CN106596925A - Use of MMPs and TIMPs in screening of medicines for diagnosing or treating myocardial matrix reconstruction related diseases - Google Patents
Use of MMPs and TIMPs in screening of medicines for diagnosing or treating myocardial matrix reconstruction related diseases Download PDFInfo
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Abstract
The invention discloses a use of matrix metalloproteinases MMPs and a matrix metalloprotease tissue inhibitor TIMPs as markers in the screening of medicines for diagnosing or treating myocardial matrix reconstruction related diseases, and belongs to the field of medical science. Research results show that the content of MMP-3, MMP-9 and TIMP-1 in preoperative blood of a congenital heart disease group (CHD group) and rheumatic heart disease group (PHD group) is higher than that of a coronary heart disease group (COR group), and the MMP-9 content increases substantially; and the distribution of the MMP-3, MMP-9 and TIMP-1 in the CHD group and the PHD group is wider than the that in the COR group, and the mRNA expression of the MMP-1, MMP-9 and TIMP-1 in patients of the CHD group and the PHD group is higher than that of the COR group. Dynamic balance of the MMP-1, MMP-9 and TIMP-1 can be used as an important myocardial matrix reconstruction marker to adjust the activity of the MMPs and the TIMPs to hopefully become a new direction for heart disease therapy.
Description
Technical field
The present invention relates to matrix metalloproteinase MMPs and matrix metalloprotease tissue depressant TIMPs are used as mark
In the purposes that screening is used in the medicine for diagnosing or treating the disease related to myocardium matrix reconstruction, belong to medical domain.
Background technology
It is considered that cardiac remodeling is only because the endogenic change of cardiac muscle cell, it is now appreciated that extracellular Matrix
The quantity of middle collagen, the change of the Nomenclature Composition and Structure of Complexes have also assisted in cardiac remodeling, the i.e. process of matrix organization's reparative regeneration, and are
The major reason of remodeling ventricle, is also called myocardium matrix reconstruction.Remodeling ventricle is to determine cardiac's heart function and its prognosis
One of principal element, be the result of the synthesis of heart matrix components or katabolism loss of equilibrium.Heart matrix is maintaining heart knot
Structure and functional completeness aspect play an important role.Matrix organization's reparative regeneration causes myocardial fibrosis and progressive ventricle to expand
, ultimately result in heart failure.Can degrade the matrix metalloproteinase of all heart matrix components present in cardiac muscle
(matrixmetalloproteinase, MMPs), is the principal element of restructuring procedure cardiac substrate degradation.In the heart of exhaustion
In dirty, MMPs activity is raised and causes fiber collagen degradation, Extracellular Matrix Remodeling, causes left room progressive expansion, contractile function
It is gradually reduced, MMPs can be conditioned before transcription with post-transcriptional level, and the interaction between substrate can be passed through and led to
Cross endogenous physiological inhibitor i.e. matrix metalloprotease tissue depressant (tissue inhibitor of
Metalloproteinase, TIMps) adjusting.Therefore the interaction between MMPs, TIMPs and its regulatory factor determines the heart
The progress of myofibrosis process.Expression and the activity of cardiac muscle MMPs, TIMPs are adjusted, becomes control heart failure progress cardiac matrix
Tissue repair and regeneration critical treatment means.Therefore, the degraded and reconstruct of myocardium matrix are understood in depth for clear and definite matrix
The mechanism of metalloproteinases and its inhibitor in reconstruct is extremely important.
At present both at home and abroad for reconstructing blood vessel after myocardial damage in terms of research it is more deep, Hojo etc. obstructs to Acute myocardial
The expression of plug matrix metalloproteinase has carried out substantial amounts of research, has drawn many matrix metalloproteases during acute myocardial infarction
Enzyme is elevated.When Creemers etc. is studied heart failure, find some metal protease inhibitors for prevention heart failure
Progress, suppression heart failure have very great help.This is to SPinale etc. in early stage for cardiac muscle cell's protein molecular and gene expression side
The basic research in face plays and greatly inherit and develop.This just gives huge prompting for our present researchs.Many hearts
Myocardial damage, openheart surgery that dirty disease causes, inevitably make cardiac muscle receive certain damage, although myocardium in recent years
The research of protection achieves significant effect, but still relatively many for the various complication that myocardial damage causes, detection
Means are still relatively single, outmoded, numerous and diverse, it is necessary to comprehensive many-sided inspection and assay, and final specificity is not
It is satisfactory.Effect of the dynamic equilibrium for MMPs and TIMPs at present in the regeneration of cardiac muscle cell's tissue repair is maintained is also
Lack prospective research, the matrix reconstruction research to causing after myocardial damage both at home and abroad is scarcely out of swaddling-clothes, thus for
The research of new detection means, new detection protein molecular and bio-pharmaceutical is imperative.
The content of the invention
It is an object of the invention to pass through to study MMPs and TIMPs in congenital heart disease group (CHD groups), rheumatic heart
Expression in sick group (PHD groups), CHD group (COR groups), so as to the dynamic for disclosing MMP-1, MMP-9 and TIMP-1 is put down
Weighing apparatus can be as the important symbol of myocardium matrix reconstruction, so as to disclose matrix metalloproteinase MMPs and matrix metalloproteinase group
The purposes that inhibitor TIMps is used in the medicine for diagnosing or treating myocardium matrix reconstruction as heart failure mark in screening is knitted, is
The new research of disease treatment offer and orientation treatment.
For achieving the above object, the technical scheme taken of the present invention is：Matrix metalloproteinase MMPs and matrix metal egg
White enzyme tissue depressant TIMPs is used to diagnosing or treating the medicine of the disease related to myocardium matrix reconstruction as mark in screening
Purposes in thing.
Used as the further improvement to above-mentioned technical proposal, the MMPs is MMP-3 and MMP-9.
Used as the further improvement to above-mentioned technical proposal, the TIMPs is TIMP-1.
As the further improvement to above-mentioned technical proposal, the dynamic equilibrium of MMP-3, MMP-9 and TIMP-1 and myocardium base
Matter reconstruct is relevant.
Used as the further improvement to above-mentioned technical proposal, the disease related to myocardium matrix reconstruction is heart failure
Exhaust.
Used as the further improvement to above-mentioned technical proposal, the heart failure is the cardiac muscle caused by myocardium matrix reconstruction
Hypertrophy thickens initiation.
The beneficial effects of the present invention is：The present invention is by understanding myocardial damage and postoperative patients' cardiac muscle matrix reconstruction
Situation, sets about studying its tissue repair and palingenesis to myocardium matrix from the dynamic equilibrium of MMPs and TIMps, seeks impact
Myocardium matrix organization repairs and the biologic product that regenerates and medicine, is matrix reconstruction is caused after myocardial damage myocardial hypertrophy, increases
Effective biological detecting method, new detection albumen, biologic product and drug therapy that the heart failure that thickness etc. causes is provided
And prevention.
Description of the drawings
Fig. 1 is the content balance figure of MMP-3, MMP-9, TIMP-1 in three groups of patient's blood, and CHD groups compare with COR groups,#P
<0.05, HD group compares with COR groups, * P<0.05；
Fig. 2 is the SABC fractions distribution figure of MMP-3, MMP-9, TIMP-1, and wherein A is CHD groups, B is PHD groups, C is
COR groups, 1 is MMP-3,2 is MMP-9,3 is TIMP-1.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment and accompanying drawing pair
The present invention is described further.
1. materials and methods
1.1 clinical data
1.1.1 research object and packet is included in January, 2012～2014 year April the Red Cross Hospital, Guangzhou row and is followed in vitro
The patient of ring openheart surgery is research object.Preoperative II～III grade of cardiac functional grading (NYHA), the classification of anesthetist association of the U.S.
(ASA) it is II～III grade, preoperative without active rheumatism and History of Coronary Heart Disease, preoperative 1 month unused hormone and nonsteroidal anti-inflammatory town
Pain medicine etc..Preoperative hemoglobin, coagulation function, electrolyte, liver, kidney and PFT in normal range (NR), divide according to random district's groups
The method of group is different according to the openheart surgery for carrying out, and research object is divided into into 3 groups, and the 1st group is congenital heart disease group (CHD
Group)；2nd group is rheumatic heart disease group (RHD groups)；3rd group be CHD group (COR groups), and preoperative Jing echocardiograms examine
Look into, the size for having no chamber changes, if it is control group.
1.1.2 collection of specimens and measure
1.1.2.1 respectively at preoperative blood sampling, (1) is with the vacuum tube containing EDTA to selected patients for collection of specimens (ELISA)
Carry out 4～5ml of venous blood collection；(2) it is stored at room temperature 1h；(3) it is centrifuged, 3000r/min, 15min；(4) in vertical super-clean bench, use
Supernatant is moved to 1.5ml centrifuge tubes by pipettor, and lid is covered in time, and each centrifuge tube moves into l ml blood plasma, when drawing liquid
Be sure not too quickly, in order to avoid causing pollution, finally can suitably leave one layer of a small amount of supernatant, to ensure the purity of blood plasma, centrifuge tube and
Pipette tips are through high-temperature sterilization process；(5) it is labelled, -80 DEG C of preservations.
1.1.2.2 AMB in collection of specimens (Rt-PCR) excision right ventricle, takes about 3mm × 3mm cardiac muscular tissues immediately
It is placed in cryopreservation tube, it is labelled, it is placed in liquid nitrogen flash freezer, -80 DEG C of Refrigerator stores, sample Jing Ethics Committees audit and ratify.
1.1.2.3 collection of specimens (Immunohistochemical Method) is separately cored muscular tissue, about 2mm × 2mm2Gauze bag is reinstated with label one
Good, pin is fixed (fixed pin, it is to avoid damage sample).Fixed, normal temperature preservation is put in the wide-mouth bottle equipped with fixer.
(flesh of coring is anomalous muscle band of right ventricle, and Jing Ethics Committees audit and ratify).
1.2 experimental procedure
1.2.1ELISA
(1) the ELISA Plate number of perforations of the coated antibody needed for this detection is determined；(2) set respectively blank well, gauge orifice,
Testing sample hole.Blank well adds BSA (2%) 0.l ml, remaining hole to add standard liquid or testing sample 0.l ml respectively, gently mix
Even, ELISA Plate covers masking foil, 37 DEG C, 120min；(3) liquid in ELISA Plate is sucked after reacting with automatic washer, or is got rid of
Remove liquid in ELISA Plate, then against blotting paper clap it is several under, wash 2 times；(4) by ready biotin antibody working solution by per hole
0.l ml are sequentially added, 37 DEG C of reaction 60min；(5) PBS is washed 3 times, and every time immersion 1min or so, dries；(6) will be ready to
ABC (substrate) working solutions sequentially add by every hole 0.l ml, 37 DEG C reaction 30min；(7) PBS wash 5 times, every time immersion 1～
2min or so, dries；(8) sequentially add oneself by every hole 0.09ml and the TMB nitrite ions of 30min are balanced at 37 DEG C, 37 DEG C of lucifuges are anti-
Should, in course of reaction, Jing often to observe, when there is obvious gradient blueness in 3～4 holes before naked eyes visual standard product, 3～4 hole afterwards
When difference is not obvious, you can add TMB terminate liquid 0.l ml/ holes, (chromogenic reaction is most long not to exceed 30min)；(9) enzyme mark is used
Instrument determines OD values in 450nm；(10) corresponding concentration is found out on coordinate according to the light absorption value of sample.The N due to Sample Dilution
Times, its actual concentrations should × N.
1.2.2 ImmunohistochemistryMethods Methods determine collagen form and the distribution of myocardium matrix
(1) preparation of routine paraffin wax section is carried out to cutting cardiac muscular tissue；(2) carry out HE dyeing, successively with dimethylbenzene and
After alcohol-pickled, then dyeed with Harris haematoxylin liquid, Yihong successively, sealed with resinene after alcohol and xylene soak
Piece；(3) immunohistochemical staining is carried out with SP methods, after conventional dehydration, is rinsed 3 times with PBS, each 3min；It is right according to antibody preparation
Tissue antigen is repaired；Will section drop μ l of 3%H,2O2 50 of Jia, be incubated 10min under room temperature, PBS flushings 3 times, every time
10min；Antibody, polymerization reinforcing agent are sequentially added, PBS gets rid of after rinsing, and adds DAB or AEC nitrite ions, treat to show under microscope
When color is red or brown, after distilled water cleaning, the differentiation of 0.1% hydrochloride alcohol is redyed with haematoxylin, rinsed afterwards, PBS is rinsed
Indigo plant is returned, is developed the color with DAB, Jing after gradient alcohol dehydration is dried resinene mounting is used.
1.2.3rt-PCR technology detects to the mRNA of mmps in cardiac muscular tissue and timps, checks its mRNA expression feelings
Condition
(1) extraction of RNA is carried out using different sulphur hydracid guanidine-chloroform classical approach；(2) synthesis of cDNA；(3) Standard PCR is anti-
Should；(4) quantitative fluorescent PCR reaction, the preparation of reaction system in strict accordance with kit operation order.
1.3 calculate
Concentration with reference material (logarithmic coordinates) as abscissa, OD values are ordinate (common coordinate), in semilog coordinate
Calibration curve is drawn on paper, corresponding concentration is found by calibration curve according to the OD values of sample；Extension rate is multiplied by again；Or with mark
The concentration of quasi- thing calculates the linear regression equation of calibration curve with OD values, and the OD values of sample are substituted into into equation, calculates
Sample concentration, then be multiplied by extension rate, the as actual concentrations of sample, recycle SPSS17.0 to carry out data analysis, with many
The Dunnett methods inspection that individual experimental group and control group compare, takes α=0.05.
2. conclusion
The clinical data that tri- groups of 2.1CHD, RHD, COR compares
Through statistical analysis, the no significant difference (P of three groups of patients in terms of age, height, weight<
0.05).Exclude the impact of age, height, weight to result.The echocardiogram result of three groups of patients shows：Jing completely with
The variance analysis of machine design data, the Dunnett methods compared with a control group using multiple experimental groups, by α=0.05 level,
It is believed that the difference of RAD, LVEF and COR group mean of CHD groups is statistically significant, illustrate RAD, LVEF of CHD groups compared with COR groups
Have occurred that different degrees of change；And the mean difference of LAD, LVED, LVEF, IVS and COR group of RHD groups has statistics
Meaning, LAD, LVED, LVEF, IVS of bright RHD groups also there occurs different degrees of change (table 1) compared with COR groups.
The clinical material contrast of 1 three groups of patients of table
Note：LAD (left room end footpath), LEVD (left room end footpath), RAD (left room end footpath), IVS (IVSTd), LVEF (are penetrated
Blood fraction), LVPW (LVPW), * (CHD compares with COR),#(RHD compares with COR)
Assay of the 2.2ELISA methods to MMP-3, MMP-9, TIMP-1
By the ELISA method inspection to 3 groups of blood samples of patients matrix metalloproteinases, using completely randomized design data
Variance analysis, the Dunnett inspections that many experimental groups of Jing compare with a control group, by α=0.05 level, CHD groups and PHD groups
MMP-3, MMP-9, TIMP-1 content in blood (P statistically significant compared with COR group differences<0.05, Fig. 1), it is believed that CHD groups
It is high compared with COR groups with MMP-3, MMP-9, TIMP-1 content in PHD group blood, and the difference in experimental group between CHD groups and PHD groups
Not statistically significant (P>0.05), illustrate that CHD groups and PHD group heart matrix there occurs different degrees of change with reconstruct.
2.3 SABC assays
MMP-3, MMP-9, TIMP-1 are in diffusivity brown color or yellowish-brown coloured particles under microscope, and normal myocardial cells are then
In uniform, sparse light brown or pink coloured particles, through Image-proplus image analysis software quantitative analyses：A1, B1's
Positive expression result is high compared with C1, significant difference, statistically significant (P<0.05), under mirror visible A1, B1 brown color or Huang
Brown particles diffuse distribution compared with C1 group showed increaseds；The positive expression result of same A2, B2 is high compared with C2, and difference has statistics
Meaning (P<0.05), diffusivity brown color or yellowish-brown coloured particles more enrich compared with C2 under mirror；Although the expression of A3, B3 compared with A1, B1,
A2, B2 are low, but its positive expression result is still above C3, significant difference (P<0.05), brown color or yellowish-brown under mirror
Grain still relatively enriches, and C3 is then presented and diffused light brown and pink coloured particles (Fig. 2).
2.4PCR reaction result
It is presented high through the mRNA of Quantitative RT PCR detection, CHD groups and PHD patient MMP-3, MMP-9, TIMP-1
Expression, many experimental groups of Jing and a Dunnett method for comparing, Levene test of homogeneity, by α=0.10 level, 3 groups of moneys
The variance of material is neat.By α=0.05 level, it is believed that the mRNA expression of MMP-3, MMP-9 of CHD groups and PHD groups is higher than COR groups
(table 2).
Table 2
#(CHD groups compare with COR groups), * (PHD groups compare with COR groups)
3. Analysis of conclusion
In the present invention, we employ various methods and caused matrix reconstruction after myocardial damage are detected, from calmly
Property and it is quantitative two aspect inquired into myocardium substrate degradation and fracture MMP-3, MMP-9 albumen blood, tissue in expression, and
And the expression using round pcr to its mRNA has carried out quantitative detection, while to preventing and suppressing heart matrix from degrading
The detection that quantitative, qualitative and mRNA is expressed is carried out with the NMPI TIMP-1 of reconstruct, from comprehensive angle
Degree analyzes the change of the amount that MMP-1, MMP-9 and TIMP-1 cause in whole myocardium matrix change procedure and matter.It was found that sending out
The congenital heart disease group (CHD groups) of raw heart matrix reconstruction, MMP-3, MMP-9 of rheumatic heart disease group (PHD groups) and
The expression of TIMP-1 is all significantly higher than the CHD group (COR groups) that heart matrix reconstruction does not occur.This just illustrates, matrix metal egg
The dynamic equilibrium of white enzyme and its inhibitor may affect the degraded of heart matrix and the fracture of collagen.Form to maintaining cardiac muscle
Play the role of with the structure of collagen huge, how to grasp this key point, maintain this dynamic equilibrium, prevent myocardial damage
Afterwards caused cardiac remodeling, finds out the action target spot of gene expression, develops with resistance for this target spot or protein molecular
Only and suppress the medicine or albuminoid inhibitor of myocardial remodelling, the power and target of our further researchs will be become.
It is last to should be noted that above example only to illustrate technical scheme rather than protect to the present invention
The restriction of shield scope, although being explained in detail to the present invention with reference to preferred embodiment, one of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent, without deviating from the essence of technical solution of the present invention.
Claims (6)
1. matrix metalloproteinase MMPs and matrix metalloprotease tissue depressant TIMPs is used to examine as mark in screening
Purposes in medicine that is disconnected or treating the disease related to myocardium matrix reconstruction.
2. purposes as claimed in claim 1, it is characterised in that the MMPs is MMP-3 and MMP-9.
3. purposes as claimed in claim 1, it is characterised in that the TIMPs is TIMP-1.
4. purposes as claimed in claim 2 or claim 3, it is characterised in that the dynamic equilibrium of MMP-3, MMP-9 and TIMP-1 and cardiac muscle
Matrix reconstruction is relevant.
5. purposes as claimed in claim 1, it is characterised in that the disease related to myocardium matrix reconstruction is heart failure
Exhaust.
6. purposes as claimed in claim 5, it is characterised in that the heart failure is the cardiac muscle caused by myocardium matrix reconstruction
Hypertrophy thickens initiation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109470848A (en) * | 2018-12-28 | 2019-03-15 | 广州市红十字会医院（暨南大学医学院附属广州红十字会医院） | Detection kit and detection method for myocardial injury markers MMPs, TIMPs and cTnI |
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| CN101646784A (en) * | 2007-01-15 | 2010-02-10 | 公共健康研究中心 | Diagnostic marker and platform for drug design in myocardial infarction and heart failure |
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Application publication date: 20170426 |