CN104606684B - The target of the medicine that CEACAM1 is damaged as screening treatment myocardial acute ischemia and its application - Google Patents
The target of the medicine that CEACAM1 is damaged as screening treatment myocardial acute ischemia and its application Download PDFInfo
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- CN104606684B CN104606684B CN201510016429.4A CN201510016429A CN104606684B CN 104606684 B CN104606684 B CN 104606684B CN 201510016429 A CN201510016429 A CN 201510016429A CN 104606684 B CN104606684 B CN 104606684B
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Abstract
The invention belongs to the function and application field of gene, target and its application of more particularly to a kind of carcinomebryonic antigen correlation adhesion molecule 1 (abbreviation CEACAM1) as the medicine of screening treatment myocardial acute ischemia damage.The present invention provides a kind of target for screening the medicine that treatment myocardial acute ischemia is damaged, and the target is CEACAM1.Application present invention also offers CEACAM1 as drug targets in the medicine that screening treatment myocardial acute ischemia is damaged.Invention further provides the medicine that the treatment myocardial acute ischemia with CEACAM1 as target is damaged.The medicine is the siRNA of CEACAM1.The present invention experiments prove that, CEACAM1 genes have cardiac muscle cell apoptosis when promoting myocardial acute ischemia/anoxic, aggravate myocardial damage and deteriorate the effect of heart function, and there is the effect for mitigating the cardiac muscle cell apoptosis that anoxic causes using siRNA silences CEACAM1 expression, the novel targets and new strategy damaged for research treatment myocardial acute ischemia provide theoretical foundation and Clinical Basis.
Description
Technical field
The invention belongs to the function and application field of gene, more particularly to a kind of carcinomebryonic antigen correlation adhesion molecule -1
(carcinoembryonic antigen-related cellular adhesion molecule 1, abbreviation CEACAM1) makees
Target and its application for the medicine of screening treatment myocardial acute ischemia damage.
Background technology
Acute myocardial infarction AMI is that on the basis of coronary artery pathological changes, coronary artery blood supply occurs and drastically reduces or interrupts,
Make the part cardiac muscle acute necrosis caused by corresponding myocardium seriously and enduringly ischemic.According to recent statistics numerical monitor, China is every
Up to 2,500,000 people, heart infarction has been in China's cause of death second to the patient of year death because of acute myocardial infarction AMI at present.Although and
When, effective coronary-artery revascularization, such as application of PCI and bypass operation of coronary artery can save
Dying cardiac muscle, prevents the expansion of infarct size, but the irreversible loss of cardiac muscle cell caused by myocardial acute ischemia, and thus trigger
The reconstruct of left ventricle pathologic be still first cause that current heart failure occurs.
Apoptosis is a kind of important form of the irreversible loss of cell caused by myocardial acute ischemia, is influence heart pathologic weight
Key factor [Abbate, A., et al., Clinical relevance of apoptosis in the early and of structure
late post-infarction left ventricular remodeling.Ital Heart J,2002.3(12):
p.699-705.Abbate,A.,G.G.Biondi-Zoccai,and A.Baldi,Pathophysiologic role of
myocardial apoptosis in post-infarction left ventricular remodeling.J Cell
Physiol,2002.193(2):P.145-53.], the occurrence and development of heart infarction later stage heart failure and are largely determined
[Gill,C.,R.Mestril,and A.Samali,Losing heart:the role of apoptosis in heart
disease--a novel therapeutic targetFASEB J,2002.16(2):p.135-46.Abbate,A.,et
al.,Acute myocardial infarction and heart failure:role of apoptosis.Int J
Biochem Cell Biol,2006.38(11):p.1834-40.].However, compared to other pathological changes, Apoptosis exists
Research in angiocardiopathy is started late, past research display anoxic, oxidative stress, mechanical stress, cell factor and god
Cardiac muscle cell apoptosis [Hori, M.and that mediation myocardial acute ischemia causes may be participated in through factors such as endocrine factors
K.Nishida,Oxidative stress and left ventricular remodelling after myocardial
infarction.Cardiovasc Res,2009.81(3):p.457-64.Webster,K.A.,Mitochondrial
membrane permeabilization and cell death during myocardial infarction:roles
of calcium and reactive oxygen species.Future Cardiol,2012.8(6):p.863-
84.Martinez Rosas,M.,[Cardiac remodeling and inflammation].Arch Cardiol Mex,
2006.76Suppl 4:P.S58-66.], and its specific molecular mechanism is still not very clear.Explore the related regulation and control machine of apoptosis
Make significant for finding the action target spot and treatment method of mitigation myocardial acute ischemia damage.
CEACAM1, also referred to as biliary glycoprotein (biliar glyeoprotein, BGP), CD66a and C-CAM, are one
Cell surface trans-membrane glycoprotein is planted, is also the member in carcinomebryonic antigen family, contactin adhesion molecule
[Laurie,N.A.,et al.,Carcinoembryonic antigen-related cell adhesion molecule
1a-4L suppression of rat hepatocellular carcinomas.Cancer Res,2005.65(23):
In p.11010-7.], being distributed widely in epithelial cell, vascular endothelial cell, lymphocyte and myelocyte [Gray-Owen,
S.D.and R.S.Blumberg,CEACAM1:contact-dependent control of immunity.Nat Rev
Immunol,2006.6(6):p.433-46.].Additionally, CEACAM1 can also be present in blood in the form of shla molecule following
[Markel, G., et al., Biological function of the soluble CEACAM1protein and in ring
implications in TAP2-deficient patients.Eur J Immunol,2004.34(8):p.2138-48.]。
Research finds that the UspA1 albumen on moraxelle catarrhalis can induce alveolar epithelial cells apoptosis by being combined with CEACAM1, from
And promote development [N'Guessan, P.D., et al., the The UspA1protein of COPD and pulmonary emphysema
of Moraxella catarrhalis induces CEACAM-1-dependent apoptosis in alveolar
epithelial cells.J Infect Dis,2007.195(11):p.1651-60.].The apoptosis-promoting effect of CEACAM1 is also
With formation [Nguyen, T., C.J.Chen, and J.E.Shively, the Phosphorylation of of the normal glandular tube of mammary gland
CEACAM1molecule by calmodulin kinase IID in a three-dimensional model of
mammary gland lumen formation.J Biol Chem,2014.289(5):] and Oral Lichen tongue p.2934-45.
Generation development [Liu, G.X., et al., The possible roles of OPN-regulated of tinea
CEACAM1expression in promoting the survival of activated T cells and the
apoptosis of oral keratinocytes in oral lichen planus patients.J Clin
Immunol,2011.31(5):P.827-39. it is] relevant.In addition, studies have reported that CEACAM1 is expressed on cardiac muscle cell, and can
Cardiovascular new life [Chen, W.J., et al., Gene the expression profiles of hypoxic precondition induction can be participated in
in hypoxic preconditioning using cDNA microarray analysis:altered expression
of an angiogenic factor,carcinoembryonic antigen-related cell adhesion
molecule 1.Shock,2005.24(2):p.124-31.].By literature search, at present independent of CEACAM1 genes in cardiac muscle
It is subjected to the content applied in the damage that the strike of severe ischemic anoxic causes first.
The content of the invention
It is an object of the invention to provide a kind of target for screening the medicine that treatment myocardial acute ischemia is damaged.
Present invention determine that the expression of CEACAM1 genes and myocardial acute ischemia damage between correlation, thus really
The target of the medicine that fixed described screening treatment myocardial acute ischemia is damaged is CEACAM1.
It is a further object of the present invention to provide the new opplication of CEACAM1.
New opplication of the present invention is the medicine that CEACAM1 is damaged as drug targets in screening treatment myocardial acute ischemia
Application in thing.
Present invention also offers the medicine that the treatment myocardial acute ischemia with CEACAM1 as target is damaged.
According to the further feature of medicine of the present invention, the medicine is the siRNA of CEACAM1.
The present invention is using the confirmation of the methods such as Western blotting and immunofluorescence, the CEACAM1 tables of cardiac muscle cell after heart infarction/anoxic
Up to substantially increase.Meanwhile, with CEACAM1 knock out mice as experimental subjects, set up by ligaturing ramus descendens anterior arteriae coronariae sinistrae
Murine myocardial infarction model.Result shows, compared with wild type C57 mouse, CEACAM1 knock out mice cardiac muscle cell apoptosis
Substantially mitigate, myocardial infarct size is significantly reduced, and remodeling ventricle and heart function are obviously improved, and the death rate is substantially reduced.Finally, utilize
The expression of siRNA interference cardiac muscle cells CEACAM1, after finding CEACAM1 expression silencings, the cardiac muscle cell apoptosis that anoxic causes are bright
It is aobvious to reduce.These results prompting CEACAM1 genes have cardiac muscle cell apoptosis when promoting myocardial acute ischemia/anoxic, aggravate the heart
The effect of injury of muscle and deterioration heart function, and have using siRNA silences CEACAM1 expression and mitigate the cardiac muscle cell that anoxic causes
The effect of apoptosis, the novel targets and new strategy damaged for research treatment myocardial acute ischemia provide theoretical foundation and clinical base
Plinth.
Brief description of the drawings
Figure 1A is that the method ligatured with coronary artery left anterior descending branch sets up C57 mouse heart infarction models, and the heart is detected with RT-PCR after 3 weeks
Column diagrams of the muscular tissue CEACAM1 in the expression of gene level.
Figure 1B is that the method ligatured with coronary artery left anterior descending branch sets up C57 mouse heart infarction models, and Western Blot are used after 3 weeks
Column diagrams of the detection cardiac muscular tissue CEACAM1 in the expression of protein level.
Fig. 1 C are to separate SD neonatal rat cardiomyocytes exposeds and carry out anoxic stimulation, are detected with Western Blot after 24 hours
Column diagrams of the cardiac muscle cell CEACAM1 in the expression of protein level.
Fig. 2 is 3 weeks use TUNEL decoration method detection myocardial infarctions edges after two groups of mouse heart infarctions of wild type and gene knockout type
The column diagram of area's Apoptosis situation.
Fig. 3 is 8 weeks figures of observation mouse survival rate after two groups of mouse heart infarctions of wild type and gene knockout type.
Electrocardiogram when Fig. 4 A are two groups of mouse ligation coronary artery left anterior descending branches of wild type and gene knockout type.
Fig. 4 B are to dye detection myocardial infarction with TTC within 24 hours after two groups of mouse of wild type and gene knockout type ligature coronary arterys
The column diagram of area.
Fig. 5 A are to dye detection myocardial fibrosis face with Masson in 8 weeks after two groups of mouse heart infarctions of wild type and gene knockout type
Long-pending column diagram.
Fig. 5 B are the comparing figures of the heart weight/weight ratio of 8 weeks after two groups of mouse heart infarctions of wild type and gene knockout type.
Fig. 6 is to use within 8 weeks after coronary artery left anterior descending branch is ligatured M types ultrasound false to wild-type mice and CEACAM1 knock-out mices
The column diagram that the heart function of operation group and operation group is estimated.
Fig. 7 is that observation anoxic is after 24 hours using the slow-virus infection cardiac muscle cell containing the siRNA for CEACAM1
The figure of cardiac muscle cell apoptosis situation.
Specific embodiment
1. experiment purpose
Explore effect and utilization siRNA silence CEACAM1 expression of the CEACAM1 genes in myocardial acute ischemia damage
Influence to cardiac muscle cell apoptosis after anoxic.
2. experimental animal and raising
Experimental animal：From wild-type mice that 8 week old, body weight about 20-25g, background are male C57BL/6 strains (WT,
There is provided by Zhongshan University's Experimental Animal Center), CEACAM1 knock out mice (CEACAM1-KO, it is big by Australian McGill
Learn Beauchemin professor friendship provide), SD rats suckling mouse (being provided by Nanfang Medical Univ's Experimental Animal Center).
Feeding environment：All experiment mices are raised at Hospital of Southern Medical University animal experimental center (SPF grades).
Mouse special feed is provided by Guangdong Province's Experimental Animal Center.
Rearing conditions：Between 22-24 DEG C, between 40-70%, it is 12 small that light and shade replaces lighting hours to humidity to room temperature
When, free water is ingested.
3. experimental technique
1) experiment in vivo packet and the foundation of heart infarction model：Male C57BL/6 backgrounds wild-type mice and CEACAM1 genes
Knock-out mice, two kinds of mouse are randomly divided into operation group and sham-operation group.
The method ligatured using LADCA sets up mouse heart infarction model, and what model was successfully established is masked as：
Visible left anterior descending branch feed region cardiac muscle is changed into pale and ECG ST section and raises under direct-view.Sham-operation group is opened chest but is not ligatured.
Experiment in vitro is grouped：Separate neonatal rat cardiomyocytes exposed, by whether give anoxic stimulate be divided into normal oxygen group and anoxic
Group.With the slow virus of the siRNA containing CEACAM1 or the empty virus of control (by Shanghai JiKai Gene Chemical Technology Co., Ltd
There is provided) infected rats neonatal rat myocardial cell, vector virus group and empty virus group are designated as, and give normal oxygen and anoxic stimulation.
2) observation index
3 weeks methods with RT-PCR and Western Blot of C57 mouse Post operation detect the table of cardiac muscular tissue CEACAM1
Reach.24 hours methods with Western Blot detect the expression of CEACAM1 after neonatal rat cardiomyocytes exposed anoxic.
C57 mouse and CEACAM1 knock out mice Post operation dye detection myocardial infarction area, 3 weeks in 24 hours with TTC
Detection infarct border area Apoptosis situation is dyeed with TUNEL afterwards, detection myocardial fibrosis level is dyeed with Masson after 8 weeks,
Measurement heart weight/weight ratio, uses echocardiography cardiac function and structure, assesses mouse survival situation.
The empty virus group of detection and vector virus group Apoptosis situation are dyeed with TUNEL within 24 hours after Myocytes Anoxia.
4. experimental result
1) cardiac muscle cell CEACAM1 expressions increase after ischemic/anoxic
The method ligatured with coronary artery left anterior descending branch sets up C57 mouse heart infarction models, and RT-PCR and Western is used after 3 weeks
The method of Blot detects expression (Figure 1A and Figure 1B) of the cardiac muscular tissue CEACAM1 in gene and protein level respectively.In addition, separating
SD neonatal rat cardiomyocytes exposeds simultaneously carry out anoxic stimulation, and cardiac muscle cell is detected with the method for Western Blot after 24 hours
Expression (Fig. 1 C) of the CEACAM1 in protein level.Result shows, cardiac muscle cell after ischemic/anoxic stimulates CEACAM1 in gene
Expression with protein level substantially increases (* P<0.01).(n=4)
2) CEACAM1 gene knockouts improve cardiac muscle cell apoptosis situation after heart infarction
The method ligatured with coronary artery left anterior descending branch sets up mouse heart infarction model, and mouse core is detected with TUNEL decoration methods after 3 weeks
Flesh infarct border area Apoptosis situation (stained positive represents apoptotic cell), as shown in Fig. 2 wild-type mice heart infarction group and base
It is significantly increased (* P ＜ 0.01) because knock-out mice heart infarction group cardiac muscle cell apoptosis ratio contrasts respective sham-operation group, and gene
Knock-out mice heart infarction group cardiac muscle cell apoptosis ratio reduces (#P ＜ 0.05) compared with wild-type mice heart infarction group.Illustrate CEACAM1 bases
Can substantially mitigate heart infarction marginal zone Apoptosis situation because knocking out.Wherein, every mouse counts cardiac infarction marginal zone at least
5000 cells.(n=4)
3) the CEACAM1 gene knockouts reduction mouse core stalk death rate
The method ligatured with coronary artery left anterior descending branch sets up mouse heart infarction model, and the survival rate of mouse is observed after 8 weeks.Result is such as
Shown in Fig. 3, the survival rate of knock out mice (n=30) contrasts wild-type mice (n=36) and significantly improves (Log rank:
Chi-square 4.438,P<0.05), illustrate that CEACAM1 gene knockouts can substantially reduce heart infarction mouse death rate.
4) CEACAM1 gene knockouts reduce myocardial infarction area
Electrocardiogram when wild-type mice and knock out mice ligation coronary artery left anterior descending branch is as shown in Figure 4 A：Two groups of mouse
ST sections is raised level unanimously, shows that left anterior descending branch ligation degree is consistent, i.e., degree of ischemia is identical.Two groups of mouse ligation coronary arterys 24 are small
When after myocardial infarction area compare as shown in Figure 4 B：Knock out mice myocardial infarct size reduces (P compared with wild-type mice<
0.01).Being knocked out with reference to Fig. 4 A explanations CEACAM1 can reduce the myocardial infarction area that same degree bloodstream blocking causes.(n=
4)
5) CEACAM1 gene knockouts mitigate the remodeling ventricle after heart infarction
The myocardial fibrosis area of 8 weeks and heart weight/weight ratio compare after wild-type mice and knock out mice heart infarction.Knot
As shown in Fig. 5 A, Fig. 5 B, knock out mice myocardial fibrosis area and heart weight/weight ratio reduce (P to fruit compared with wild-type mice
<0.05), illustrating that CEACAM1 is knocked out can suppress the remodeling ventricle after heart infarction.(n=4)
6) CEACAM1 gene knockouts improve cardiac function after heart infarction
M types ultrasound is used within 8 weeks after the ligation of coronary artery left anterior descending branch to wild-type mice and CEACAM1 knock-out mice sham-operation groups
With the assessment of the heart function of operation group.Result as shown in fig. 6, compared with wild-type mice heart infarction group, knock out mice heart infarction
The left LVSF of group substantially increases (#P ＜ 0.05), illustrates that CEACAM1 knocks out the heart function that can improve heart infarction mouse.(n
=4)
7) siRNA of CEACAM1 genes mitigates the cardiac muscle cell apoptosis that anoxic causes
Using the slow-virus infection cardiac muscle cell containing the siRNA for CEACAM1, observation anoxic is myocardium thin after 24 hours
The apoptosis situation of born of the same parents.Result is as shown in fig. 7, cardiac muscle cell apoptosis substantially increase (* P under anoxia condition<0.01), RNAi silences
After the expression of CEACAM1, the apoptosis of cardiac muscle cell reduces (#P<0.05), illustrating the expression of siRNA silences CEACAM1 can subtract
Negligent muscle cell apoptosis.(n=3)
Above test result indicate that, after ischemic/anoxic cardiac muscle cell CEACAM1 expressions increase.CEACAM1 can pass through
Promote cardiac muscle cell apoptosis during myocardial acute ischemia/anoxic, aggravate myocardial damage and deteriorate heart function, and utilize siRNA to sink
Silent CEACAM1 expression has the effect for mitigating the cardiac muscle cell apoptosis that anoxic causes.
Claims (2)
1. carcinomebryonic antigen correlation adhesion molecule -1 is the medicine of the inhibitor in preparation treatment myocardial acute ischemia damage of CEACAM1
In application.
2. application according to claim 1, it is characterised in that：The inhibitor of the CEACAM1 is the siRNA of CEACAM1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100261169A1 (en) * | 2007-01-29 | 2010-10-14 | Shira Wallach | Novel nucleotide and amino acid sequences, and methods of use thereof for diagnosis |
| CN102812359A (en) * | 2009-11-13 | 2012-12-05 | Bg医药公司 | Risk Factors And Prediction Of Myocardial Infarction |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100261169A1 (en) * | 2007-01-29 | 2010-10-14 | Shira Wallach | Novel nucleotide and amino acid sequences, and methods of use thereof for diagnosis |
| CN102812359A (en) * | 2009-11-13 | 2012-12-05 | Bg医药公司 | Risk Factors And Prediction Of Myocardial Infarction |
Non-Patent Citations (1)
| Title |
|---|
| CEACAM1 inhibits Toll-like receptor 2–triggered antibacterial responses of human pulmonary epithelial cells;Hortense Slevogt et al;《NATURE IMMUNOLOGY》;20081005;第9卷;标题，第1277页左栏第20-24行 * |
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