CN108660203A - Purposes of the CXCR2 genes in cardiac-related diseases - Google Patents
Purposes of the CXCR2 genes in cardiac-related diseases Download PDFInfo
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- CN108660203A CN108660203A CN201810481747.1A CN201810481747A CN108660203A CN 108660203 A CN108660203 A CN 108660203A CN 201810481747 A CN201810481747 A CN 201810481747A CN 108660203 A CN108660203 A CN 108660203A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
Abstract
The invention discloses purposes of the CXCR2 genes in the diagnostic kit or medicine composition for preparing arrhythmia cordis relevant disease.Inventor has found, after CXCR2 gene knockouts, improves Atrial fibrosis；Further, after CXCR2 gene knockouts, the mRNA level in-site of Atrial fibrosis marker also significantly improves, and has protective effect to auricular fibrillation, it was demonstrated that CXCR2 can be applied to the clinical treatment of cardiac-related diseases as pharmaceutical composition target.
Description
Technical field
The invention belongs to biomedicine field, be related to CXCR2 genes in the diagnostic kit for preparing cardiac-related diseases or
Purposes in medicine composition.
Background technology
Arrhythmia cordis is one of angiocardiopathy of most serious, and harm is that original heart disease can not only be aggravated, also
It can cause patient's die by visitation of God.And auricular fibrillation (abbreviation atrial fibrillation) is clinically most common perpetual arrhythmia, morbidity
Rate and the death rate increase year by year, and there are about 10,000,000 patients in China at present.Atrial fibrillation can lead to headstroke and heart failure, make case fatality rate
And disability rate obviously increases, it has also become seriously threatens one of angiocardiopathy of human health.Currently, point of atrial fibrillation occurrence and development
Handset system and control strategy have become the hot spot and difficult point in cardiovascular research field.
Research thinks that atrial fibrillation is number of mechanisms interaction as a result, main risk factor and the heart including arrhythmia cordis
In room exist make its maintain two broad aspect of matrix, and be related to neuroendocrine system activation, metabolic disorder, electricity reconstruct and it is more
Heart muscle structural remodeling caused by kind factor.Wherein, renin-angiotensin-aldosterone system (RAAS) activation is hypertension
The important link occurred with atrial fibrillation.The treatment means of atrial fibrillation mainly maintain sinus rhythm, i.e. antiarrhythmic drug group at present
Close object.But the treatment of current medical composition has larger limitation, such as arrhythmia cordis complication, treatment is resisted and bad knot
Office etc., limits its clinical application to a certain extent.
Therefore, finding a novel targets of the cardiac-related diseases such as prevention arrhythmia cordis becomes research hotspot.
Invention content
In order to solve the above-mentioned technical problem, inventor has carried out a large amount of experiment, it has unexpectedly been found that, CXCR2 knockouts can be shown
Writing improves mouse atrial fibrillation, Atrial fibrosis and the inflammatory cell infiltration of Angiotensin II induction, and then proves that CXCR2 is prevention
The novel targets of cardiac-related diseases, thereby completing the present invention.
An aspect of of the present present invention provides purposes of the CXCR2 genes in the diagnostic kit for preparing cardiac-related diseases, institute
It includes the steps that detection CXCR2 gene expression doses to state purposes.
In one embodiment of the invention, the step of detection CXCR2 gene expression doses be using RT-PCR,
What real-time quantitative PCR or high-energy sequencing approach were completed.
In one embodiment of the invention, the kit includes being capable of specific amplification CXCR2 genes
Primer pair.
In yet another embodiment of the present invention, the step of detection CXCR2 gene expression doses are using in situ
What hybrid method was completed.
In another specific embodiment of the present invention, the kit includes being capable of specific hybrid CXCR2 genes
Probe.
In yet another embodiment of the present invention, the step of detection CXCR2 gene expression doses are using immune
What the method for detection was completed.
In another specific embodiment of the present invention, the kit includes that can specifically bind CXCR2 albumen
Antibody.
In embodiments of the invention, the cardiac-related diseases are arrhythmia cordis.
In specific embodiments of the present invention, the arrhythmia cordis is auricular fibrillation, ventricular fibrillation or room property mistake aroused in interest
Speed.
Another aspect of the present invention provides use of the CXCR2 genes in the medicine composition for preparing cardiac-related diseases
On the way, the purposes includes the steps that detection CXCR2 gene expression doses.
In one embodiment of the invention, the step of detection CXCR2 gene expression doses be using RT-PCR,
What real-time quantitative PCR or high-energy sequencing approach were completed.
In yet another embodiment of the present invention, the step of detection CXCR2 gene expression doses are using in situ
What hybrid method was completed.
In yet another embodiment of the present invention, the step of detection CXCR2 gene expression doses are using immune
What the method for detection was completed.
In embodiments of the invention, the cardiac-related diseases are arrhythmia cordis.
In specific embodiments of the present invention, the arrhythmia cordis is auricular fibrillation, ventricular fibrillation or room property mistake aroused in interest
Speed.
In embodiments of the invention, the purposes further comprises accepting step：
(1) candidate pharmaceutical compounds processing expression or the system containing CXCR2 genes or CXCR2 albumen are utilized；With
(2) expression of CXCR2 genes or CXCR2 albumen or activity in the system are detected.
Another aspect of the present invention provides a kind of pharmaceutical composition for treating cardiac-related diseases, described pharmaceutical composition packet
Include the inhibitor of CXCR2, and/or with other medicine classes and pharmaceutically acceptable carrier of the inhibitor compatibility and/or auxiliary
Material.
In embodiments of the invention, the inhibitor is selected from：Nucleic acid inhibitor, protein inhibitor, proteolytic enzyme,
Protein binding molecule.
In specific embodiments of the present invention, the nucleic acid inhibitor is the siRNA of selectively targeted CXCR2 genes.
In specific embodiments of the present invention, the protein inhibitor is the antibody for specifically binding CXCR2 albumen.
Description of the drawings
Fig. 1 shows that CXCR2 knocks out the influence to mouse blood pressure.
Fig. 2 shows CXCR2 to knock out the influence to mouse Atria function.
Fig. 3 shows that CXCR2 knocks out the influence to mouse Atrial fibrosis.
Fig. 4 shows that CXCR2 knocks out the influence to mouse atrium Fibrosis Markers expression.
Fig. 5 shows that CXCR2 knocks out the influence to mouse atrium inflammatory cell infiltration.
Fig. 6 shows that CXCR2 knocks out the influence to mouse atrium inflammatory Cytokines Expression level.
Fig. 7 shows that CXCR2 is knocked out and induces Incidence of Atrial Fibrillation and the influence of atrial fibrillation duration to mouse.
Specific implementation mode
The present invention after extensive and in-depth study, inventor by the method for gene knockout, unexpectedly CXCR2 genes with
There are strong correlations between cardiac-related diseases.In order to make technical problem solved by the invention, technical solution and beneficial
Effect is more clearly understood, and with reference to embodiments, the present invention will be described in further detail.It should be appreciated that this place is retouched
The specific embodiment stated is only used to explain the present invention, is not intended to limit the present invention.
" protein ", " peptide " and " polypeptide " may be used interchangeably and broadly refer to have two or more amino acid sub-
The compound of base, amino acid analogue or peptidomimetic.The subunit can be connected by peptide bond.Protein or peptide must include at least
Two amino acid and amino acid maximum number is unlimited can include the sequence of protein or peptide.Terms used herein " ammonia
Base acid " refers to natural and/or non-natural or the amino acid of synthesis, including both glycine and D and L optical isomers, amino
Acid-like substance and peptidomimetic.
CXCR2 genes
Cohort study shows that Chemokines CC XCL10 and CXCL1 is horizontal significantly raised in hypertensive patient's blood.In addition,
Zooscopy has a large amount of inflammatory cells especially macrophage as a result, it was confirmed that in the model that Angiotensin II (Ang II) is perfused
Cell invades profit in cardiac muscular tissue.Therefore, chemokine mediated inflammatory cell invades the potential prevention and control that profit may be atrial fibrillation
Treat target spot.
Chemotactic factor (CF) mainly by with its receptor in conjunction with by play adjust inflammatory reaction effect.CXCL1 belong to chemotactic because
Sub- CXC families, mainly by with Gro-beta-T receptor 2 (CXCR2) in conjunction with by play a role.CXCR2 receptors are mainly expressed in
The cells such as macrophage, neutrophil leucocyte and monocyte, mast cell, T lymphocytes and vascular endothelial cell, with its ligand
Performance promotes antigen to offer, activates T and B cell, promotion inflammatory cell proliferation, migrating and going back to the nest after specific bond and inflammation is anti-
The effects that answering, new vessels promoted to generate.
Cardiac-related diseases
Cardiac-related diseases it is common include arrhythmia cordis, it is specific again aroused in interest including auricular fibrillation, ventricular fibrillation or room property
It overruns.
Detection method
The expression of the gene of the present invention is examined using a variety of detection techniques known to persons of ordinary skill in the art
It surveys, these technologies include but not limited to detect the technology of gene or protein expression level.
The expression of gene " detection " refer to CXCR2 genes in determining biological sample mRNA exist and its expression with
Just cardiac-related diseases are predicted and the amount by measuring mRNA can be achieved.Analysis method is but not limited to RT- for this purpose
PCR, competitive RT-PCR (competitive RT-PCR), real-time RT-PCR (real-time RT PCR), RNA enzyme protection are surveyed
Determine method (RNase protection assay, RPA), Northern blottings (Northern blotting), DNA microarray
Chip etc..
The expression of albumen " detection ", which refers to CXCR2 albumen in determining biological sample, to be existed and its horizontal to predict heart
Relevant disease, and can the amount of protein be determined by using the antibody combined with above-mentioned CXCR2 protein-specifics.For
This purpose analysis method is but not limited to western blot method (Western blotting), ELISA (survey by Enzyme-linked Immunosorbent Assay
Calmly), radioimmunoassay (radio immunoassay), radioimmunoassay diffusion method (radio
Immunodiffusion), Auchterlonie (Ouchterlony) immunodiffusion, rocket (Rocket) electrophoresis, tissue are exempted from
Epidemic disease decoration method, immunoprecipitation assay (immune precipitation assay), complement fixation assay (complete
Fixation assay), FACS, protein-chip (protein chip) etc..
In one embodiment of the invention, the detection method RT-PCR, real-time quantitative PCR or high-energy sequencing side
Method, the kit being prepared as a result, include capableing of the primer pair of specific amplification CXCR2 genes.
In yet another embodiment of the present invention, the detection method is hybridization in situ, the examination being thus prepared
Agent box includes the probe for capableing of specific hybrid CXCR2 genes.
In yet another embodiment of the present invention, the detection method is immune detection, the reagent being thus prepared
Box includes the antibody that can specifically bind CXCR2 albumen.
Prepare the purposes of medicine composition
As one embodiment of the present invention, include preparing medicine composition：To the candidate compound of acquisition
Object carries out further cell experiment and/or animal experiment, further to select and determine from candidate compound for preventing,
Alleviate or treat the useful substance of cardiac-related diseases.
As embodiments of the present invention, screening prevents or the system of the candidate compound for the treatment of cardiac-related diseases is unlimited
Further include cell system, subcellular system, solution system, organizational framework, organ systems or animal system etc. in cell system,
The system is not limited to above-mentioned form, if the system can detect test compound can reduce CXCR2 expression and/
Activity.
Medicine composition
Discovery based on inventor includes CXCR2 inhibitor the present invention provides one kind.As used herein, described
The inhibitor of CXCR2 includes but not limited to inhibitor, antagonist, retarding agent, blocking agent, nucleic acid inhibitor etc..
The inhibitor of the CXCR2 genes or CXCR2 albumen refers to any activity for reducing CXCR2 albumen, reduces
The stability of CXCR2 genes or CXCR2 albumen, lower CXCR2 albumen expression, reduce CXCR2 albumen effective acting times or
The substance of the transcription and translation of CXCR2 genes, these substances is inhibited to be used equally for the present invention, as useful for lowering CXCR2
Substance, so as to be used to prevent or treat osteosarcoma.For example, the inhibitor is：Nucleic acid inhibitor, protein inhibitor,
Antibody, ligand, proteolytic enzyme, protein binding molecule etc., as long as it can lower CXCR2 albumen on albumen or gene level
Or the expression of CXCR2 genes.
As a kind of selection mode of the present invention, the inhibitor of the CXCR2 is a species specificity and CXCR2 albumen knots
The antibody of conjunction.The specific antibody includes monoclonal antibody, polyclonal antibody；The present invention includes not only complete antibody point
Son also includes any segment or the modification of antibody, for example, chimeric antibody etc..As long as the segment can retain and CXCR2 albumen
Binding ability.Well known to a person skilled in the art and the present invention can when preparation for the antibody of protein level
The antibody is prepared to use any method.
As a kind of preferred embodiment of the present invention, the inhibitor of the CXCR2 is a kind of small interference of CXCR2 specificity
RNA molecule.As used herein, " siRNA " refers to a kind of short-movie section double stranded rna molecule, can be with homologous complementary
The mRNA of sequence is the target specific mRNA of degradation, this process is exactly RNA interference (RNA interference) processes.It is small
RNA interfering can be prepared into the form of double-strandednucleic acid, it contains there are one positive-sense strand and an antisense strand, this two chains are only hybridizing
Under conditions of form double-strand.One double-stranded RNA compound can be prepared by the positive-sense strand that is separated from each other and antisense strand.Therefore,
For example, complementary positive-sense strand and antisense strand are chemical synthesis, and can generate the double-strand of synthesis by anneal thereafter
RNA compounds.
As a kind of optional mode of the present invention, the inhibitor of the CXCR2 can also be a kind of " children purpura nephritis
(Small hairpin RNA, shRNA) " is the non-coding small RNA molecular that can form hairpin structure, children purpura nephritis energy
Enough by RNA interference channels come the expression of suppressor.As above-mentioned, shRNA can be expressed by double-stranded DNA template.Double-stranded DNA
Template is inserted into a carrier, such as plasmid or viral vectors, is then connected to a promoter carry out table in vitro or in vivo
It reaches.ShRNA under the action of DICER enzymes, can be cut into siRNA molecule in eukaryocyte, hence into RNAi approach.
" shRNA expression vectors " refers to plasmid of some this fields conventionally used for building shRNA structures, exist on the usual plasmid "
Every sequence " and positioned at " intervening sequence " both sides multiple cloning sites or for replace sequence, to people can by shRNA (or
Analog) corresponding DNA sequence dna be inserted by way of forward and reverse multiple cloning sites or replace thereon for replacing sequence,
RNA after DNA sequence dna transcription can form shRNA (Short Hairpin) structure." the shRNA expression vectors " is current
It can be bought and be obtained by commercially available approach completely, such as some viral vectors.
The present invention also provides a kind of pharmaceutical compositions, it contains the inhibitor and medicine of a effective amount of CXCR2
Acceptable carrier on.The pharmaceutical composition can be used for treating cardiac-related diseases.The inhibition of any CXCR2 above-mentioned
Agent is used equally for the preparation of pharmaceutical composition.The carrier include but is not limited to diluent, excipient, adhesive, disintegrant,
Sorbefacient, surfactant, Humectant, absorption carrier, lubricant, buffer, stabilizer, bacteriostatic agent, isotonic agent, chelating
Agent, pH controlling agents.
Pharmaceutical composition can be various oral or parenteral dosage forms.Using including filler, filler, adhesive,
Conventional thinner including wetting agent, disintegrant and surfactant or excipient pharmaceutical composition.Solid orally ingestible
Including tablet, pill, pulvis, granule, capsule etc..These solid pharmaceutical preparations can by by least one compound with it is a kind of or more
The mixing such as excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin are planted to prepare.In addition to simple excipient, it is possible to use
Lubricant such as magnesium stearate or talcum.In addition, liquid oral medicine includes suspension, solution, emulsion and syrup etc..In addition to usual
Outside water and atoleine as simple diluent, it may also include various excipient, such as wetting agent, sweetener, fragrance, anti-corrosion
Agent etc..The preparation of parenteral administration includes sterile water solution, nonaqueous solvents, suspending agent, emulsion, freeze-dried, suppository etc..The third two
Alcohol, polyethylene glycol, vegetable oil such as olive oil, injectable esters such as ethyl oleate etc. may be used as nonaqueous solvents and suspending agent.Suppository
Main component may include witepsol, polyethylene glycol, Tween61, cocoa butter, laurel tallow, glycerin gelatine etc..
Pharmaceutical composition can have any one preparation selected from the group below：Tablet, pill, powder, particle, capsule, suspension
Liquid, solution, emulsion, syrup, sterile water solution, non-aqueous solution, suspension, lotion, lyophilized preparation and suppository.
As used in the present invention, " effective quantity " refers to that its dosage is enough to treat disease, with the conjunction suitable for any therapeutic treatment
Interests/risk-ratio of reason.The effective dose level of pharmaceutical composition can be according to subject type, the serious journey of disease
Degree, the age of subject and gender, pharmaceutical composition activity, the sensibility to pharmaceutical composition, administration time, administration route,
Excretion rate, treatment time, with pharmaceutical composition associated in pharmaceutical composition and medical field other known facts determine.This
The pharmaceutical composition of invention can be used alone or is administered in combination with other therapeutic agents, and can with conventional therapeutic agent successively or
It is administered simultaneously.It can be used and apply pharmaceutical composition in one or more dosage forms.Consider all above-mentioned factors, can show most
Most important using pharmaceutical composition under big minimum of the effect without causing side effect, which can be by people in the art
Member is readily determined.
The pharmaceutical composition of the present invention can also be with the drug combination of other treatment cardiac-related diseases, other therapeuticization
Closing object can be administered simultaneously with main active constituent, or even is administered simultaneously in same composition.It can also be with individual medicine
Compositions or the dosage form different from main active constituent individually give other therapeutic compounds.
Preferably, the means that gene therapy can be used carry out.For example, can be directly by the inhibitor of CXCR2 by such as noting
It the methods of penetrates and to deliver medicine to subject；Alternatively, can will be carried by certain approach the inhibitor of CXCR2 ceneme (such as
Expression vector or virus etc. or siRNA or shRNA) it is delivered on target spot, and it is allowed to the CXCR2 inhibitor of expression activity, specifically
Situation need to be depending on the type of the inhibitor, these are well-known to those skilled in the art.
Embodiment
Following example is used herein to demonstration the preferred embodiments of the invention.Those skilled in the art, it will be appreciated that under
State the technology disclosed in example represent inventor discovery can be used for implement the present invention technology, therefore can be considered as implementation this
The preferred embodiment of invention.But those skilled in the art should be understood that specific reality disclosed herein according to this specification
Many modifications can be made by applying example, still can be obtained identical or similar as a result, rather than away from the spirit or scope of the present invention.
Unless otherwise defined, the term of all technologies as used herein and science, and the technology in fields of the present invention
Personnel institute is normally understood equivalent in meaning, and being disclosed reference and their materials of reference will all be incorporated.
Those skilled in the art will recognize or just will appreciate that by routine test many described here
Invention particular embodiment many equivalent technologies.These will equally be comprised in claims.
Embodiment 1
1. establishing Angiotensin II (Ang II) inducing mouse hypertension model
Take SPF grades of male C57BL/6 mouse of 6-8 week old, 75% alcohol disinfecting operative region after anesthesia, in its dorsal sc
The micro slow-releasing pump 3 weeks of embedment perfusion physiological saline or 2000ng/kg/min Ang II, continuously monitors blood pressure in the process,
With clear mouse hypertension model modeling success.
2. experiment packet
It is randomly divided into 4 groups (every group 8)：Control group, CXCR2 knockouts group, Ang II groups, CXCR2 knockout+Ang II groups.
Ang II groups, CXCR2 knockout+Ang II groups give Ang II perfusions, and control group and CXCR2 knockout groups give normal salt
Water.
3. establishing the detection platform of Ang II inducing mouse hypertension models
Ordinary circumstance is observed：Developmental state, action, fur, diet, weight etc..
Record mouse survival rate.
Mouse induces Incidence of Atrial Fibrillation and the detection of atrial fibrillation duration：It induces and detects small using biological multiple tracks electrophysiology instrument
Mouse Incidence of Atrial Fibrillation and duration.
Mouse atrium Function detection：Using high-resolution toy ultrasonic image system detectio mouse Atria function (left room
Internal diameter etc.).
Mouse atrium histopathology morphologic detection：, the paraffin embedding longitudinal sectional perpendicular to long axis of heart in the middle part of heart, with 5 μ
M thickness is sliced.Paraffin section de-waxing illustrates to water according to kit, carries out MassonTrichrome and immuning tissue respectively
Learn dyeing (Mac-2).Masson Trichrome dyeing：Collagenous fibres are in blue-green, and cardiac muscle fibre takes on a red color.Immuning tissue
Learn dyeing observation atrial tissue Mac-2 positive cells infiltration.
The Fibrosis Markers detection of mouse atrium：Using real time PCR methods detection mouse atrium Collagen I and
The mRNA expressions of Collagen III.
The inflammatory factor detection of mouse atrium：Using real time PCR methods detection mouse atrium IL-1 β, IL-6, TNF-α
And the mRNA expressions of MCP-1.
4. experimental result
The foundation of Ang II inducing mouse hypertension models：Each group mouse growth physically well develops, and fur is smooth, movable spirit
It is living, take the photograph water and ingest normally.3rd week blood pressure is the results show that compared with the control group, Ang II group mouse systolic pressures significantly increase, table
Bright model foundation success (Fig. 1).
CXCR2 knocks out the influence to Ang II induced hypertensions：Compared with Ang II groups, CXCR2 knockout+Ang II groups are small
Mouse systolic pressure is decreased obviously (Fig. 1).
Mouse core Function detection：3rd week echocardiogram is the results show that compared with the control group, Ang II group mouse left rooms
Internal diameter dramatically increases, and CXCR2 is obviously improved (Fig. 2) after knocking out.Illustrate that CXCR2 knockouts can significantly improve Ang II and induce high blood
Press the Atria function of mouse.
Mouse Atrial fibrosis detects：Ang II group mouse atrium fibrosis area dramatically increases, and CXCR2 is obtained after knocking out
It is obviously improved (Fig. 3).
The Fibrosis Markers detection of mouse atrium：Real-time quantitative PCR detection is shown, in Ang II group mouse atrium
The mRNA expressions of Collagen I and Collagen III obviously raise, and CXCR2 is significantly improved (figure after knocking out
4)。
The inflammatory cell detection of mouse atrium：The Mac-2 positive cells infiltration of Ang II group mouse atrium dramatically increases, CXCR2
It is obviously improved after knockout (Fig. 5).
The inflammatory factor detection of mouse atrium：Real-time quantitative PCR, which detects, to be shown, IL-1 β, IL- in Ang II group mouse atrium
6, the mRNA expressions of TNF-α and MCP-1 obviously raise, and CXCR2 is significantly improved (Fig. 6) after knocking out.
Mouse induces Incidence of Atrial Fibrillation and the detection of atrial fibrillation duration：Compared with the control group, Ang II groups mouse induces room
Incidence of quivering and atrial fibrillation duration obviously increase, and CXCR2 is remarkably decreased (Fig. 7) after knocking out.
In conclusion CXCR2 is knocked out has protective effect to the atrial fibrillation of Ang II inductions, it is anti-to show that CXCR2 genes can be used as
Control a kind of novel targets of the cardiac-related diseases such as atrial fibrillation.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
- Purposes of the 1.CXCR2 genes in the diagnostic kit for preparing cardiac-related diseases, which is characterized in that including detection The step of CXCR2 gene expression doses.
- 2. purposes according to claim 1, which is characterized in that the step of detection CXCR2 gene expression doses is profit It is completed with RT-PCR, real-time quantitative PCR or high-energy sequencing approach, it is preferable that the kit includes being capable of specificity expansion Increase the primer pair of CXCR2 genes.
- 3. purposes according to claim 1, which is characterized in that the step of detection CXCR2 gene expression doses is profit It is completed with hybridization in situ, it is preferable that the kit includes capableing of the probe of specific hybrid CXCR2 genes.
- 4. purposes according to claim 1, which is characterized in that the step of detection CXCR2 gene expression doses is profit It is completed with the method for immune detection, it is preferable that the kit includes that can specifically bind the antibody of CXCR2 albumen.
- 5. purposes according to claim 1, which is characterized in that the cardiac-related diseases are arrhythmia cordis, it is preferable that institute It is auricular fibrillation, ventricular fibrillation or Ventricular Tachycardia to state arrhythmia cordis.
- Purposes of the 6.CXCR2 genes in the medicine composition for preparing cardiac-related diseases, which is characterized in that including detection The step of CXCR2 gene expression doses, it is preferable that further comprise accepting step：(1) candidate pharmaceutical compounds processing expression or the system containing CXCR2 genes or CXCR2 albumen are utilized；With(2) expression of CXCR2 genes or CXCR2 albumen or activity in the system are detected.
- 7. a kind of pharmaceutical composition for treating cardiac-related diseases, which is characterized in that described pharmaceutical composition includes the suppression of CXCR2 Preparation, and/or other medicine classes and pharmaceutically acceptable carrier and/or auxiliary material with the inhibitor compatibility.
- 8. pharmaceutical composition according to claim 7, which is characterized in that the inhibitor is selected from：Nucleic acid inhibitor, albumen Inhibitor, proteolytic enzyme, protein binding molecule.
- 9. pharmaceutical composition according to claim 8, which is characterized in that the nucleic acid inhibitor is selectively targeted The siRNA of CXCR2 genes.
- 10. pharmaceutical composition according to claim 8, which is characterized in that the protein inhibitor is specific binding The antibody of CXCR2 albumen.
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