CN115851907A - Annular non-coding RNA-circZBTB46 and application thereof - Google Patents
Annular non-coding RNA-circZBTB46 and application thereof Download PDFInfo
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Abstract
The invention discloses a circular non-coding RNA circZBTB46, and an application of a preparation for detecting the influence and the expression quantity of the circular non-coding RNA circZBTB46 on the progression of coronary atherosclerotic heart disease in the preparation of a coronary atherosclerotic diagnostic reagent. According to the invention, by researching the regulation and control function of the circZBTB46 on the proliferation and migration of human coronary artery smooth muscle cells, the circZBTB46 is found to play an important role in the whole occurrence and development process of atherosclerosis and can be used as a biomarker for diagnosing coronary atherosclerotic heart disease. The invention provides a biomarker for diagnosing coronary atherosclerosis, which is used for biological identification and clinical application of coronary atherosclerotic heart disease, so that timely and effective intervention can be performed on atherosclerotic patients through screening the target spot in clinic, and clinical events are reduced. Therefore, the invention provides a new molecular marker and an intervention target for diagnosing and treating atherosclerosis.
Description
Technical Field
The invention belongs to the field of molecular biology, and particularly relates to a circular non-coding RNA circZBTB46, and an application of a preparation for detecting the influence and expression quantity of the circular non-coding RNA circZBTB46 on the progression of coronary atherosclerotic heart disease in the preparation of a coronary atherosclerotic diagnostic reagent.
Background
Coronary heart disease (CAD) is one of the most major cardiovascular diseases affecting human health worldwide and has been shown to be a genetically predisposed disease with a number of genes involved in the development of the disease. There is increasing evidence that gene expression, transcriptional control, and structural stability are closely related to epigenetic modifications. Atherosclerosis (AS) is a chronic complex disease involving multiple cells by multiple factors. It is characterized by the initiation of vascular endothelial injury, accompanied by inflammation, immune response, lipid deposition in the vessel wall, and involved in inflammatory and proliferative cascades of major functional cells including smooth muscle cells, endothelial cells, and immune cells. The existing research methods and means have already provided certain cognition and understanding on the occurrence and development of AS, and have substantially improved the diagnosis and treatment of cardiovascular diseases, but the factors and mechanisms for controlling the formation of advanced atherosclerotic lesions are still poorly understood.
Smooth Muscle Cells (SMC) play an important role in the formation, progression, and rupture of AS plaques, and studies have shown that about 70% of the various cells contained within AS plaques are derived from SMC. The migration of SMC through abnormal proliferation and the synthesis of extracellular matrix at the early stage of AS is the key of early damage of AS; in addition, SMC can secrete a plurality of proinflammatory and proliferation promoting factors to activate SMC and recruit macrophages; SMC also phagocytose lipid uptake, forming foam cells, and as lesions progress, increased SMC apoptosis is the leading cause of plaque rupture. Therefore, the abnormal proliferation and migration of SMC are indistinguishable from the occurrence and development of AS.
Circular RNA (circular RNA), an emerging class of non-coding RNAs, is ubiquitous in eukaryotes, expression-stable, and highly conserved across species. Research shows that the circRNA has different levels of changes in the conditions of atherosclerosis, coronary plaque formation, plaque rupture and the like, the AS is used AS a genetic susceptibility disease, the research on the development mechanism of the AS at the transcription level can deeply explain the AS, the research is helpful for better understanding of the pathogenesis of the AS, and a new diagnosis and treatment target point is provided for the AS from the RNA level.
Disclosure of Invention
The invention aims to provide a non-coding circular RNA circZBTB46 which is remarkably high expressed in Peripheral Blood Mononuclear Cells (PBMC) of patients with coronary heart disease and influences the functions of Human Coronary Artery Smooth Muscle Cells (HCASMCs) in vitro, and provides application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme: the circular non-coding RNA-circZBTB46 has a nucleotide sequence shown in SEQ ID NO. 1.
Use of a preparation for detecting the expression level of circular non-coding RNA-circZBTB46 in the preparation of a diagnostic reagent for diagnosing or predicting the risk of developing coronary atherosclerosis, wherein the nucleotide sequence of the RNA-circZBTB46 is shown as SEQ ID No. 1.
Further, the test agent is used for judging whether the subject has or is at risk of developing coronary atherosclerosis by detecting the expression of RNA-circZBTB46 in PBMC cells of the subject, and the expression is obviously up-regulated compared with a healthy control group.
A marker for diagnosing and predicting the risk of coronary atherosclerosis, wherein the marker is circular non-coding RNA-circZBTB46, and the nucleotide sequence is shown as SEQ ID NO. 1.
A diagnostic reagent for coronary atherosclerosis comprising: a preparation for detecting the expression quantity of RNA-circZBTB46, wherein the nucleotide sequence of the RNA-circZBTB46 is shown as SEQ ID NO. 1.
A diagnostic kit for coronary atherosclerosis, comprising the diagnostic reagent of claim 4.
Further, the diagnostic reagent comprises a forward primer and a reverse primer, wherein the nucleotide sequence of the forward primer is shown as SEQ ID NO.2, and the nucleotide sequence of the reverse primer is shown as SEQ ID NO. 3.
Compared with the prior art, the invention has the beneficial effects that: the invention discovers that the circZBTB46 plays an important role in the development and development process of atherosclerosis by researching the regulation and control function of the circZBTB46 on the proliferation and migration of vascular smooth muscle cells, and provides a standard gene and a molecular identification method suitable for the molecular identification of coronary atherosclerosis by detecting the expression level of the circZBTB46 in PBMCs of patients with coronary heart disease and a control group. The invention can find patients with coronary heart disease at early stage, reduce death rate of coronary heart disease and improve prognosis of patients by screening the target spot in clinic. At present, the main diagnostic method of the coronary atherosclerotic heart disease has the risks of high surgical risk coefficient, large radiation and the like, and the peripheral blood of a patient is collected for detection, so that the method has the advantages of small wound, good repeatability and the like, and is easier to accept.
Drawings
FIG. 1 shows the cyclic structure of circZBTB46 by forward and reverse primer PCR, RNase R treatment and sanger sequencing.
FIG. 2 shows siRNA silencing effect.
FIG. 3 is a CCK8 experiment demonstrating that silencing the expression of circZBTB46 in human coronary artery smooth muscle cells in vitro inhibits the proliferative activity of smooth muscle cells.
FIG. 4 is a cell scratch experiment demonstrating that in vitro silencing of circZBTB46 expression in human coronary smooth muscle cells inhibits smooth muscle migration. (ii) a
FIG. 5 is a characterization of circZBTB46 expression in clinical specimens;
FIG. 6 shows the results of the analysis of the working characteristic curve of circZBTB46 in clinical specimens.
Detailed Description
In order to make the technical solutions of the present application better understood by those skilled in the art, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only some embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that the terms "comprises" and "comprising," and any variations thereof, in the description and claims of this application and the above-described drawings, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
Example 1: structural identification of circZBTB46
1. Material
1.1 cells
Human coronary Smooth Muscle cells (HCASMC) used in the present invention were purchased from Sigma and cultured using the Vascular Smooth Muscle Cell Growth Kit. The culture conditions were 37 ℃ and 5% CO2.
1.2 reagents
TRIzol Reagent, reverse transcription kit
III RT SuperMix for qPCR (+ gDNA wiper), fluorescent Real-time (Real-time) quantitative PCR (polymerase chain reaction from Biotech, inc., of Kinzyme Biotech Co., ltd.) agarose was purchased from Sigma, gelred was purchased from Bio-ium, inc., DNA Marker and Loading Buffer were purchased from Beijing Tiangen, inc. PCR specific primers were designed and synthesized by Biotechnology, inc. primers are as follows:
2. method of producing a composite material
2.1 RNA extraction
Cell RNA was extracted using Trizol reagent according to the instructions of the reagents and cells were placed in 1mL Trizol reagent. After standing at room temperature for 5min, cell nuclei were lysed sufficiently. Adding 0.2mL of chloroform, vortexing vigorously while shaking for 15 seconds, standing at room temperature for 5-10min, 4 ℃,12000 rpm, centrifuging for 15min, then observing the liquid to separate into three layers, transferring the colorless aqueous phase to another clean 1.5mL centrifuge tube (note that the middle layer cannot be touched), adding equal amount of isopropanol (about 0.4 mL), mixing by gentle inversion, and incubating at room temperature for 5-10min to precipitate RNA. Centrifuging at 12000 rpm at 4 deg.C for 10min, discarding supernatant, adding 1mL 75% ethanol (diluted with DEPC water, prepared as before), washing precipitate, and repeatedly beating. Centrifuging at 4 deg.C and 12000 r/min for 5-6min, discarding supernatant, adding 1mL of anhydrous ethanol, washing precipitate, centrifuging at 4 deg.C for 5-6min, and discarding supernatant. And (5) automatically drying the white RNA precipitate for 5-10min. 20-50uL DEPC water is added to dissolve the precipitate, and the total RNA concentration and purity are measured by ultraviolet spectrophotometry.
2.2 reverse transcription
Reverse transcription reaction was performed using reverse transcription kit (HiScript III RT Supermix for qPCR (+ gDNA wiper)) as per the instructions.
2.3 PCR
The PCR reaction was carried out according to the following system (10 ul system) according to the instruction of the ChamQ SYBR qPCR Master Mix kit of Novozam
SYBR Green Master 5μl
Forward primer(F) 0.2μl
Reverse primer(R) 0.2μl
RNase Free water 3.6μl
After the system is prepared, pre-denaturation is carried out at 95 ℃ for 30s, and PCR results are obtained by cycling 40 times according to the denaturation at 95 ℃ for 10s and the annealing process at 60 ℃ for 30 s.
2.4 agarose gel electrophoresis
Preparing glue: 1.5% agarose gel, 1.05g agarose was weighed, dissolved in 70ml 0.5 x TBE solution, 2. Mu.l Gelred dye was added, shaken and mixed well, heated for 2min to dissolve agar powder sufficiently. And (6) pouring the glue. Standing for about 30min, and slightly pulling off the comb after the gel is completely solidified; electrophoresis: DNA marker I6. Mu.l, DNA product 5. Mu.l + loading buffer 1. Mu.l, mixed well, 120v constant voltage electrophoresis. Imaging: and imaging by using a Berle gel imager and taking a picture.
3. Results
The cyclic structure characteristics of the circZBTB46 are determined through forward and reverse primer PCR, RNase R treatment and sanger sequencing experiments, and a foundation is laid for further researching the functions of the circZBTB 46.
Example 2: construction of silencing model of smooth muscle cell circZBTB46
1. Material
1.1 cells and siRNA
The cells and culture conditions used in this example were as in example 1. The design and synthesis of small interfering RNA (siRNA) was accomplished by Suzhou Jima Gen GmbH. Silencing circZBTB46 (siRNA) sequence, RNAi-1 Sense strand (Sense): CCACUCGCUGUCCAGUUCUTT, antisense strand (Antisense): AGACUGGGACAGCGAGGUGGTT, RNAi-2 Sense strand (Sense): UCGCUGCCAGUCUGUAGTT, antisense strand (Antisense): CUACAGACAGUCGGAGCAGCGATT
2. Method of producing a composite material
2.1 Expression of circZBTB46 in smooth muscle cells
After the cells in vigorous growth are counted, cell inoculation is carried out according to the required cell amount, and the cell density can reach 50-80% after the cells grow for 3-4 days. Using Lipofectamine TM 2000 transfection reagent for cell transfection experiment, the preparation and process of transfection reagent mixed solution are as follows, lipofectamine TM 2000, preparation: a sterile Eppendorf tube (EP tube) of 1.5ml was added first 250. Mu.l of serum-free and antibiotic-free DMEM medium and then 5. Mu.l of Lipofectamine TM 2000 transfection reagent is dissolved in DMEM medium and kept standing for 5min at room temperature to fully mix the transfection reagent in DMEM medium. Preparation of circRNA: a1.5 ml sterile Eppendorf tube was taken, 250. Mu.l of sterile DMEM medium (without serum and antibiotics) was added first, and then 5. Mu.l of a circRNA solution was added to the medium in an appropriate amount, and allowed to stand at room temperature for 5min to sufficiently mix the circRNA in the DMEM medium. After 5min, DMEM medium containing Lipofectamine TM 2000 transfection reagent and culture medium containing circRNA were addedThe culture medium was mixed, and left at room temperature for 20min to allow them to be fully combined, and 500. Mu.l of DMEM medium was added to prepare a circRNA transfection solution. The original medium in the six-well plate was removed, the cells were gently washed 1-2 times along the walls of the wells with pre-warmed PBS solution, PBS was then dropped directly onto the cells, and the PBS was removed. The circRNA transfection solution was slowly added to the prepared cells along the pore wall, the solution was aspirated after 8h at 37 ℃ and 2ml of complete DMEM medium was added to continue the culture. After culturing the cells for 48-72h, cell density growth to 90% was observed and the expression of circZBTB46 in the cells was detected by Real-time PCR.
3. Results
The extracted total RNA of smooth muscle cells was analyzed for the expression of circZBTB46 by Real-time PCR. Compared with the si-NC transfected group, the expression level of the circZBTB46 in the si-RNA transfected group is obviously reduced, which indicates that the cell silencing model of the circZBTB46 is successfully modeled (figure 2), thereby laying a foundation for further research on the function of the circZBTB46 in the smooth muscle cell function.
Example 3: regulation of smooth muscle cell proliferation by circZBTB46
1 Material
1.1 cells
The cells and culture method used in the experiment were the same as in example 1.
1.2 reagents
The siRNA used in the experiment was the same as in example 2.CCK-8 was purchased from APEXBIO.
2. Method of producing a composite material
2.1 CCK8 value-added experiment
Transfecting siRNA according to example 2, inoculating transfected cells to a 96-well plate, inoculating the cells at a cell density of 5000 cells per well, and placing the culture plate into a constant temperature incubator at 37 ℃ for pre-culture (wall adhesion is 6-8 h); after the cells were treated for a while, the original medium was replaced with a pre-prepared medium containing 10% of CCK-8, cultured for 2 hours, and the absorbance (OD value) at 450nm of a 96-well plate was measured with a microplate reader. And continuously measuring for several days, and drawing a growth curve.
3 results
According to the invention, the proliferation condition of smooth muscle cells after in vitro transfection siRNA silenced circZBTB46 is detected through a CCK8 experiment, and the cell proliferation of the circZBTB46 silencing group is found to be obviously inhibited (figure 3), which indicates that the circZBTB46 has the capacity of promoting the proliferation of human coronary artery smooth muscle cells.
Example 4: regulation of smooth muscle cell migration by circZBTB46
1. Cells
The cells and culture method used in the experiment were the same as in example 1.
1.2 reagents
The siRNA used in the experiment was the same as in example 2.
2. Method of producing a composite material
2.1 cell scratch test
Cells were routinely digested to a density of 5X 10 cells per ml 5 And (3) suspending the cells, inoculating the cells into a 6-well culture plate, and culturing for 16-24 h in a conventional mode until a monolayer of cells is formed. Culturing in serum-free culture medium for 4h. Scratch is carried out along the bottom of the culture plate in a straight line shape, and the relative distance of a scratch area is recorded under a mirror. The cells were washed 3 times with PBS and serum-free medium was added. 37 deg.C, 5% CO2, and culturing in incubator. Samples were taken at 0h, 24h and photographed.
3. Results
In order to verify whether the circZBTB46 affects the migration ability of smooth muscle cells, the invention detects the change of the cell migration ability after siRNA transfection of cells for 24h through a cell scratch experiment, and finds that the migration level of the circZBTB46 silencing group cells is obviously inhibited (figure 4), which indicates that the circZBTB46 has the ability of promoting the migration of smooth muscle cells.
Example 5: judging the efficacy of circZBTB46 as a coronary heart disease diagnostic marker
1. Patients were enrolled: 125 patients with continuous coronary heart disease confirmed by coronary angiography and 33 patients with continuous coronary heart disease confirmed by normal control group are used. Based on the results of the imaging, at least one subject with > 50% degree of coronary stenosis was selected as the patient group, and all subjects with <50% degree of coronary stenosis were selected as the control group.
2. Method of producing a composite material
2.1 isolating the sample
PBMCs were separated by density gradient centrifugation with sample to lymphocyte separation volume of 1:1,2000rpm 20min, after layering, inserting into a cloud layer by using a liquid shifter, sucking a mononuclear cell, then storing the mononuclear cell in a TRIzol reagent, centrifuging total RNA for 15min by using 12000g of chloroform, centrifuging for 12000g of 10min by using equal volume of isopropanol, precipitating, centrifuging for 7500g of 5min by using 75% ethanol, purifying, and finally dissolving in water without RNase.
2.2 design of primers
The same Divergent (circular) primer as in example 1.
2.3 reverse transcription
The same as in example 1.
PCR amplification
The same as in example 1.
4. Results
Statistical analysis results show that circZBTB46 has significant expression difference (p < 0.05) between the two groups, and the gene has high expression in the coronary heart disease group. The analysis result of the working characteristic curve of the subject shows that the area under the curve is more than 0.5 (figure 5), and the gene has certain diagnostic capacity for the coronary atherosclerosis.
The results show that the circZBTB46 is involved in the process of coronary atherosclerosis, can obviously influence the functions of human coronary artery smooth muscle cells, and has feasibility for diagnosing and identifying patients with coronary atherosclerosis by detecting the expression level of the molecule.
It is to be understood that this invention has been described by way of example only and that modifications may be made within the scope and spirit of the invention. The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (7)
1. A circular non-coding RNA-circZBTB46, characterized by: the nucleotide sequence of the RNA-circZBTB46 is shown as SEQ ID NO. 1.
2. Use of an agent for detecting the expression level of circular non-coding RNA-circZBTB46 for the preparation of a diagnostic agent for diagnosing or predicting the risk of developing coronary atherosclerosis, characterized in that: the nucleotide sequence of the RNA-circZBTB46 is shown as SEQ ID NO. 1.
3. Use according to claim 2, characterized in that: the detection preparation is used for judging whether the subject has or is at risk of developing coronary atherosclerosis by detecting the expression of RNA-circZBTB46 in PBMC cells of the subject and obviously increasing the expression compared with a healthy control group.
4. Marker for diagnosing and predicting the risk of developing coronary atherosclerosis characterized in that: the marker is circular non-coding RNA-circZBTB46, and the nucleotide sequence is shown in SEQ ID NO. 1.
5. A diagnostic reagent for coronary atherosclerosis, comprising: a preparation for detecting the expression quantity of RNA-circZBTB46, wherein the nucleotide sequence of the RNA-circZBTB46 is shown as SEQ ID NO. 1.
6. A diagnostic kit for coronary atherosclerosis, characterized in that: the diagnostic kit comprising the diagnostic reagent according to claim 4.
7. The diagnostic kit of claim 6, wherein: the diagnostic reagent comprises a forward primer and a reverse primer, wherein the nucleotide sequence of the forward primer is shown as SEQ ID NO.2, and the nucleotide sequence of the reverse primer is shown as SEQ ID NO. 3.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017211999A1 (en) * | 2016-06-08 | 2017-12-14 | Aalborg Universitet | Antisense oligonucleotides for modulation of long noncoding rnas |
| CN114032237A (en) * | 2021-10-11 | 2022-02-11 | 哈尔滨医科大学 | Circular non-coding RNA circSTK39 and application thereof in preventing and treating atherosclerosis |
| CN115058420A (en) * | 2022-06-09 | 2022-09-16 | 哈尔滨医科大学 | Circular non-coding RNA-circSP3, interference RNA thereof and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017211999A1 (en) * | 2016-06-08 | 2017-12-14 | Aalborg Universitet | Antisense oligonucleotides for modulation of long noncoding rnas |
| CN114032237A (en) * | 2021-10-11 | 2022-02-11 | 哈尔滨医科大学 | Circular non-coding RNA circSTK39 and application thereof in preventing and treating atherosclerosis |
| CN115058420A (en) * | 2022-06-09 | 2022-09-16 | 哈尔滨医科大学 | Circular non-coding RNA-circSP3, interference RNA thereof and application thereof |
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