CN116590398A - Application of ATF7 gene in preparing heart disease diagnosis product and medicine - Google Patents
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- 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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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of an ATF7 gene in preparing a heart disease diagnosis product and a medicine. The inventor discovers for the first time that the expression level of ATF7 gene is obviously increased in myocardial cells and heart tissues where necrosis occurs, and has a promoting effect on myocardial cell necrosis. Based on this, the present invention provides a reagent or kit for diagnosing related heart diseases, and a medicament for preventing and treating heart diseases. The medicine for preventing and treating heart diseases contains a pharmaceutical preparation for targeting and reducing ATF7 gene expression, and can well play a role in preventing and treating various heart diseases. Meanwhile, the medicine has obvious treatment effect, wide application range and environment-friendly use.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of an ATF7 gene in preparing a heart disease diagnosis product and a medicine.
Background
The heart is a dynamic source of human blood transport, which transports blood to various parts of the body, providing oxygen and nutrition to other organs and tissues, and is one of the most important organs of the human body. However, with unhealthy dietary structure and lifestyle, and increased aging, the incidence and mortality of cardiovascular disease increases year by year, and a younger situation is presented with cardiovascular disease mortality that is far higher than other common diseases.
Death of cardiomyocytes is the pathological basis of numerous heart diseases, while cell necrosis is one of the major forms of cell death. Necrosis has long been considered a passive way of cell death due to pathological causes such as physical or chemical injury, hypoxia and malnutrition. However, in recent years, it has been found that, unlike conventional cognitive necrosis, there is a new cell necrosis method, which is also called as programmed necrosis or necrosis. Unlike apoptosis and pyro-apoptosis, programmed necrosis is similar to traditional necrosis, such as plasma membrane rupture, causing an inflammatory response. The production and accumulation of pro-inflammatory cytokines, the destruction of biological membranes, and the release of intracellular injury-related molecules are closely related to the development and progression of the events. Programmed necrosis is regulated by a complex network of cell signals. Current studies indicate that RIPK1 and RIPK3 can phosphorylate each other to form a dead body under tnfα induction. RIPK1 and RIPK3 are phosphorylated to obtain kinase activity, mixed lineage kinase domain like proteins (MLKL) are phosphorylated to obtain activity, further mediating cell necrosis. Meanwhile, necrosis is associated with ischemic injury and neurodegenerative diseases, and has become a hot spot for research on cell death in recent years. Cell death plays an extremely important role in normal development of embryos, maintaining normal physiological functions of cell populations and malignant lesions, and ensuring repair in the healthy survival process of multicellular organisms. However, the current research on the signal pathway of cardiomyocyte death is far from deep enough.
ATF7 is one of the members of the ATF2 transcription factor subfamily, belonging to the ATF/CREB protein superfamily. These proteins are characterized by the presence of a B-Zip DNA binding domain. ATF/CREB plays an important role in energy metabolism and cell growth, while the function of the ATF7 gene in heart tissue is not yet known.
At present, the pathogenesis of heart diseases is not completely clear, and the prevention, diagnosis and treatment of heart diseases cannot achieve satisfactory effects, so that development of new technical methods for diagnosis and prevention of heart diseases is urgently needed. The key factors targeted to heart diseases have wide prospects in clinical application, and can also provide a new thought for treating heart diseases.
The present invention has been made in view of the present circumstances.
Disclosure of Invention
A first object of the present invention is to provide the use of the ATF7 gene as biomarker for the preparation of a product for diagnosing heart diseases.
The second object of the present invention is to provide the use of an inhibitor containing an ATF7 gene capable of targeting in the preparation of a medicament for the prevention and treatment of heart diseases.
In order to solve the technical problems, the invention adopts the following technical scheme:
in a first aspect, the invention provides the use of the ATF7 gene as a biomarker for the manufacture of a product for diagnosing heart disease.
In alternative embodiments, the heart disease comprises coronary heart disease, or, alternatively, myocardial injury resulting from ischemia, myocardial hypertrophy, myocardial infarction, heart failure, myocardial fibrosis, or atrial fibrillation.
In alternative embodiments, the product is used as a test sample for cells, tissues or blood to diagnose disease by measuring the amount of ATF7 gene expression.
In an alternative embodiment, the product comprises reagents for diagnosing heart disease comprising a primer pair for detecting the amount of ATF7 gene expression.
In an alternative embodiment, the nucleotide sequences of the upstream and downstream primers in the primer pair are shown in SEQ ID NOs 1-2, respectively.
In a second aspect, the invention provides a diagnostic reagent or kit for heart disease, including coronary heart disease, or myocardial injury, myocardial hypertrophy, myocardial infarction, heart failure, myocardial fibrosis or atrial fibrillation caused by ischemia; the reagent or kit comprises a primer pair for amplifying the expression level of the ATF7 gene.
In an alternative embodiment, the nucleotide sequences of the upstream and downstream primers in the primer pair are shown in SEQ ID NOs 1-2, respectively.
In a third aspect, the present invention provides a medicament for preventing or treating heart disease, the medicament comprising a pharmaceutical formulation that targets and inhibits expression of the ATF7 gene.
In alternative embodiments, the medicament further comprises one or more of a carrier, a drug delivery formulation or an adjuvant.
Optionally, the vector comprises a viral vector.
Alternatively, the viral vector comprises one or more of an adenovirus vector, a lentiviral vector or a retroviral vector, preferably an adenovirus vector.
Optionally, the drug delivery formulation comprises one or more of liposomes, chitosan, cholesterol or nanoparticles, preferably liposomes.
Optionally, the auxiliary material comprises one or more of phosphate buffer, mannitol or physiological saline, preferably comprises phosphate buffer; the pH of the phosphate buffer is preferably 6.5 to 8.0.
In alternative embodiments, the pharmaceutical formulation that inhibits the expression of the ATF7 gene comprises a small interfering RNA that targets the ATF7 gene.
The inventor discovers for the first time that the expression level of ATF7 gene is obviously increased in myocardial cells and heart tissues where necrosis occurs, and has a promoting effect on myocardial cell necrosis. Based on this, the present invention provides a reagent or kit for diagnosing related heart diseases, and a medicament for preventing or treating heart diseases. The medicine for preventing or treating heart diseases contains a pharmaceutical preparation for targeting and reducing ATF7 gene expression, and can well play a role in preventing and treating various heart diseases. Meanwhile, the medicine has obvious treatment effect, wide application range and environment-friendly use.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing experimental results of hypoxia/reoxygenation (H/R) treated cardiomyocytes according to an embodiment of the present invention;
FIG. 2 shows the experimental results of myocardial ischemia reperfusion (I/R) injury in mice according to the present invention;
FIG. 3 is a map of the original plasmid vector used in example 2 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments of the present invention.
In a specific embodiment, the invention provides in a first aspect the use of the ATF7 gene as biomarker for the manufacture of a product for diagnosing heart disease.
In alternative embodiments, the heart disease comprises coronary heart disease, or, alternatively, myocardial injury resulting from ischemia, myocardial hypertrophy, myocardial infarction, heart failure, myocardial fibrosis, or atrial fibrillation.
In alternative embodiments, the product is used as a test sample for cells, tissues or blood to diagnose disease by measuring the amount of ATF7 gene expression.
In an alternative embodiment, the product comprises reagents for diagnosing heart disease comprising a primer pair for detecting the amount of ATF7 gene expression.
In an alternative embodiment, the nucleotide sequences of the upstream and downstream primers in the primer pair are shown in SEQ ID NOs 1-2, respectively.
In a second aspect, the invention provides a diagnostic reagent or kit for heart disease, including coronary heart disease, or myocardial injury, myocardial hypertrophy, myocardial infarction, heart failure, myocardial fibrosis or atrial fibrillation caused by ischemia; the reagent or kit comprises a primer pair for amplifying the expression level of the ATF7 gene.
In an alternative embodiment, the nucleotide sequences of the upstream and downstream primers in the primer pair are shown in SEQ ID NOs 1-2, respectively.
In a third aspect, the present invention provides a medicament for preventing or treating heart disease, the medicament comprising a pharmaceutical formulation that targets and inhibits expression of the ATF7 gene.
In alternative embodiments, the medicament further comprises one or more of a carrier, a drug delivery formulation or an adjuvant.
Optionally, the vector comprises a viral vector.
Alternatively, the viral vector comprises one or more of an adenovirus vector, a lentiviral vector or a retroviral vector, preferably an adenovirus vector.
Optionally, the drug delivery formulation comprises one or more of liposomes, chitosan, cholesterol or nanoparticles, preferably liposomes.
Optionally, the auxiliary material comprises one or more of phosphate buffer, mannitol or physiological saline, preferably comprises phosphate buffer; the pH of the phosphate buffer is preferably 6.5 to 8.0.
In alternative embodiments, the pharmaceutical formulation that inhibits the expression of the ATF7 gene comprises a small interfering RNA that targets the ATF7 gene.
Some embodiments of the present invention are described in detail below with reference to the accompanying drawings. The following embodiments and features of the embodiments may be combined with each other without conflict.
The terms involved in the following examples and drawings are explained as follows:
ATF7 mrrnalevels: mRNA expression level of ATF7 gene;
control: a control group;
H/R: H/R treatment groups;
sh-NC+H/R: H/R treatment group after transfection of negative control adenovirus;
sh-ATF7+H/R: post-adenovirus H/R treatment groups targeted to knockdown ATF7 gene;
sham: the false operation group is a negative control of the I/R group;
I/R: myocardial ischemia reperfusion treatment group, which refers to ischemia reperfusion operation of mice;
sh-NC+I/R: performing myocardial ischemia reperfusion treatment after tail vein injection of negative control adenovirus;
sh-ATF7+I/R: tail vein injection is carried out on a myocardial ischemia reperfusion treatment group after adenovirus of which the target ATF7 gene is knocked down;
PI positive cells (%): percentage of PI staining positive cells;
LDH concentration (fold of control): LDH activity values relative to Control group;
EBD-positive area (%): percentage of EBD staining positive cells;
FS (%): left ventricular fractional shortening;
INF/AAR (%): the percentage of myocardial infarction area to risk area;
AAR/LV (%): percentage of risk area to left ventricular area.
Example 1
In this example, cardiomyocytes for experiments were prepared, and the cardiomyocytes were subjected to hypoxia-reoxygenation (H/R) treatment, specifically:
1.1 cardiomyocytes: the cardiomyocytes used in this experiment were primary cardiomyocytes from mice, the hearts of 1-2 day old neonatal mice were taken and rinsed 3-4 times with pre-chilled PBS. The ventricular zone was then isolated and minced in HEPES buffered saline. Dispersing the tissue in digestion liquid containing pancreatic juice and collagenase II at 37 deg.C, repeating digestion treatment, and collecting the first type myocardial cells.On the basis of the first kind of myocardial cells, adenovirus is generally dripped into cells with good growth state, and the infection titer is 1 multiplied by 10, wherein the adenovirus is used for constructing an ATF7 gene knockdown vector in the cells to achieve the aim of knocking down the ATF7 gene 10～12 PFU, preferably 1X 10 10 PFU, the second class cardiomyocytes were obtained.
1.2H/R treatment: the two cardiomyocytes were pretreated in sugar-free DMEM/F-12 medium for 12h, respectively, and then placed in an anoxic environment at 37℃for 12h. After the completion of the culture, the DMEM/F12 medium containing 5% serum was replaced, and the culture was placed at 37℃with 5% CO 2 、95％ O 2 Reoxygenation is carried out for 6h in an incubator, and cells are collected for subsequent experiments.
Example 2
The present example provides a follow-up experimental animal and constructs an ischemia reperfusion (I/R) injury model, specifically:
2.1 experimental animals: the animals purchased from Jinan Pengyue laboratory animal breeding Limited company, the animal strain was C57BL/6 male mice, and about 8 weeks old mice were selected for the experiment. All mice were kept in the temperature controlled university of Qingdao animal center, in normal light/dark cycle, and food and water were freely available throughout the experiment. All animal studies were conducted in accordance with the protocols approved by the animal care committee of the institute and those approved by government authorities.
2.2I/R injury: after anesthetizing the mice, the trachea was accessed, the left chest carefully opened to expose the heart, and the anterior left descending coronary artery (LAD) was ligated in the temporal area. Ischemia 45min. After the completion, the coil was opened to allow blood to be refilled for 3 hours, thereby completing the operation. For sham mice, the same procedure was performed except that the LAD was ligated. Throughout the procedure, the mice were placed in a supine position on a heated pad at 37 ℃. For the purpose of in vivo completion of ATF7 gene knockdown, construction of ATF7 gene knockdown vector using adenovirus is usually carried out by tail vein injection 5 days before sham operation or I/R operation in mice, and virus infection titer is 1X 10 10～14 PFU, preferably 1X 10 12 PFU。
The original plasmid vector used for constructing the ATF7 gene knockdown or over-expression vector by using adenovirus is pAdEasy-U6, a plasmid map is shown in figure 3, a shRNA hairpin structure is designed according to an siRNA sequence, and then the shRNA sequence is inserted between XhoI and HindIII elements of the original plasmid vector to construct a control group virus vector and a recombinant virus vector for knocking out the target gene ATF 7. The nucleotide sequences of the siRNA and shRNA of the two recombinant viral vectors are shown below:
example 3
In this example, protein extraction and western blotting were performed on two types of cardiomyocytes treated in example 1, and on myocardial tissue from different animal models in example 2, specifically:
3.1 protein extraction: total protein is isolated from cardiomyocyte or myocardial tissue samples at low temperature using RIPA lysate containing protease inhibitors.
Specifically, RIPA lysate containing protease inhibitor is added into heart muscle cells or crushed tissue homogenate, and the mixture is cracked on ice for 30min; then, the supernatant was transferred by centrifugation at 12000rpm/min for 10min using a centrifuge at 4 ℃; adding 4 x protein loading buffer solution into the supernatant, wherein the volume ratio is 3:1, using a metal bath, and boiling at 98 ℃ for 10min.
3.2 Western immunoblotting: the protein samples obtained were separated by SDS-PAGE gel electrophoresis and transferred to PVDF membrane. Sealing for 1h at normal temperature with 5% skimmed milk powder prepared with PBS; the primary antibody was then incubated overnight at 4℃with ATF7 and GAPDH, and the secondary antibody was incubated for 1h at room temperature. GAPDH was used as an internal reference. Scanning photographing was performed using an enhanced chemiluminescent detection system.
Example 4
In this example, RNA extraction and RT-qPCR were performed on the cardiomyocytes treated in example 1 and the myocardial tissue from the animal model in example 2, specifically:
4.1RNA extraction: total RNA was isolated from cardiomyocyte and tissue samples using Trizol reagent.
Specifically, after cells or tissues were mixed using Trizol, the volume ratio was 5:1, standing for 5min after violent shaking, and centrifuging at 12000rpm/min for 15min by using a centrifuge at 4 ℃ to obtain a supernatant; adding isopropyl alcohol with the same volume, standing for 30min, centrifuging at 12000rpm/min for 15min, and separating out RNA; adding 75% ethanol prepared by pre-chilled DEPC water, washing and airing to obtain total RNA.
4.2RT-qPCR: removing genome DNA according to the instruction by using a reverse transcription kit, and then reversely transcribing cDNA; then, qRT-PCR is carried out in a fluorescent quantitative qPCR instrument by using a quantitative reagent; the results were normalized using GAPDH. The primer sequences involved in this experiment are shown in the following table.
Example 5
In this example, PI staining and quantitative cell analysis were performed on cardiomyocytes treated in example 1, specifically:
5.1PI staining: washing the cells subjected to the preliminary experiment with PBS, and dyeing with PI at 37 ℃ in a dark condition for 30min; after PBS washes for 3 times, 4% paraformaldehyde is fixed for 15-25 min at room temperature; the PBS was washed 3 times and then the slides were stained with DAPI solution.
5.2 quantitative analysis: observing and photographing the slide subjected to PI dyeing under a fluorescence microscope; PI marks necrotic cardiomyocyte nuclei red and DAPI marks all nuclei blue; the percentage of red nuclei to blue nuclei was calculated.
Example 6
In this example, the cardiomyocytes treated in example 1 were examined for LDH activity, specifically:
the activity of LDH in the cell culture broth was determined according to the instructions using an LDH detection kit (Shanghai Biyun biotechnology Co., ltd., A020-2); all the reagents are added according to the steps and then mixed uniformly, and the mixture is kept stand at room temperature for 3 to 5 minutes, and an enzyme-labeled instrument is used for measuring absorbance at the wavelength of 450 nm. LDH activity was calculated from [ (assay well OD value-control well OD value)/(standard well OD value-blank well OD value) ]xstandard concentration x N x 1000.
Example 7
This example carries out evans blue staining (EBD staining) and quantitative analysis of the mouse model constructed in example 2, specific Wie:
7.1 Evan blue staining: injecting 0.1-0.15 ml of 1% Evan blue dye solution (EBD dye solution) into the tail vein of the mice; after 24h, performing I/R or Sham surgery on the mice, and taking out the hearts, placing the hearts in a frozen slice embedding agent, and performing quick freezing; slicing the tissue into 7nm sections with a frozen microtome, staining the frozen sections with wheat germ lectin (WGA); and finally, staining the cell nucleus by DAPI and sealing the cell nucleus.
7.2 quantitative analysis: observing the staining result of the section by using a confocal fluorescence microscope; evan blue dye can permeate necrotic cell membranes to mark cells as red, WGA can mark the outline of the cell membranes as green, and DAPI can mark all cell nuclei as blue; the percentage of red cells to total cell number was calculated.
Example 8
The present example performed cardiac ultrasound tests on the mouse model constructed in example 2, specifically:
after I/R or Sham surgery, mice were subjected to M-mode echocardiography measurements using a Vevo2100 (Visual Sonic) imaging system, cardiac function was assessed, and left ventricular fractional shortening (FS%) was calculated using the system.
Example 9
The present example performed detection and quantitative analysis of the area of heart infarction on the mouse model constructed in example 2, specifically:
9.1 detection of heart infarct size: after I/R or Sham surgery, 1% evans blue dye was injected into the coronary circulation of the mice to delineate the myocardial perfusion area. After the heart was removed, the remaining blood and evans blue dye were washed off and directly sectioned. Dyeing with 2% 2,3, 5-triphenyltetrazolium chloride (TTC) solution at 37deg.C in the absence of light for 20min, and fixing with 4% paraformaldehyde.
9.2 quantitative analysis: photographing the slice by using a camera; the normal heart region is marked as blue by the Evan blue dye liquor, the red part is an ischemia dangerous region, and the white part is an infarct region; imageJ was used to analyze the percentage of infarct area to total risk area and the percentage of risk area to left ventricle area.
The experimental data obtained by the detection in the above examples were statistically analyzed: all data are expressed as mean ± standard deviation (mean ± SD); statistical analysis was performed using Graphpad Prism; the comparison among multiple groups adopts One-way ANOVA followed by Tukey multiple comparison single-factor analysis of variance; experiments were repeated at least 3 times independently, with similar results. The difference p <0.05 is statistically significant.
The experimental results and analyses of the above examples are as follows:
the cardiomyocyte-related experimental results are shown in fig. 1, and the mouse model-related experimental results are shown in fig. 2, which can be seen from the figure:
protein expression (a in fig. 1) and mRNA levels (B in fig. 1) of the ATF7 gene in cardiomyocytes were significantly increased after H/R stimulation in vitro; whereas knocking down the ATF7 gene blocked H/R-induced myocardial cell necrosis (C in FIG. 1) and LDH release (D in FIG. 1).
Protein expression (a in fig. 2) and mRNA levels (B in fig. 2) of the ATF7 gene in the mouse heart after I/R injury; knocking down the ATF7 gene reduced myocardial cell necrosis after I/R injury (C in fig. 2), improved ventricular function (D in fig. 2) and reduced heart infarct size (E in fig. 2).
It was found that the ATF7 gene expression level was increased in the injured cardiomyocytes and hearts; the knockdown ATF7 gene can effectively reduce myocardial cell death and infarct size and improve heart function. Therefore, the ATF7 gene can be used as a biomarker for preparing related heart disease diagnosis products; and the ATF7 gene is used as a target point to prepare the therapeutic drugs for the related heart diseases, so that the method has wide application prospect.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
- The application of ATF7 gene as biomarker in preparing cardiac disease diagnosis related product.
- 2. The use according to claim 1, wherein the heart disease comprises coronary heart disease, or myocardial injury caused by ischemia, myocardial hypertrophy, myocardial infarction, heart failure, myocardial fibrosis or atrial fibrillation.
- 3. The use according to claim 1, wherein the product is for diagnosing a disease by detecting the expression level of ATF7 gene using cells, tissues or blood as a detection sample.
- 4. The use according to claim 3, wherein the product comprises reagents for diagnosing heart diseases, the reagents comprising a primer pair for detecting the expression level of the ATF7 gene.
- 5. The method according to claim 4, wherein the nucleotide sequences of the upstream and downstream primers in the primer pair are shown in SEQ ID NO. 1-2, respectively.
- 6. A diagnostic reagent or kit for heart disease, characterized in that the heart disease comprises coronary heart disease, or myocardial injury, myocardial hypertrophy, myocardial infarction, heart failure, myocardial fibrosis or atrial fibrillation caused by ischemia; the reagent or kit comprises a primer pair for amplifying the expression level of the ATF7 gene.
- 7. The reagent or kit according to claim 6, wherein the nucleotide sequences of the upstream and downstream primers in the primer pair are shown in SEQ ID NO. 1-2, respectively.
- 8. A medicament for preventing or treating heart disease, comprising a pharmaceutical formulation that targets and inhibits ATF7 gene expression.
- 9. The medicament of claim 8, further comprising one or more of a carrier, a drug delivery formulation, or an adjuvant;optionally, the vector comprises a viral vector;optionally, the viral vector comprises one or more of an adenovirus vector, a lentiviral vector or a retroviral vector, preferably an adenovirus vector;optionally, the drug delivery formulation comprises one or more of liposomes, chitosan, cholesterol or nanoparticles, preferably liposomes;optionally, the auxiliary material comprises one or more of phosphate buffer, mannitol or physiological saline, preferably comprises phosphate buffer; the pH of the phosphate buffer is preferably 6.5 to 8.0.
- 10. The medicament of claim 9, wherein the pharmaceutical formulation that inhibits expression of the ATF7 gene comprises a small interfering RNA that targets the ATF7 gene.
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