinflammationtothedevelopmentofglucosedisordersintheelderly:theCardiovascularHealthStudy.Diabetes.2001,50(10):2384-9.
2、YoshidaS,OnoM,ShonoT,etal.Involvementofinterleukin-8,vascularendothelialgrowthfactor,andbasicfibroblastgrowthfactorintumornecrosisfactoralpha-dependentangiogenesis.MolecularandCellularBiology,1997,17:4015-4023.
3、LeeSJ,KimWJ,MoonSK.TNF-αregulatesvascularsmoothmusclecellresponsesingenetichypertension.InternationalImmunopharmacology,2009;9:837-843.
4、Kharitonenkov,ChenZ,SuresI,etal.Afamilyofproteinsthatinhibitsignallingthroughtyrosinekinasereceptors.Nature.1997;386(6621):181-6.
5、ComuS,WengW,OlinskyS,etal.ThemurineP84neuraladhesionmoleculeisSHPS-1,amemberofthephosphatase-bindingproteinfamily.JNeurosci.1997;17(22):8702-10.
6、ZhiyongLiao,MingjiangWu,XiaoliChen.NovelfunctionofRECS1asanegativeregulatorofTNF-a-inducedNF-kBactivation.MolCellBiochem.2009.
7、NeznanovN,NeznanovaL,KondratovRV,etal.DominantNegativeFormofSignal-regulatoryProtein-α(SIRPα/SHPS-1)InhibitsTumorNecrosisFactor-mediatedApoptosisbyActivationofNF-κB.TheJournalofBiologicalChemistry.2003;278(6):3809-15。
Summary of the invention
For solving defect and the deficiency of above-mentioned prior art, the object of the invention is to determine the expression of SHPS1 and the mutual relation of angiostenosis after damage, provide one for preventing, alleviating and/or treat the novelty teabag of target gene SHPS1 of angiostenosis after damage.
Object of the present invention is achieved through the following technical solutions:
The present invention with wild type C57BL/6 mice and SHPS1 knock out mice (SHPS1-KO mice) for experimental subject, mice vascular injury model (vascularinjury is obtained by the induction of carotid artery seal wire damage model, VI), carry out the research that vascular injury model (VI) mice neointima measures, cells of vascular wall breeds the detection of level and the detection of smooth muscle cell phenotype, result shows: contrast with wild type C57BL/6 mice, and SHPS1 knock out mice shows neointima and cell proliferation is obviously greater than WT mice; SHPS1 gene knockout can promote the expression of proliferating cell nuclear antigen (ProliferatingCellNuclearAntigen, PCNA) and cyclin (CyclinD1), can promote propagation and the neointimal hyperplasia of smooth muscle cell; SHPS1 gene knockout can suppress smooth muscle actin (SmoothMuscleActin, and Smoothing Probablities (smoothmuscle22alpha SMA), SM22 α) expression, can promote that smooth muscle cell is by the Phenotypic change of shrinkage type to synthesis type, thus promote neointimal hyperplasia.The above results shows that SHPS1 gene knockout can promote the generation of angiostenosis after damage, SHPS1 can suppress the formation of angiostenosis after damage, and the novel targets and the New Policy that prevent, alleviate and/or treat angiostenosis after damage for studying provide theoretical foundation and Clinical Basis.
Research of the present invention demonstrates: in angiostenosis after damage model, and SHPS1 can suppress neointima and cell proliferation, suppresses smooth muscle cell to be changed to synthesis type by shrinkage type, particularly improves the effect of angiostenosis after damage.
For the above-mentioned functions of SHPS1, provide the application of a kind of SHPS1, major embodiment be SHPS1 preparation prevention, alleviate and/or treatment angiostenosis after damage medicine in apply.
A medicine narrow again after prevention, alleviation and/treatment blood vessel injury, comprises SHPS1.
Prevention, alleviation and/or treatment angiostenosis after damage an arterial bracket, it is coated with SHPS1.
In the present invention, described blood vessel injury mainly Digital arteries blood vessel injury.
In the present invention, described blood vessel injury refers to the blood vessel injury that atherosclerosis causes, or the blood vessel injury that causes when treating atherosclerosis, such as, by balloon expandable or put into the blood vessel injury that support causes, or transplants the blood vessel injury that arteriopathy or pulmonary hypertension cause.
In the present invention, described atherosclerosis had both comprised the angiostenosis phase of atherosclerosis compared with commitment, also comprise atherosclerosis serious time the blood vessel obstruction phase.
In the present invention, described arterial bracket refers to narrow, the inaccessible blood vessel for support human body endogenous cause of ill pathological changes, recovers the tubular device of blood circulation, adopts metal or processing of high molecular material to make, can stay in human vas for a long time or temporarily.On the basis that tube chamber balloon expandable is shaped, support stenosis occlusion section blood vessel at pathological changes section Stent Implantation to reach, reduce blood vessel elasticity retraction and more moulding, keep the object that tube chamber blood flow is unobstructed, both comprised peripheral arterial support, also comprised coronary stent.
In the present invention, described restenosis refers to when damage occurs local vascular, the done universality biologically causing vessel lumen restenosis.Here mainly refer to the vascular restenosis that iatrogenic injury causes, damage process is primarily of Arterial Remodeling and endotheliosis composition.
The present invention has following advantage and effect relative to prior art:
(1) present invention finds the New function of SHPS1 gene, namely SHPS1 can suppress the effect of angiostenosis after damage.
(2) suppressing the function of angiostenosis after damage based on SHPS1, for the medicine developing angiostenosis after damage provides basis, can be used for preparing prevention, alleviating and/or narrow again after treatment blood vessel injury in medicine.
(3) SHPS1 can be used for preparing the arterial bracket preventing, alleviate and/or treat angiostenosis after damage.
Accompanying drawing explanation
Fig. 1 is that WT and the SHPS1-KO mice HE of postoperative 28 days dyes and Intimal area result statistics block diagram; Wherein, A:HE colored graph, B: Intimal area statistics block diagram (*: p < 0.05vsWTVI group).
Fig. 2 is immunofluorescence dyeing and the result statistics block diagram of horizontal mark PCNA, CyclinD1 expression of cells of vascular wall propagation in postoperative 28 days of WT and SHPS1-KO mice; Wherein, A: immunofluorescence dyeing, B: result statistics block diagram (*: p < 0.05vsWTVI group).
Fig. 3 is immunofluorescence dyeing and the result statistics block diagram of WT and SHPS1-KO mice postoperative 28 days smooth muscle cell phenotype transition flag thing SMA, SM22 alpha expressions; Wherein, A: immunofluorescence dyeing, B: block diagram (*: p < 0.05vsWTVI group).
Detailed description of the invention
Below in conjunction with specific embodiments and the drawings, further detailed description is done to the present invention.Should be understood that the following examples are only not used in for illustration of the present invention to limit the scope of the invention.
Animal for research and raising
Laboratory animal: select 8-10 age in week, body weight is at 24-27g, male, C57BL/6 mice (WT mice, purchased from Fukang bio tech ltd of China, Beijing) and SHPS1 knock out mice (SHPS1-KO, purchased from Japanese RIKEN company, article No.: RBRC01544).
Feeding environment: all experiment mices are all raised in angiocardiopathy institute of Wuhan University SPF level Experimental Animal Center.The large mouse feed of SPF level purchased from Beijing China Fukang bio tech ltd, rearing conditions: room temperature is between 22-24 DEG C, and humidity is between 40-70%, and it is 12h that light and shade replaces lighting hours, freely drinks water and ingests.
Embodiment 1 mice vascular injury model (VI) obtains
1. laboratory animal grouping: use 8-10 age in week, WT and the SHPS1-KO mice of body weight 24-27g, is divided into 2 groups: WT blood vessel injury group, SHPS1-KO blood vessel injury group, often organizes each 20 mices.Within 28 days, put to death mice after surgery respectively, get damage segmental vessels and analyze.
2. mice vascular injury model operating process:
1) under dynamic mode, accurately Mouse Weight (g) is taken with electronic balance, 3% Nembutal sodium solution is accurately configured with distilled water, shake makes it fully dissolve gently, adopt 80mg/kg body weight dose, respective volume solution is accurately extracted with 1mL syringe after calculating required Nembutal sodium solution volume, row intraperitoneal injection of anesthesia mice, fully anaesthetizes down after (about 3min) until mice, 8% sodium sulfide cervical region depilation.
2) be separated in neck and external carotid artery.
3) prick external carotid artery at internal carotid artery and external carotid artery crotch 8-0 toe-in, use the temporary blocking-up internal carotid artery of vascular clamp (WPI, 501784-G) and common carotid artery blood supply simultaneously.
4) with microscissors (WPI, 501839) Transverse Shear osculum above ligation of external carotid artery line.Insert the seal wire (No.C-SF-15-15, Cook, Bloomington, Indiana) of diameter 0.015 inch through this blood vessel otch, rotate seal wire advance and retreat 5-6 time.
5) at otch proximal part ligation external carotid artery, unclamp in neck and common carotid artery puts the vascular clamp stayed, cut off the end of a thread, cleaning visual area, sews up cervical incision.
Embodiment 2 vascular injury model (VI) mice neointima measures
1. mice is drawn materials
1) anesthetized mice, breaks heart blood-letting.
2) cut carotid artery from the nearly crotch of carotid artery, get 0.5-0.6cm long, retain external carotid artery toe-in.
3) carotid artery is put into PBS, softly drain intraluminal residual blood with microforceps.
4) blood vessel is put into the 1.5mLEP pipe that 1mL4% paraformaldehyde is housed to fix.
2. pathology detect
2.1 prepare paraffin specimen section
Prepare paraffin specimen by laboratory profession pathology staff to cut into slices, main operation sequence comprises: in 4% paraformaldehyde overnight fixing after, blood vessel filter paper is carefully wrapped, puts into embedding frame → running water → dehydration → transparent → waxdip → embedding → section (3 μm) → stand sheet → dry or for subsequent use after toasting.
2.2 hematoxylin-eosins (HE) dye
Key step is: 55 DEG C of baking 30min → dimethylbenzene 5min, 3 times → 100% ethanol 1min → 95% ethanol 1min → 70% ethanol 1min → distilled water 1min → haematoxylin solution (Zhuhai shellfish rope, BA-4021) 5min → washing 1min → 1% hydrochloride alcohol (getting 3mL concentrated hydrochloric acid fully to mix homogeneously with 297mL70% ethanol) 1-3s → washing 1min → Scott liquid (sodium bicarbonate 0.35g, magnesium sulfate 2g, distilled water 100mL) 1min → washing 1min → Yihong solution (Zhuhai shellfish rope, BA-4024) 3-5min → distilled water washes away loose colour → 70% ethanol 1s → 95% ethanol 1s → 100% ethanol 30s, 3 times → dimethylbenzene 2min, 3 times → take advantage of in the not dry mounting → fume hood immediately of dimethylbenzene and dry up, microscope is taken pictures.
With Ink vessel transfusing elastic fibers and outer elastic fibers for boundary, being tunica intima within interior elastic plate, is tunica adventitia beyond outer elastic plate, is tunica media between inside and outside elastic plate.Each vascular lumen area is enclosed respectively with Image-ProPlus6.0 software.
The calculating of Intimal area size is as follows with reference to formula:
Neointimal area=interior elastic plate area-Lumen Area;
Media area=outer elastic plate area-Nei elastic plate area.
The result of the tunica intima new life after mice HE dyes is as Fig. 1.Normal wall structures is complete, marshalling, and tunica intima is monolayer endothelial cell, structural integrity, middle film smooth muscle cell marshalling.Observed by HE dyeing, blood vessel injury group (VI group) wall structures is imperfect, and vascular endothelial cell lacks, and neointimal hyperplasia is obvious, and with a large amount of cell infiltration; SHPS1-KO group 28 days after surgery neointimal area obviously will increase than WT mice.Equally, the ratio of Intimal area/media area is higher than WT group in the postoperative SHPS1-KO group of VI.This illustrates the neointima caused after the disappearance of SHPS1 gene can promote blood vessel injury.
The detection of embodiment 3 cells of vascular wall propagation level
Immunofluorescence dyeing detects the expression of proliferating cell nuclear antigen (ProliferatingCellNuclearAntigen, PCNA), cyclin (CyclinD1).Required primary antibodie information: PCNA(#2586; 1:100; Mouse; CellSignalingTechnology), cyclinD1(#2978; 1:25; Rabbit; CellSignalingTechnology); Required two anti-information: AlexaFluor568-conjugatedgoatanti-rabbitIgG(A11011; Invitrogen, Carlsbad, CA), AlexaFluor568-conjugatedgoatanti-mouseIgG(A11004; Invitrogen, Carlsbad, 150d, CA).
Key step is:
1) roasting sheet: paraffin section is placed in 55 DEG C of more than baking box 30min.
2) dewax: dimethylbenzene 5min × 3.
3) hydration: 100% ethanol 5min × 2; 95% ethanol 5min; 70% ethanol 5min; ddH
2o embathes 5min × 2.
4) citrate tissue antigen recovery (Pressure method): get a certain amount of pH6.0 citrate antigen retrieval working solution and (step neoplasm Science and Technology Ltd. purchased from Foochow, article No. MVS-0100) in reparation box, enough whole of the submergence sections of the necessary energy of amount of repair liquid, reparation box is put into the pressure cooker adding appropriate tap water, big fire is heated to boiling, tissue slice after dewaxing hydration is placed on high temperature resistant staining rack, again staining rack is slowly put into and repair box, cover pot cover, buckle pressure valve, continue to be heated to jet, after starting timing 5min, pressure cooker deenergization, valve is gone to uncap, take out and repair box, room temperature takes out section after placing 20min natural cooling.
5) ddH
2o rinsing 5min × 2 time, PBS rinsing 5min × 2 time.
6) groupization stroke circle, drips 10% sheep blood serum (GTX27481, GeneTex) and closes, 37 DEG C of closed 60min in wet box.
7) abandon confining liquid, drip the primary antibodie of proper proportion dilution, 4 DEG C of overnight incubation, 37 DEG C of rewarming 30min, discard primary antibodie, PBS washes 10min × 3 time.
8) drip two to resist, in wet box, hatch 60min for 37 DEG C, discard two and resist, PBS embathes 5min × 3 time.
9) SlowFadeGoldantifadereagentwithDAPI(S36939, Invitrogen) mounting.
10) viewed under fluoroscopy, takes pictures.Preserve if need, 4 DEG C of preservations in dark wet box.
Fluorescence statistical method: PCNA immunofluorescence dyeing statistics adopts IPP software counting, total DAPI number * 100% of PCNA positive cell percentage=PCNA positive cell number/(inner membrance+middle film); CyclinD1 immunofluorescence dyeing statistics adopts IPP software directly to survey positive absorbance.
Immunofluorescence observes smooth muscle cell proliferation mark PCNA, CyclinD1 expression change after WT and SHPS1-KO mice blood vessel injury, the results are shown in Figure 2.PCNA, CyclinD1 have expression in vascular tissue, the positive cell number of SHPS1-KO mice 28 days after surgery PCNA and the fluorescence intensity of CyclinD1 all will increase in the WT mice with group, show that SHPS1 gene knockout can promote the expression of PCNA, CyclinD1, propagation and the tunica intima new life of smooth muscle cell can be promoted.
The detection of embodiment 4 smooth muscle cell phenotype
Immunofluorescence dyeing detects SMC differentiation mark: the expression of smooth muscle actin (SmoothMuscleActin, SMA), Smoothing Probablities (smoothmuscle22alpha, SM22 α).Required primary antibodie information: SMA(ab5694; 1:100; Rabbit; Abcam) andSM22 α (ab14106; 1:100; Rabbit; Abcam); Required two anti-information: AlexaFluor488-conjugatedgoatanti-rabbitIgG(A11008; Invitrogen, Carlsbad, CA).
Key step is with reference to embodiment 3.
Fluorescence statistical method: adopt IPP software directly to survey positive absorbance.
Under normal physiological condition, vascular smooth muscle cell remains static, and main manifestations is shrinkage type; After blood vessel injury, vascular smooth muscle cell is moved to inner membrance by middle film, the Proliferation and apoptosis loss of equilibrium of smooth muscle cell, and phenotype is changed to synthesis type by shrinkage type, and blood vessel wall discomfort is reinvented, thus causes neointimal hyperplasia.Immunofluorescence observes the expression change of SMA, SM22 α after WT and SHPS1-KO mice blood vessel injury, the results are shown in Figure 3.SMA, SM22 α has expression in vascular tissue, SHPS1-KO mice after surgery 28 days SMA, SM22 α fluorescence intensity all will lower than with group WT mice, show that SHPS1 gene knockout can suppress the expression of SMA, SM22 α, can promote that smooth muscle cell is by the Phenotypic change of shrinkage type to synthesis type, thus promote neointimal hyperplasia.
With the display of above-described embodiment result, all there is angiostenosis after damage in wild-type mice and SHPS1-KO mice under the induction of vascular injury model (VI).The conversion of the neointima of SHPS1 knock out mice, cell proliferation level and smooth muscle cell phenotype is all remarkable than wild-type mice.These results show, SHPS1 can improve the propagation of smooth muscle cell of blood vessel injury induction, Phenotypic Change and blood vessel neointima and be formed.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (4)
- The application of 1.SHPS1 in the medicine of preparation treatment angiostenosis after damage.
- 2. application according to claim 1, is characterized in that: the blood vessel injury that described blood vessel injury is atherosclerosis, atherosclerosis interventional therapy or pulmonary hypertension cause.
- 3. treat an arterial bracket for angiostenosis after damage, it is characterized in that: be coated with SHPS1.
- 4. arterial bracket according to claim 3, is characterized in that: the blood vessel injury that described blood vessel injury is atherosclerosis, atherosclerosis interventional therapy or pulmonary hypertension cause.
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| CN101780283A (en) * | 2010-03-16 | 2010-07-21 | 中国人民解放军第二军医大学 | Application of signal adjusting protein alpha in preparation of DC vaccine for preventing and treating tumors |
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Non-Patent Citations (3)
| Title |
|---|
| Dominant Negative Form of Signal-regulatory Protein-α(SIRPα/SHPS-1) Inhibits Tumor Necrosis Factor-mediated Apoptosis by Activation of NF-κB;Neznanov N et al;《The Journal of Biological Chemistry》;20031231;第3809-3815页 * |
| Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis;Yoshida S et al.;《Molecular and Cellular Biology》;19971231;第4015-4023页 * |
| The murine P84 neural adhesion molecule is SHPS-1, a member of the phosphatase-binding protein family;Comu S et al.;《J Neurosci》;19971231;第8702-8710页 * |
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