CN104606684A - CEACAM1 as target for screening drugs for treating severe myocardial ischemia injury and application of CEACAM1 - Google Patents
CEACAM1 as target for screening drugs for treating severe myocardial ischemia injury and application of CEACAM1 Download PDFInfo
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- CN104606684A CN104606684A CN201510016429.4A CN201510016429A CN104606684A CN 104606684 A CN104606684 A CN 104606684A CN 201510016429 A CN201510016429 A CN 201510016429A CN 104606684 A CN104606684 A CN 104606684A
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Abstract
The invention belongs to the field of functions and applications of genes and particularly relates to a carcino-embryonic antigen related cellular adhesion molecule-1 (CEACAM1 for short) as a target for screening drugs for treating severe myocardial ischemia injury and an application of the carcino-embryonic antigen related cellular adhesion molecule-1. The invention provides a target for screening the drugs for treating the severe myocardial ischemia injury. The target is the CEACAM1. The invention further provides the application of the CEACAM1 as the drug target in screening the drugs for treating the severe myocardial ischemia injury. The invention further provides a drug treating the severe myocardial ischemia injury by taking the CEACAM1 as the target. The drug is siRNA (small interfering ribonucleic acid) of the CEACAM1. Experiments confirm that a CEACAM1 gene has effects of promoting myocardial cell apoptosis during severe myocardial ischemia/anoxia, aggravating myocardial injury and deteriorating a cardiac function, while CEACAM1 expression silencing by siRNA has effects of relieving the myocardial cell apoptosis caused by the anoxia, and a theoretical basis and a clinical foundation are provided for researching a new target and a new strategy of treating the severe myocardial ischemia injury.
Description
Technical field
The invention belongs to function and the application of gene, be correlated with adhesion molecule-1 (carcinoembryonic antigen-related cellular adhesion molecule 1 is called for short CEACAM1) as target and the application thereof of screening the medicine that treatment myocardial acute ischemia damages in particular to a kind of carcinoembryonic antigen.
Background technology
Acute myocardial infarction is on the basis of coronary artery pathological changes, coronary blood occurs for sharply reducing or interrupting, and makes the part cardiac muscle acute necrosis of corresponding cardiac muscle seriously and enduringly caused by ischemia.According to recent statistics numerical monitor, because of acute myocardial infarction, the patient of death reaches 2,500,000 people every year in China, and heart infarction has been in China's cause of death second at present.Although in time, effective coronary-artery revascularization, application as PCI and bypass operation of coronary artery can save dying cardiac muscle, prevent the expansion of infarct size, but the irreversible loss of the myocardial cell caused by myocardial acute ischemia, and the left ventricle pathologic caused thus reconstruct remains the 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, the key factor [Abbate affecting heart disease rational reconstruction, A., et al., Clinical relevance of apoptosis in early and latepost-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 myocardialapoptosis in post-infarction left ventricular remodeling.J Cell Physiol, 2002.193 (2): p.145-53.], and determine generation and the development [Gill of heart infarction later stage heart failure to a great extent, C., R.Mestril, and A.Samali, Losing heart:the role of apoptosis in heart disease--a novel therapeutictarget? FASEB J, 2002.16 (2): p.135-46.Abbate, A., et al., Acute myocardialinfarction and heart failure:role of apoptosis.Int J Biochem Cell Biol, 2006.38 (11): p.1834-40.].But, compare other pathological change, the research of apoptosis in cardiovascular disease is started late, the research display anoxia in past, oxidative stress, mechanical stress, the factor such as cytokine and neuroendocrine factor all may participate in the apoptosis of cardiac muscle [Hori that mediation myocardial acute ischemia causes, M.and K.Nishida, Oxidative stress and left ventricular remodelling after myocardial infarction.Cardiovasc Res, 2009.81 (3): p.457-64.Webster, K.A., Mitochondrial membranepermeabilization and cell death during myocardial infarction:roles of calcium andreactive 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 concrete molecular mechanism is still not fully aware of.Explore the apoptosis regulatory mechanism of being correlated with for find the action target spot that alleviates myocardial acute ischemia damage and Therapeutic Method significant.
CEACAM1, be also referred to as biliary glycoprotein (biliar glyeoprotein, BGP), CD66a and C-CAM, it is a kind of cell surface trans-membrane glycoprotein, member in Ye Shi carcinoembryonic antigen family, contactin adhesion molecule [Laurie, N.A., et al., Carcinoembryonic antigen-related celladhesion molecule 1a-4L suppression of rat hepatocellular carcinomas.Cancer Res, 2005.65 (23): p.11010-7.], be distributed widely in epithelial cell, vascular endothelial cell, [Gray-Owen in lymphocyte and myelocyte, S.D.and R.S.Blumberg, CEACAM1:contact-dependent controlof immunity.Nat Rev Immunol, 2006.6 (6): p.433-46.].In addition, CEACAM1 can also be present in [Markel in blood circulation with the form of shla molecule, G., et al., Biological function ofthe soluble CEACAM1protein and implications in TAP2-deficient patients.Eur JImmunol, 2004.34 (8): p.2138-48.].Research finds, UspA1 albumen on moraxelle catarrhalis can induce alveolar epithelial cells apoptosis by being combined with CEACAM1, thus promote chronic obstructive pulmonary disease and emophysematous development [N'Guessan, P.D., et al., The UspA1protein of Moraxella catarrhalisinduces CEACAM-1-dependent apoptosis in alveolar epithelial cells.J Infect Dis, 2007.195 (11): p.1651-60.].The apoptosis-promoting effect of CEACAM1 is the formation [Nguyen of normal glandular tube with mammary gland also, T., C.J.Chen, and J.E.Shively, Phosphorylation of CEACAM1molecule bycalmodulin kinase IID in a three-dimensional model of mammary gland lumenformation.J Biol Chem, 2014.289 (5): p.2934-45.] and oral lichen planus develop [Liu, G.X., et al., The possible roles of OPN-regulated CEACAM1expression in promotingthe survival of activated T cells and the apoptosis of oral keratinocytes in oral lichenplanus patients.J Clin Immunol, 2011.31 (5): p.827-39.] relevant.In addition, studies have reported that CEACAM1 expresses on myocardial cell, and the cardiovascular new life [Chen of hypoxic precondition induction may be participated in, W.J., et al., Gene expression profiles in hypoxic preconditioning using cDNAmicroarray analysis:altered expression of an angiogenic factor, carcinoembryonicantigen-related cell adhesion molecule 1.Shock, 2005.24 (2): p.124-31.].By literature search, haveing nothing to do at present in CEACAM1 gene suffers severe ischemic anoxia to hit the content applied in the damage caused at cardiac muscle first.
Summary of the invention
The object of the present invention is to provide a kind of target screening the medicine for the treatment of myocardial acute ischemia damage.
The present invention determine the expression of CEACAM1 gene and myocardial acute ischemia damage between mutual relation, thus determine that the target of the medicine of described screening treatment myocardial acute ischemia damage is CEACAM1.
Another object of the present invention is to provide the new opplication of CEACAM1.
New opplication of the present invention is that CEACAM1 is as the application of drug targets in the medicine of screening treatment myocardial acute ischemia damage.
Present invention also offers with CEACAM1 the medicine of the treatment myocardial acute ischemia damage being target.
According to the further feature of medicine of the present invention, described medicine is the siRNA of CEACAM1.
The present invention utilizes the method such as immunoblotting and immunofluorescence to confirm, after heart infarction/anoxia, the CEACAM1 of myocardial cell expresses and obviously increases.Meanwhile, with CEACAM1 knock out mice for experimental subject, set up murine myocardial infarction model by ligation ramus descendens anterior arteriae coronariae sinistrae.Result shows, compared with wild type C57 mice, CEACAM1 knock out mice apoptosis of cardiac muscle obviously alleviates, and myocardial infarct size obviously reduces, and remodeling ventricle and cardiac function obviously improve, and mortality rate obviously reduces.Finally, utilize siRNA to disturb the expression of myocardial cell CEACAM1, after finding CEACAM1 expression silencing, the apoptosis of cardiac muscle that anoxia causes obviously reduces.Apoptosis of cardiac muscle when these results prompting CEACAM1 gene has promotion myocardial acute ischemia/anoxia, increase the weight of the effect of myocardial damage and deterioration cardiac function, and utilizing the reticent CEACAM1 expression of siRNA to have the effect alleviating the apoptosis of cardiac muscle that anoxia causes, the novel targets damaged for research treatment myocardial acute ischemia and New Policy provide theoretical foundation and Clinical Basis.
Accompanying drawing explanation
Figure 1A is the method establishment C57 mice heart infarction model with the ligation of arteria coronaria left anterior descending branch, detects the bar diagram of cardiac muscular tissue CEACAM1 in the expression of gene level after 3 weeks with RT-PCR.
Figure 1B is the method establishment C57 mice heart infarction model with the ligation of arteria coronaria left anterior descending branch, detects the bar diagram of cardiac muscular tissue CEACAM1 in the expression of protein level after 3 weeks with Western Blot.
Fig. 1 C is separated SD neonatal rat cardiomyocytes exposed and carries out anoxia stimulation, detects the bar diagram of myocardial cell CEACAM1 in the expression of protein level after 24 hours with WesternBlot.
Fig. 2 is the bar diagram detecting myocardial infarction marginal zone apoptosis situation after wild type and gene knockout type two groups of mice heart infarction for 3 weeks with TUNEL staining.
Fig. 3 is the figure observing mouse survival rate after wild type and gene knockout type two groups of mice heart infarction for 8 weeks.
Fig. 4 A be wild type and gene knockout type two groups of mice ligation arteria coronaria left anterior descending branches time electrocardiogram.
Fig. 4 B is the bar diagram with TTC staining examine myocardial infarction area in 24 hours after wild type and gene knockout type two groups of mice ligation arteria coronaria.
Fig. 5 A is the bar diagram with Masson staining examine myocardial fibrosis area in 8 weeks after wild type and gene knockout type two groups of mice heart infarction.
Fig. 5 B is the comparison diagram of the heart weight/weight ratio of after wild type and gene knockout type two groups of mice heart infarction 8 weeks.
Fig. 6 adopts the ultrasonic bar diagram assessed the cardiac function of wild-type mice and CEACAM1 knock-out mice sham operated rats and operation group of M type for after the ligation of arteria coronaria left anterior descending branch 8 weeks.
Fig. 7 utilizes the slow virus infection myocardial cell containing for the siRNA of CEACAM1, observes the figure of anoxia apoptosis of cardiac muscle situation after 24 hours.
Detailed description of the invention
1. experiment purpose
Explore the effect in myocardial acute ischemia damage of CEACAM1 gene and utilize the reticent CEACAM1 of siRNA to express the impact of apoptosis of cardiac muscle after on anoxia.
2. laboratory animal and raising
Laboratory animal: select 8 week age, body weight is about 20-25g, wild-type mice (WT that background is male C57BL/6 strain, thered is provided by Zhongshan University's Experimental Animal Center), CEACAM1 knock out mice (CEACAM1-KO, teaching friendship by Australian McGill University Beauchemin provides), SD rat neonatal rat (being provided by Nanfang Medical Univ's Experimental Animal Center).
Feeding environment: all experiment mices are all raised in Hospital of Southern Medical University animal experimental center (SPF level).Mice special feed is provided by Guangdong Province's Experimental Animal Center.
Rearing conditions: room temperature is between 22-24 DEG C, and humidity is between 40-70%, and it is 12 hours that light and shade replaces lighting hours, freely drinks water and ingests.
3. experimental technique
1) foundation of experiment in vivo grouping and heart infarction model: male C57BL/6 background wild-type mice and CEACAM1 knock out mice, two kinds of mices are divided into operation group and sham operated rats at random.
Adopt the method establishment mice heart infarction model of left anterior descending coronary artery ligation, what model was successfully established is masked as: the lower visible left anterior descending branch feed region cardiac muscle of direct-view becomes pale and ECG ST section and raises.Sham operated rats opens breast but not ligation.
Experiment in vitro divides into groups: be separated neonatal rat cardiomyocytes exposed, stimulates be divided into normal oxygen group and anoxia group by whether giving anoxia.With slow virus or the empty virus of contrast (providing by Shanghai JiKai Gene Chemical Technology Co., Ltd) infected rats neonatal rat myocardial cell of the siRNA containing CEACAM1, be designated as vector virus group and sky virus group, and give normal oxygen and anoxia stimulation.
2) observation index
The expression of the C57 mice Post operation 3 weeks detection of the method with RT-PCR and Western Blot cardiac muscular tissue CEACAM1.The expression of the 24 hours detection of the method with Western Blot CEACAM1 after neonatal rat cardiomyocytes exposed anoxia.
C57 mice and CEACAM1 knock out mice Post operation 24 hours TTC staining examine myocardial infarction area, by TUNEL staining examine infarct border district apoptosis situation after 3 weeks, by Masson staining examine myocardial fibrosis level after 8 weeks, measure heart weight/weight ratio, use echocardiography cardiac function and structure, assessment mouse survival situation.
Within after Myocytes Anoxia 24 hours, organize and vector virus group apoptosis situation by the empty virus of TUNEL staining examine.
4. experimental result
1) after ischemia/anoxia, myocardial cell CEACAM1 expression increases
With the method establishment C57 mice heart infarction model of arteria coronaria left anterior descending branch ligation, the method for 3 weeks rear RT-PCR and Western Blot detects the expression (Figure 1A and Figure 1B) of cardiac muscular tissue CEACAM1 at gene and protein level respectively.In addition, be separated SD neonatal rat cardiomyocytes exposed and carry out anoxia stimulation, after 24 hours, detecting the expression (Fig. 1 C) of myocardial cell CEACAM1 at protein level by the method for Western Blot.Result shows, and myocardial cell CEACAM1 after ischemia/anoxia stimulates all obviously increases (* P<0.01) in the expression of gene and protein level.(n＝4)
2) CEACAM1 gene knockout improves apoptosis of cardiac muscle situation after heart infarction
With the method establishment mice heart infarction model of arteria coronaria left anterior descending branch ligation, murine myocardial infarction marginal zone apoptosis situation (stained positive represents apoptotic cell) is detected with TUNEL staining after 3 weeks, as shown in Figure 2, wild-type mice heart infarction group and knock out mice heart infarction group apoptosis of cardiac muscle ratio contrast respective sham operated rats and are all significantly increased (* P < 0.01), and knock out mice heart infarction group apoptosis of cardiac muscle ratio comparatively wild-type mice heart infarction group minimizing (#P < 0.05).Illustrate that CEACAM1 gene knockout obviously can alleviate heart infarction marginal zone apoptosis situation.Wherein, every mice statistics at least 5000, cardiac infarction marginal zone cell.(n＝4)
3) CEACAM1 gene knockout reduces mouse core stalk mortality rate
With the method establishment mice heart infarction model of arteria coronaria left anterior descending branch ligation, after 8 weeks, observe the survival rate of mice.Result as shown in Figure 3, survival rate contrast wild-type mice (n=36) of knock out mice (n=30) significantly improves (Log rank:Chi-square 4.438, P<0.05), illustrate that CEACAM1 gene knockout can obviously reduce heart infarction mouse death rate.
4) CEACAM1 gene knockout reduces myocardial infarction area
Electrocardiogram when wild-type mice and knock out mice ligation arteria coronaria left anterior descending branch is as shown in Figure 4 A: it is consistent that two groups of mice ST sections raise level, and show that left anterior descending branch ligation degree is consistent, namely degree of ischemia is identical.Two groups of mice ligation arteria coronaria myocardial infarction area after 24 hours is more as shown in Figure 4 B: knock out mice myocardial infarct size comparatively wild-type mice reduces (P<0.01).Composition graphs A illustrates that CEACAM1 knocks out the myocardial infarction area that can reduce same degree bloodstream blocking and cause.(n＝4)
5) CEACAM1 gene knockout alleviates the remodeling ventricle after heart infarction
After wild-type mice and knock out mice heart infarction, the myocardial fibrosis area of 8 weeks and heart weight/weight ratio compare.Result is as shown in Fig. 5 A, Fig. 5 B, and knock out mice myocardial fibrosis area and heart weight/weight ratio all comparatively wild-type mice reduce (P<0.05), illustrate that CEACAM1 knocks out the remodeling ventricle after can suppressing heart infarction.(n＝4)
6) CEACAM1 gene knockout improves cardiac function after heart infarction
Within after the ligation of arteria coronaria left anterior descending branch 8 weeks, adopt the assessment of the ultrasonic cardiac function to wild-type mice and CEACAM1 knock-out mice sham operated rats and operation group of M type.As shown in Figure 6, compared with wild-type mice heart infarction group, the left LVSF of knock out mice heart infarction group obviously increases (#P < 0.05) result, illustrates that CEACAM1 knocks out the cardiac function that can improve heart infarction mice.(n＝4)
7) siRNA of CEACAM1 gene alleviates the apoptosis of cardiac muscle that anoxia causes
Utilize containing the slow virus infection myocardial cell for the siRNA of CEACAM1, observe the apoptosis situation of anoxia myocardial cell after 24 hours.Result as shown in Figure 7, under anoxia condition, apoptosis of cardiac muscle obviously increases (* P<0.01), and after the expression of the reticent CEACAM1 of RNAi, the apoptosis of myocardial cell reduces (#P<0.05), illustrates that the expression of the reticent CEACAM1 of siRNA can alleviate apoptosis of cardiac muscle.(n＝3)
Above experimental result shows, after ischemia/anoxia, myocardial cell CEACAM1 expression increases.CEACAM1, by promoting apoptosis of cardiac muscle during myocardial acute ischemia/anoxia, increases the weight of myocardial damage and worsens cardiac function, and utilizing the reticent CEACAM1 expression of siRNA to have the effect alleviating the apoptosis of cardiac muscle that anoxia causes.
Claims (4)
1. screen the target of medicine for treatment myocardial acute ischemia damage, it is characterized in that: described target is carcinoembryonic antigen adhesion molecule-1 of being correlated with is CEACAM1.
2. carcinoembryonic antigen adhesion molecule-1 of being correlated with is CEACAM1 as the application of drug targets in the medicine of screening treatment myocardial acute ischemia damage.
3. to be correlated with carcinoembryonic antigen the medicine for the treatment of myocardial acute ischemia damage that adhesion molecule-1 be CEACAM1 is target.
4. medicine according to claim 3, is characterized in that: described medicine is the siRNA of CEACAM1.
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| 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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| 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 |
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| HORTENSE SLEVOGT ET AL: "CEACAM1 inhibits Toll-like receptor 2–triggered antibacterial responses of human pulmonary epithelial cells", 《NATURE IMMUNOLOGY》 * |
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