CN104174010A - Functions and application of SHPS1 in treatment of post-vascular injury restenosis - Google Patents
Functions and application of SHPS1 in treatment of post-vascular injury restenosis Download PDFInfo
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Abstract
The invention discloses functions and application of SHPS1 in treatment of post-vascular injury restenosis, belonging to the field of functions and applications of genes. SHPS1 gene knockout mice and wild type mice are taken as experimental subjects, and due to a vascular injury model, the mouse neointima formation, vascular wall cell proliferation level and smooth muscle cell phenotype transform are detected. The result proves that SHPS1 gene knockout can obviously promote neointima neogenesis and cell proliferation and promote transformation of smooth muscle cells from a shrinkage manner to a synthetic manner. Thus the functions of SHPS1 in post-vascular injury restenosis are realized, which mainly shows that SHPS1 has the functions of inhibiting neointima formation and cell proliferation and inhibiting smooth muscle cell phenotype transformation. Aiming at the functions of the SHPS1, the SHPS1 can be used for preparing medicines and arterial stents for preventing, relieving and/or treating the post-vascular injury restenosis.
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 applies in the medicine of preparation prevention, alleviation and/or treatment angiostenosis after damage.
Background technology
Along with the variation of dietary structure and the aging process of population, atherosclerosis occlusive disease presents the trend increasing year by year and becomes one of main cause of death of our country.At present this class disease be there is no to radical cure way, the treatment means of vascular surgery comprises that balloon expandable, support are 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 forming in damage, new intima and middle membrane tissue hyperplasia and the extracellular matrix simultaneously followed form, and are the main pathological basis that causes restenosis after reconstructing blood vessel.Vascular smooth muscle cell (vascular smooth muscle cells, VSMCs) Phenotypic Change is being played the part of important role in Neointimal formation process.VSMCs has two kinds of different phenotype states, 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, thereby form new intima, and then cause the generation of serious vascular proliferative disease.If can prevent even to reverse VSMCs Phenotypic Change, can contain in early days developing of above-mentioned disease.
Tumor necrosis factor-alpha (tumor necrosis factor-α, TNF-α) be a multifunctional cytokine, it is the main regulatory factors of apoptosis, inflammation and immunity, after the specific receptors bind on it and cell membrane, brings into play Promote cell's growth, differentiation, apoptosis and brings out the important function such as inflammation.The imbalance of TNF-alpha signal and septicemia, diabetes, cancer, osteoporosis and atherosclerosis etc. closely related [1].TNF-α by the relevant signal path of inflammation in active cell especially NF-κ B path and inducing cell is expressed various marker of inflammation, at the inflammatory cell of blood vessel injury local infiltration, induces VSMC Phenotypic Change and propagation by TNF secretion-α.The albumen of TNF-α self and abduction delivering thereof and the process closely related [2,3] of VSMC propagation and migration are studies have reported that.
Signal adjusting protein (signal regulatory proteins, SIRPs) family's contactin member, first found SIRP family member is SHPS1, contain Protein-tyrosine-phosphatase substrate 1(Src homology 2 (SH2) the domain-containing protein tyrosine phosphatase substrate1 of Src homeodomain 2), be called again the neural adhesion molecule of SIRP α (signal regulatory protein α), BIT, MFR or P84 [4,5].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, performance negativity regulates the phagocytosis of macrophage, activation, the activation of dendritic cell and the effect of promotion apoptosis of mastocyte.Recent studies have found that SHPS1 can negativity regulate the activation of NF-κ B signal to promote the apoptosis of TNF-α induction, thereby bring into play the effect [6,7] of cell growth inhibiting and propagation.Infer thus, SHPS1, as the adjusting albumen of Tumor Necrosis Factor Receptors TNFR1, may regulate the downstream signal path of TNF-α and the expression of relevant genes of interest by negativity, affects the function of blood vessel V SMC, thereby plays a role in vascular restenosis.
[list of references]
1、Barzilay?JI1,?Abraham?L,?Heckbert?SR,?et?al.?The?relation?of?markers?of?inflammation?to?the?development?of?glucose?disorders?in?the?elderly:?the?Cardiovascular?Health?Study.?Diabetes.2001,?50(10):2384-9.
2、Yoshida?S,?Ono?M,?Shono?T,?et?al.?Involvement?of?interleukin-8,?vascular?endothelial?growth?factor,?and?basic?fibroblast?growth?factor?in?tumor?necrosis?factor?alpha-dependent?angiogenesis.?Molecular?and?Cellular?Biology,?1997,?17:4015-4023.
3、Lee?SJ,?Kim?WJ,?Moon?SK.?TNF-α?regulates?vascular?smooth?muscle?cell?responses?in?genetic?hypertension.?International?Immunopharmacology,?2009;?9:837-843.
4、Kharitonenkov,Chen?Z,Sures?I,et?al.A?family?of?proteins?that?inhibit?signalling?through?tyrosine?kinase?receptors.Nature.1997;386(6621):181-6.
5、Comu?S,Weng?W,?Olinsky?S,?et?al.?The?murine?P84?neural?adhesion?molecule?is?SHPS-1,?a?member?of?the?phosphatase-binding?protein?family.?J?Neurosci.?1997;?17(22):8702-10.
6、Zhiyong?Liao,?Mingjiang?Wu,?Xiaoli?Chen.?Novel?function?of?RECS1?as?a?negative?regulator?of?TNF-a-induced?NF-kB?activation.?Mol?Cell?Biochem.2009.
7、Neznanov?N,?Neznanova?L,?Kondratov?RV,?et?al.?Dominant?Negative?Form?of?Signal-regulatory?Protein-α(SIRPα/SHPS-1)?Inhibits?Tumor?Necrosis?Factor-mediated?Apoptosis?by?Activation?of?NF-κB.?The?Journal?of?Biological?Chemistry.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, alleviate and/or treat the new purposes of target gene SHPS1 of angiostenosis after damage.
Object of the present invention is achieved through the following technical solutions:
The present invention is taking wild type C57BL/6 mice and SHPS1 knock out mice (SHPS1-KO mice) as experimental subject, obtain mice blood vessel damage model (vascular injury by the induction of carotid artery seal wire damage model, VI), carry out the research of the newborn mensuration of blood vessel injury model (VI) mice inner membrance, the cells of vascular wall propagation detection of level and the detection of smooth muscle cell phenotype, result shows: with the contrast of wild type C57BL/6 mice, SHPS1 knock out mice shows inner membrance new life and cell proliferation is obviously greater than WT mice; SHPS1 gene knockout can promote the expression of proliferating cell nuclear antigen (Proliferating Cell Nuclear Antigen, PCNA) and cyclin (Cyclin D1), can promote propagation and the neointimal hyperplasia of smooth muscle cell; SHPS1 gene knockout can suppress smooth muscle actin (Smooth Muscle Actin, and smooth muscle 22 α (smooth muscle 22 alpha SMA), SM22 α) expression, can promote smooth muscle cell by shrinkage type the Phenotypic change to synthesis type, thereby 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, for novel targets and the New Policy of research prevention, alleviation and/or treatment angiostenosis after damage provide theoretical foundation and Clinical Basis.
Of the present invention having studies have shown that: in angiostenosis after damage model, SHPS1 can suppress inner membrance new life and cell proliferation, suppresses smooth muscle cell and is changed to synthesis type by shrinkage type, particularly improves the effect of angiostenosis after damage.
For the above-mentioned functions of SHPS1, the application of a kind of SHPS1 is provided, major embodiment is that SHPS1 applies in the medicine of preparation prevention, alleviation and/or treatment angiostenosis after damage.
Prevention, alleviation and/treatment blood vessel injury after a narrow medicine again, comprise SHPS1.
An arterial bracket for prevention, alleviation and/or treatment angiostenosis after damage, it is coated with SHPS1.
In the present invention, described blood vessel injury mainly refers to vessel injury.
In the present invention, described blood vessel injury refers to the blood vessel injury that atherosclerosis causes, or the blood vessel injury causing when atherosclerosis in treatment, for example, 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 that atherosclerosis was compared with the angiostenosis phase of commitment, also comprised blood vessel infraction phase when atherosclerosis is serious.
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, and can stay in human vas for a long time or temporarily.On the basis being shaped at tube chamber balloon expandable, support stenosis occlusion section blood vessel at pathological changes section Stent Implantation to reach, reduce blood vessel elasticity retraction and more moulding, keep the unobstructed object of tube chamber blood flow, both comprised peripheral arterial support, also comprise coronary stent.
In the present invention, described restenosis refers in the time that damage occurs local vascular, the universality biologically that causes vessel lumen restenosis of having done.Here mainly refer to the vascular restenosis that iatrogenic injury causes, damage process is mainly made up of Arterial Remodeling and endotheliosis.
The present invention has following advantage and effect with respect to prior art:
(1) the present invention has found the new function of SHPS1 gene, and SHPS1 can suppress the effect of angiostenosis after damage.
(2) based on SHPS1 suppressing the function of angiostenosis after damage, be the drug provision basis of development angiostenosis after damage, can be used for preparation prevention, alleviate and/or treatment blood vessel injury after medicine in narrow again.
(3) SHPS1 can be used for the arterial bracket of preparation prevention, alleviation and/or treatment angiostenosis after damage.
Brief description of the drawings
Fig. 1 is WT and the SHPS1-KO mice HE of postoperative 28 days dyeing and Intimal area result statistics block diagram; Wherein, A:HE colored graph, B: Intimal area statistics block diagram (*: p < 0.05 vs WT VI group).
Fig. 2 is immunofluorescence dyeing and the result statistics block diagram of WT and the SHPS1-KO mice horizontal mark PCNA of cells of vascular wall propagation, CyclinD1 expression in postoperative 28 days; Wherein, A: immunofluorescence dyeing, B: result statistics block diagram (*: p < 0.05 vs WT VI group).
Fig. 3 is immunofluorescence dyeing and the result statistics block diagram of postoperative 28 days smooth muscle cell Phenotypic change mark SMA of WT and SHPS1-KO mice, SM22 alpha expression; Wherein, A: immunofluorescence dyeing, B: block diagram (*: p < 0.05 vs WT VI group).
Detailed description of the invention
Below in conjunction with specific embodiments and the drawings, the present invention is done to further detailed description.Should be understood that the following examples are only not used in and limit the scope of the invention for the present invention is described.
Animal for research and raising
Laboratory animal: select age in 8-10 week, body weight 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 the SPF of angiocardiopathy institute of Wuhan University level Experimental Animal Center.The large mouse feed of SPF level is purchased from Fukang bio tech ltd of China, Beijing, raising condition: 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 blood vessel damage model (VI) obtains
1. laboratory animal grouping: use 8-10 age in week, the WT of body weight 24-27g and SHPS1-KO mice, be divided into 2 groups: WT blood vessel injury group, SHPS1-KO blood vessel injury group, every group of each 20 mices.Within latter 28 days, put to death mice in operation respectively, get damage segmental vessels and analyze.
2. mice blood vessel damage model operating process:
1) under dynamic mode, accurately take Mouse Weight (g) with electronic balance, with accurately configuration 3% pentobarbital sodium solution of distilled water, shake is fully dissolved it gently, adopt 80mg/kg body weight dosage, calculate after required pentobarbital sodium liquor capacity and accurately extract respective volume solution with 1mL syringe, row intraperitoneal injection of anesthesia mice, after mice is fully anaesthetized down (about 3min), 8% sodium sulfide cervical region depilation.
2) separate in neck and external carotid artery.
3) prick external carotid artery at internal carotid artery and external carotid artery crotch with 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) osculum of Transverse Shear above ligation of external carotid artery line.Insert the seal wire (No. C-SF-15-15, Cook, Bloomington, Indiana) of 0.015 inch of diameter through this blood vessel otch, rotation seal wire advance and retreat 5-6 time.
5) at otch proximal part ligation external carotid artery, unclamp in neck and common carotid artery is put the vascular clamp staying, cut off the end of a thread, cleaning visual area, sews up cervical incision.
Embodiment 2 blood vessel injury model (VI) mice inner membrances are newborn to be measured
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 that the 1.5mL EP pipe of 1mL 4% paraformaldehyde is housed is fixing.
2. pathology detect
2.1 prepare paraffin specimen section
Prepare paraffin specimen section by laboratory specialty pathology staff, main operation sequence comprises: in 4% paraformaldehyde overnight fixing after, blood vessel is carefully wrapped with filter paper, put into the flushing → dehydration → transparent → waxdip → embedding → section of embedding frame → flowing water (3 μ m) → stand sheet → dry or toast for subsequent use afterwards.
2.2 hematoxylin-eosins (HE) dyeing
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 mixs homogeneously with 297mL 70% 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.
Taking elastic fibers in blood vessel and outer elastic fibers as boundary, interior elastic plate, taking interior as tunica intima, is tunica adventitia beyond outer elastic plate, is tunica media between inside and outside elastic plate.Enclose respectively each vessel lumen area with Image-Pro Plus 6.0 softwares.
The calculating of Intimal area size is as follows with reference to formula:
New intima area=interior elastic plate area-tube chamber area;
Media area=outer elastic plate area-Nei elastic plate area.
The result of tunica intima new life after mice HE dyeing is as Fig. 1.Normal blood vessel wall structural integrity, marshalling, tunica intima is monolayer endothelial cell, structural integrity, middle film smooth muscle cell marshalling.Dyeed and observed by HE, blood vessel injury group (VI group) blood vessel wall structure is imperfect, vascular endothelial cell disappearance, and new intima hypertrophy is obvious, and with a large amount of cell infiltration; 28 days after surgery new intima areas of SHPS1-KO group obviously will increase than WT mice.Equally, the ratio of Intimal area/media area will be higher than WT group in the postoperative SHPS1-KO group of VI.The disappearance of this explanation SHPS1 gene can promote the inner membrance new life who causes after blood vessel injury.
The detection of embodiment 3 cells of vascular wall propagation levels
Immunofluorescence dyeing detects the expression of proliferating cell nuclear antigen (Proliferating Cell Nuclear Antigen, PCNA), cyclin (Cyclin D1).Required primary antibodie information: PCNA(#2586; 1:100; Mouse; Cell Signaling Technology), cyclin D1(#2978; 1:25; Rabbit; Cell Signaling Technology); Required two anti-information: Alexa Fluor 568-conjugated goat anti-rabbit IgG(A11011; Invitrogen, Carlsbad, CA), Alexa Fluor 568-conjugated goat anti-mouse IgG(A11004; Invitrogen, Carlsbad, 150 d, CA).
Key step is:
1) roasting sheet: more than paraffin section is placed in to 55 DEG C of baking box 30min.
2) dewaxing: 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 repairing box, necessary enough whole sections of submergence of amount of repair liquid, put into by repairing box the pressure cooker that adds 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 repaired box, cover pot cover, buckle pressure valve, continue to be heated to jet, start after timing 5min, pressure cooker deenergization, go valve to uncap, take out and repair box, room temperature is taken 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) sealing, 37 DEG C of sealing 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, and PBS washes 10min × 3 time.
8) drip two and resist, in wet box, hatch 60min for 37 DEG C, discard two and resist, PBS embathes 5min × 3 time.
9) SlowFade Gold antifade reagent with DAPI(S36939, Invitrogen) mounting.
10) fluorescence Microscopic observation, takes pictures.Preserve 4 DEG C of preservations in dark wet box if need.
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 is observed smooth muscle cell proliferation mark PCNA, the expression of CyclinD1 after WT and SHPS1-KO mice blood vessel injury changes, and the results are shown in Figure 2.PCNA, CyclinD1 have expression in vascular tissue, the positive cell number of 28 days after surgery PCNA of SHPS1-KO mice and the fluorescence intensity of CyclinD1 all will increase in WT mice on the same group, show that SHPS1 gene knockout can promote the expression of PCNA, CyclinD1, can promote propagation and the tunica intima new life of smooth muscle cell.
The detection of embodiment 4 smooth muscle cell phenotypes
Immunofluorescence dyeing detects smooth muscle cell differentiation mark: the expression of smooth muscle actin (Smooth Muscle Actin, SMA), smooth muscle 22 α (smooth muscle 22 alpha, SM22 α).Required primary antibodie information: SMA(ab5694; 1:100; Rabbit; Abcam) and SM22 α (ab14106; 1:100; Rabbit; Abcam); Required two anti-information: Alexa Fluor 488-conjugated goat anti-rabbit IgG(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 state, 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, thereby causes neointimal hyperplasia.Immunofluorescence is observed SMA, the SM22 α expression after WT and SHPS1-KO mice blood vessel injury and is changed, and the results are shown in Figure 3.SMA, SM22 α have expression in vascular tissue, the fluorescence intensity of SHPS1-KO mice 28 days after surgery SMA, SM22 α all will be lower than WT mice on the same group, show that SHPS1 gene knockout can suppress the expression of SMA, SM22 α, can promote smooth muscle cell by shrinkage type the Phenotypic change to synthesis type, thereby promote neointimal hyperplasia.
Show with above-described embodiment result, all there is angiostenosis after damage in wild-type mice and SHPS1-KO mice under the induction of blood vessel injury model (VI).Inner membrance new life, cell proliferation level and the smooth muscle cell phenotype conversion of SHPS1 knock out mice are all remarkable than wild-type mice.These results show, propagation, Phenotypic Change and angiogenesis inner membrance that SHPS1 can improve the smooth muscle cell of blood vessel injury induction form.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (4)
- The application of 1.SHPS1 in the medicine of preparation prevention, alleviation and/or treatment angiostenosis after damage.
- 2. a medicine for prevention, alleviation and/or treatment angiostenosis after damage, is characterized in that: comprise SHPS1.
- 3. an arterial bracket for prevention, alleviation and/or treatment angiostenosis after damage, is characterized in that: be coated with SHPS1.
- 4. application according to claim 1, medicine claimed in claim 2 or arterial bracket claimed in claim 3, is characterized in that: described blood vessel injury is the blood vessel injury that atherosclerosis, atherosclerosis interventional therapy, transplanting arteriopathy or pulmonary hypertension cause.
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| NL2030464A (en) | 2021-01-11 | 2022-07-25 | Guangxi Int Zhuang Medicine Hospital | Aralia armata (wall.) seem-derived total saponin and use thereof in preparation of drug for treating post-vascular injury restenosis |
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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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| 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 |
Non-Patent Citations (3)
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| COMU S ET AL.: "The murine P84 neural adhesion molecule is SHPS-1, a member of the phosphatase-binding protein family", 《J NEUROSCI》, 31 December 1997 (1997-12-31) * |
| NEZNANOV N ET AL: "Dominant Negative Form of Signal-regulatory Protein-α(SIRPα/SHPS-1) Inhibits Tumor Necrosis Factor-mediated Apoptosis by Activation of NF-κB", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》, 31 December 2003 (2003-12-31) * |
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| NL2030464A (en) | 2021-01-11 | 2022-07-25 | Guangxi Int Zhuang Medicine Hospital | Aralia armata (wall.) seem-derived total saponin and use thereof in preparation of drug for treating post-vascular injury restenosis |
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