CN116897885B - Method for constructing atrial fibrillation small animal model and application thereof - Google Patents
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/02—Breeding vertebrates
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/30—Animals modified by surgical methods
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/102—Caprine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/103—Ovine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/107—Rabbit
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/108—Swine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
Abstract
The invention discloses a method for constructing an atrial fibrillation small animal model, which comprises the steps of injecting dexamethasone into the abdominal cavity of the small animal every day in an animal model construction period, and obtaining the animal model after the modeling period is finished. The small animal model of atrial fibrillation represents the most common type of atrial fibrillation in clinic, and has wider research and application range compared with the spontaneous atrial fibrillation model; compared with tail intravenous injection, the intraperitoneal injection has the advantages of less damage to small animals, low operation technical difficulty and higher molding success rate; the invention has lower cost for constructing the animal model and higher economic benefit.
Description
Technical Field
The invention belongs to the field of medical animal experiments, and particularly relates to a method for constructing an atrial fibrillation small animal model and application thereof.
Background
Atrial fibrillation, also known as atrial fibrillation, is one of the more refractory cardiac arrhythmias in clinical treatment, and its morbidity and mortality show an increasing trend year by year. Studies have reported that the incidence of atrial fibrillation is significantly increased in people over 55 years old. Since the exact physiological and pathological mechanisms of atrial fibrillation occurrence have not been elucidated, research of atrial fibrillation mechanisms by an atrial fibrillation animal model has positive significance for the treatment of atrial fibrillation.
At present, an atrial fibrillation animal model is mainly carried out on large animals (such as sheep, dogs, rabbits and the like), but the animal model has the defects of long period, complex operation, high cost, poor modeling stability and the like because a pacemaker is needed to be arranged at the chest. Although mice are used as model animals in the genetic engineering atrial fibrillation model, the research of the model animals is still in the initial stage due to the lack of a definite atrial fibrillation gene and the fact that the mice are too small in atrium and are not easy to accommodate multiple reentrant loops.
Drug induction is one of the main methods for constructing an atrial fibrillation animal model, chen Chunlin and the like take rats as modeling animals, and an SD rat atrial fibrillation model is established by injecting an acetylcholine-calcium chloride mixed solution through tail veins (Chen Chunlin, sweetness, shang Yiqun and the like). Qian Cheng A model of aseptic pericarditis atrial fibrillation of rats was established by uniformly sowing aseptic talc powder on the atrial surface of rats (Qian Cheng. TRPV4 was blocked to inhibit the onset of atrial fibrillation in the aseptic pericarditis model of rats [ D ]. Wuhan: university of science and technology, 2017.). Hu Yingying A model of mouse atrial fibrillation was created by applying chlorhexidine gluconate (Hu Yingying. BMSC inhibits chlorhexidine gluconate-induced mouse atrial fibrillation [ D ] via IL-10. Wuhan: affiliated synergetic with the university of science and technology, china, pediatric, 2019.). The mouse atrial fibrosis model is constructed by adopting a mode of subcutaneously pumping angiotensin II into a mouse (the mouse atrial fibrosis model miRNA expression profile analysis, the effect of miR-483-5p in fibrosis and the prognosis analysis of patients with atrial fibrillation after biological valve replacement [ D ]. Beijing: beijing institute of synergetic medical science, 2021 ]).
However, the above drug induction method has the following drawbacks:
1. the acetylcholine-calcium chloride model represents an autonomic-mediated spontaneous atrial fibrillation model, which is not very representative in clinic, unlike the most common atrial fibrillation model in clinic, which is very small in proportion.
2. When aseptic talcum powder, glucose chlorhexidine or angiotensin II are adopted to build animal models, wound operation is needed to be carried out on animals, death of model animals is easy to cause, modeling operation difficulty is high, and cost is high.
Disclosure of Invention
In order to solve the technical problems, the injury of a trauma operation to a modeling animal is reduced, the technical difficulty of the modeling operation and the modeling cost are reduced, and the animal model is more suitable for clinical research and application. Based on the long-term animal model construction study, the inventor discovers that the dexamethasone-induced amyotrophy animal model can generate atrial fibrillation phenomenon for the first time, so that the dexamethasone-induced amyotrophy animal model is cited in the study on the aspect of constructing the atrial fibrillation animal model. The invention provides the following technical scheme:
in a first aspect, the invention provides a method of constructing a small animal model of atrial fibrillation, comprising:
and injecting dexamethasone into the small animal intraperitoneally every day in an animal model construction period, and obtaining the animal model after the modeling period is finished.
Preferably, the dexamethasone is injected at a dose of 0.5-3.0 mg/kg/day, more preferably 0.5-2.0 mg/kg/day, e.g. 0.5 mg/kg, 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg.
Preferably, the animal model construction period is 10 to 20 days, more preferably 10 to 17 days, still more preferably 10 to 14 days, for example: 10 days, 11 days, 12 days, 13 days, 14 days.
In one embodiment of the invention, prior to the start of modeling, small animals need to be tested for their susceptibility to body weight, electrocardiogram, limb muscle strength and/or atrial fibrillation, so that a sufficient number of animals can be selected from a large number of animals to meet the needs of the modeling and control group for building the model.
In another embodiment of the invention, the process of constructing the animal model further comprises detecting the susceptibility of the model-building small animals and the control group small animals to body weight, electrocardiogram, limb muscle strength and/or atrial fibrillation after the modeling is completed. The animal model was successfully constructed when the test results exhibited significant differences between the model animals and the control animals.
In each of the above embodiments, the small animal is selected from the group consisting of mice.
Preferably, the small animal is selected from a rat or a mouse.
Further preferably, the rat is selected from Wistar rats or SD rats, more preferably SD rats.
Further preferably, the mouse is selected from the group consisting of KM mice, ICR mice, NIH mice, CREM-IbΔC-X transgenic mice, C57/B6 mice or C57BL/6N mice.
In a second aspect, the invention provides a small animal model of atrial fibrillation, which is built by using the small animal model building method of the first aspect.
In a third aspect, the invention provides the use of the small animal model of atrial fibrillation of the first aspect.
Preferably, the application may be the creation of an animal model associated with atrial fibrillation.
Further preferably, the animal model is a large animal (e.g., sheep, dog, rabbit, pig, etc.) or a small animal (e.g., rat, mouse).
The invention has the beneficial effects that:
1. the invention adopts dexamethasone to induce and construct an atrial fibrillation small animal model which represents the most common atrial fibrillation type in clinic, and has wider research and application range compared with a spontaneous atrial fibrillation model.
2. The method adopts the intraperitoneal injection mode, has smaller damage to small animals, and has lower operation technical difficulty and higher molding success rate compared with tail vein injection.
3. The dexamethasone adopted by the invention is about 0.8 yuan/mg, and compared with acetylcholine-calcium chloride which is about 25.3 yuan/mg, the molding cost is lower, and the economic benefit is higher.
Drawings
FIG. 1 shows a mouse animal model construction flow;
FIG. 2 shows the results of statistical analysis of body weight, forelimb grip, atrial fibrillation induction rate, and average atrial fibrillation duration of a pre-modeled mouse;
a in fig. 2 represents the body weight of the mouse, B represents the forelimb grip of the mouse, C represents the atrial fibrillation induction rate of the mouse, and D represents the average atrial fibrillation duration of the mouse;
FIG. 3 shows the results of statistical analysis of the modeled mice body weight, forelimb grip, atrial fibrillation induction rate, and average atrial fibrillation duration;
a in fig. 3 represents the body weight of the mouse, B represents the forelimb grip of the mouse, C represents the atrial fibrillation induction rate of the mouse, and D represents the average atrial fibrillation duration of the mouse;
FIG. 4 shows analysis results of Masson staining, alpha-SMA western blotting, fibrosis region occupancy and alpha-SMA relative expression levels of the modeled mice;
a in FIG. 4 represents Masson staining of mice, B represents alpha-SMA western blotting of mice, C represents the fibrosis region ratio of mice, and D represents the relative expression amount of alpha-SMA of mice.
Detailed Description
The advantages and features of the present invention will become more apparent from the following description when taken in conjunction with the accompanying drawings and detailed description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
The reagents and experimental methods used in the present invention are conventional reagents and experimental methods in the art unless otherwise specified.
The experimental materials, reagents and manufacturers adopted in the invention are as follows:
C57/B6 mice: the genetic background was completely consistent with JAX C57BL/6J (https:// www.jax.org/strain/000664) and genetic stability tests were performed periodically, purchased from Beijing Deg Biotechnology Co.
Dexamethasone sodium phosphate injection: GMP veterinary drug certificate (approval paper: 153931563) was obtained from Ruichang veterinary drug Co., ltd., product No. 2019103014, shanxi proving.
Example 1 construction of a mouse atrial fibrillation model.
The mouse animal model is constructed according to the construction flow shown in fig. 1, and the specific animal model construction process is as follows:
1.1 adaptive feeding of C57/B6 mice
14 male 8-week-old C57/B6 mice (body weight: 20.39 g.+ -. 1.06 g) were randomly divided into a model group and a control group, each group having 7 mice. The mice were then numbered, with model group mice numbered 1-7 and control group mice numbered 8-14. All mice were then subjected to baseline (e.g., body weight, forelimb grip, atrial fibrillation susceptibility, average atrial fibrillation duration) testing, and the results of the testing are shown (tables 1, 2, and fig. 2).
After analysis of the data in Table 1, it can be seen that the average body weight of the model mice was 20.81 and g, and the average forelimb grip strength of the model mice was 0.9 and N; while the average body weight of the control mice was 19.96 g, and the average forelimb grip strength of the control mice was 0.86N. The baseline test results of the model building group and the control group are compared, so that the difference of baseline data (weight and forelimb grip strength) of the two groups of mice is not obvious, and the two groups of mice meet the requirements of a modeling experiment.
After analysis of the data in table 2, it can be seen that only the number 5 mice among the model mice exhibited atrial fibrillation, and the maximum duration of atrial fibrillation was 21.02 s; whereas only mice number 8 and 14 of the control mice exhibited atrial fibrillation, with maximum atrial fibrillation durations of 9.24 s and 1.29 s, respectively. By comparing the baseline test results of the model building group and the control group, the baseline data (atrial fibrillation susceptibility and average atrial fibrillation duration) of the two groups of mice are not obvious, and the two groups of mice meet the requirements of modeling experiments.
In addition, as can be seen from FIG. 2, the model mice had a weight of 20.81.+ -. 0.58. 0.58 g and the control mice had a weight of 19.96.+ -. 1.30 g prior to model construction; the weight difference between model mice and control mice was not significant (p=0.14, and P > 0.05); the forelimb grip strength of the model group mice is 0.90+/-0.10N, the forelimb grip strength of the control group mice is 0.86+/-0.09N, and the forelimb grip strength difference between the model group mice and the control group mice is not obvious (P=0.42 and P is more than 0.05); the atrial fibrillation induction rate of the model building mice is 1/7, the atrial fibrillation induction rate of the control mice is 2/7, and the atrial fibrillation induction rate difference between the model building mice and the control mice is not obvious (P is more than 0.99 and P is more than 0.05); the average atrial fibrillation duration of the model mice was 21.02 s, the average atrial fibrillation duration of the control mice was 9.24 s, and the average atrial fibrillation durations of the model mice and the control mice were not significantly different (P > 0.99, and P > 0.05). The results of figure 2 demonstrate that two groups of mice meet the requirements of the modeling experiment.
1.2 construction of model of atrial fibrillation in C57/B6 mice
The molding group mice are intraperitoneally injected with dexamethasone for 10-14 days at a rate of 0.5-2.0 mg/kg each day; control mice were given the same volume of physiological saline. A model of atrial fibrillation in C57/B6 mice was obtained after drug injection.
1.3 identification of C57/B6 mouse models
1.3.1, body weight, forelimb grip strength, atrial fibrillation susceptibility and average atrial fibrillation duration of control mice and model mice were measured after drug injection was completed. Statistical measurements, results are shown in table 3, table 4 and fig. 3.
After analysis of the data in Table 3, it can be seen that the average body weight of the model mice was 19.32 and g, and the average forelimb grip strength of the model mice was 0.93 and N; while the average body weight of the control mice was 24.30. 24.30 g, and the average forelimb grip strength of the control mice was 1.33. 1.33N. Comparing the test results of the model building group and the control group, the weight of the model building group mouse is lower than that of the control group mouse, and the weight of the model building group mouse is 20.49% lighter than that of the control group mouse; the forelimb grip strength of the model building group mice is lower than that of the control group mice by 30.08 percent. The results in Table 3 demonstrate that the weight and forelimb grip strength differences between the model and control mice are evident after dexamethasone treatment. The use of dexamethasone enables the efficient construction of a mouse atrial fibrillation model.
After the data analysis of table 4, it can be seen that only mice No. 2 and No. 4 in the model mice show atrial fibrillation character, the other mice all show atrial fibrillation character, and the atrial fibrillation maximum duration of mice No. 1, no. 3, no. 5, no. 6 and No. 7 is 2.17 s, 56.54 s, 20.13 s, 4.25 s, 18.22 s, and even 56.54 s; none of the mice in the control group exhibited atrial fibrillation. Comparing the test results of the model and the control group, it can be seen that the atrial fibrillation character of the model mice is obvious, and particularly, the atrial fibrillation character of the No. 5 mice after being treated by dexamethasone. And the atrial fibrillation duration of the model mice is long. The atrial fibrillation character of the mice in the control group is not obvious, particularly the mice No. 8 and No. 14, and the atrial fibrillation character before modeling disappears. The results in Table 4 demonstrate that the atrial fibrillation behavior and duration of atrial fibrillation differ significantly between the model mice and the control mice after dexamethasone treatment. The use of dexamethasone enables the efficient construction of a mouse atrial fibrillation model.
In addition, as can be seen from fig. 3, after the model was constructed, the model mice had a body weight of 19.32±0.76 g, and the control mice had a body weight of 24.31±0.64 g; the weight difference between model group mice and control group mice is significant (P < 0.05); the forelimb grip strength of the model group mice is 0.94+/-0.05N, the forelimb grip strength of the control group mice is 1.33+/-0.12N, and the forelimb grip strength difference between the model group mice and the control group mice is obvious (P is less than 0.05); the atrial fibrillation induction rate of the model building mice is 5/7, the atrial fibrillation induction rate of the control mice is 0, and the atrial fibrillation induction rate of the model building mice and the atrial fibrillation induction rate of the control mice are obviously different (P is less than 0.05); the average duration of atrial fibrillation of the model group mice is 14.47 and s, the average duration of atrial fibrillation of the control group mice is 0.00 and s, and the average durations of atrial fibrillation of the model group mice and the control group mice are obviously different (P < 0.05). The results of fig. 3 demonstrate that after intraperitoneal injection of dexamethasone for molding, the body weight and forelimb grip strength of the molded mice are significantly less than those of the control group; the atrial fibrillation induction rate and average atrial fibrillation duration of the model-built mice are obviously higher than those of the control group, and a mouse atrial fibrillation model can be effectively built by adopting dexamethasone.
1.3.2, after measurement, atrial tissues of mice in the model and control groups were subjected to fibrosis staining (Masson staining), and a fibrosis region ratio was analyzed for fibrosis-related protein (α -SMA) Western blotting experiments. The results are shown in FIG. 4.
As can be seen from fig. 4, after the model is constructed, fibrosis (blue region in fig. a) of the mouse cardiomyocytes (red region in fig. a) of the model-building group is remarkable, and the fibrotic tissue ratio is large, whereas fibrosis of the mouse cardiomyocytes of the control group is not remarkable, and the fibrotic tissue ratio is small; the atrial fibrosis region of the model mice was 13.3% and that of the control mice was 10.7% (see panel C), the atrial fibrosis region of the model mice was significantly higher than that of the control mice (p < 0.05); western blotting results of the atrial tissue fibrosis related proteins of the model mice and the control mice show that the expression level of alpha-SMA in the atrial tissue of the model mice is significantly higher than that of the control mice (see graph B and graph D, p < 0.05). The results of fig. 4 demonstrate that atrial tissue fibrosis is evident in model mice after intraperitoneal injection of dexamethasone compared to control mice, and that the use of dexamethasone is effective in constructing models of atrial fibrillation in mice.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A method of constructing a mouse model of atrial fibrillation, comprising: the method comprises the following steps: and injecting dexamethasone into the abdominal cavity of the mouse every day in an animal model construction period, and obtaining the animal model after the modeling period is finished.
2. The method according to claim 1, characterized in that: the injection dosage of dexamethasone is 0.5-2.0 mg/kg/day.
3. The method according to claim 1, characterized in that: the construction period is 10-20 days.
4. The method according to claim 1, characterized in that: the method further comprises performing a weight, electrocardiogram, limb muscle strength and/or atrial fibrillation susceptibility test on the mice prior to initiation of modeling.
5. The method according to claim 1, characterized in that: the method further comprises the steps of detecting weight, electrocardiogram, limb muscle strength and/or atrial fibrillation susceptibility of the model-building mice and the control mice after modeling is finished; the animal model was successfully constructed when the test results exhibited significant differences between the model-building mice and the control mice.
6. The method according to claim 1, characterized in that: the mice are selected from C57/B6 mice, KM mice, ICR mice and NIH mice.
7. The method according to claim 6, wherein: the mice are C57/B6 mice.
8. Use of the method of any one of claims 1 to 7 in the construction of an animal model of atrial fibrillation.
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