CN113244397A - Application of immune-related transcription factor Bach2 - Google Patents
Application of immune-related transcription factor Bach2 Download PDFInfo
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- CN113244397A CN113244397A CN202110521386.0A CN202110521386A CN113244397A CN 113244397 A CN113244397 A CN 113244397A CN 202110521386 A CN202110521386 A CN 202110521386A CN 113244397 A CN113244397 A CN 113244397A
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Abstract
The invention relates to application of an immune-related transcription factor Bach2, belonging to the technical field of biological medicines. The invention provides an application of an immune-related transcription factor Bach2 in preparation of a medicament for protecting myocardial cells; and the application of an immune-related transcription factor Bach2 in the preparation of medicaments for treating and preventing cardiovascular diseases. The prepared medicine is used for promoting the expression of immune-related transcription factor Bach2, and provides a new target and a new path for the treatment and prevention of cardiovascular diseases.
Description
Technical Field
The invention relates to application of an immune-related transcription factor Bach2, belonging to the technical field of biological medicines.
Background
Cardiovascular diseases are the leading causes of death in Chinese, and the incidence rate tends to increase year by year. In addition, 80% of the sudden deaths are now sudden cardiac deaths, i.e. sudden death caused by cardiac arrest. According to the 'report 2019 on cardiovascular health and disease in China', the number of patients with cardiovascular diseases in China reaches 3.3 hundred million, wherein the number of patients with hypertension reaches 2.45 hundred million, and the patients are at the head; 1300 thousands of cerebral apoplexy, 1100 thousands of coronary heart disease, 450 thousands of heart failure, 250 thousands of rheumatic heart disease and 200 thousands of congenital heart disease account for more than 40 percent of death of resident diseases, become important public health problems and prevent and treat cardiovascular diseases.
There are many risk factors for cardiovascular disease, such as: hypertension, smoking, dyslipidemia, diabetes, overweight, physical inactivity and the like, although a large number of clinical basic subjects are currently under development, such as coronary heart disease, arrhythmia, heart failure and the like, the prevalence and mortality of cardiovascular diseases are increasing year by year, and therefore, the identification of new cardiovascular disease diagnosis and treatment targets is particularly important.
The heart is mainly composed of cardiomyocytes and stroma, wherein the cardiomyocytes account for 75% of the heart volume and are the main components of the heart. Abnormalities in cardiomyocyte structure and function are an important basis for the development of cardiovascular disease. For example, in hypertensive heart, the diameter of myocardial cells increases and the number of sarcomere increases, showing myocardial hypertrophy; in a diabetes model, myocardial cell apoptosis and necrosis and massive proliferation of myocardial interstitium lead to cardiac fibrosis; the sensitivity of KATP channels is reduced in the process of arrhythmia, and calcium of myocardial cells is overloaded, thus finally leading to hypoxia, fibrosis and heart tissue necrosis. Therefore, the normality or abnormality of the function of cardiomyocytes is the key to the regulation of cardiovascular disease.
BTB and CNC homologous gene 2(BTB and CNC homology 2, BACH2) is a transcription factor with basic leucine zipper structure (bZIP domain), which can form heterodimer with small Maf protein and bind with specific sequence Maf recognition elements (MARE) on DNA, inhibit expression of downstream genes, and participate in various cell transcription regulation processes. BACH2 is mainly expressed in cells such as T cells, B cells, and nerve cells, but recently, it was found that BACH2 is also expressed in the heart and intestine. The current research mostly focuses on the correlation between BACH2 and the immune system, and BACH2 can regulate the cycle of lymphocytes through multi-step regulation of immune-related diseases, participation in the development of B lymphocytes and T lymphocytes. BACH2 is a regulator of T lymphocyte to maintain immune homeostasis, and is closely related to the occurrence and development of various immune-related diseases. The abnormal expression of BACH2 can not normally regulate the development and differentiation of B cells, so that the B cells are abnormally differentiated to plasma cells, the initial T cells are continuously differentiated to effector T cells and release inflammatory cytokines such as IFN-gamma, IL-6 and the like. On the other hand, the abnormal expression of BACH2 can inhibit the generation and function of Tregs, so that the Tregs cannot play a role in immunosuppression well, and therefore, the abnormal expression of BACH2 can finally cause the massive production of autoantibodies and the combination with autoantigens to form immune complex deposition, thereby promoting the occurrence of autoimmune diseases. Reduced expression of BACH2 in peripheral blood of patients with multiple sclerosis, affecting the function of CD4+ T cells; in inflammatory bowel disease, BACH2 may exacerbate disease development by affecting antibody class switching. However, no role of BACH2 in cardiomyocytes has been reported.
Disclosure of Invention
The invention aims to solve the technical problem of application of an immune-related transcription factor Bach2 in protecting myocardial cells.
In order to solve the problems, the technical scheme adopted by the invention is to provide the application of an immune-related transcription factor Bach2 in preparation of a medicine for protecting myocardial cells.
The invention provides application of an immune-related transcription factor Bach2 in preparation of medicaments for treating and preventing cardiovascular diseases.
Preferably, the cardiovascular disease includes hypertension, diabetic myocardial injury, drug-induced myocardial injury, myocardial infarction and arrhythmia.
Preferably, the use of said an immune-related transcription factor Bach2 in the preparation of a medicament for the protection of cardiomyocytes; the medicine is used for promoting the expression of an immune-related transcription factor Bach 2.
Preferably, the application of the immune-related transcription factor Bach2 in preparation of medicaments for treating and preventing cardiovascular diseases is used for promoting the expression of the immune-related transcription factor Bach 2.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a specific application of an immune-related transcription factor Bach2 in protecting myocardial cells, and provides a treatment target for diseases such as clinical hypertension, diabetic myocardial injury, drug-induced myocardial injury and the like. The invention provides application of an immune-related transcription factor Bach2 in preparation of a medicament for protecting myocardial cells and application in preparation of medicaments for treating and preventing cardiovascular diseases, and provides a new target and a new path for diagnosis and treatment of cardiovascular diseases.
Drawings
FIG. 1 is a photograph and a schematic diagram of indications that Bach2 can improve myocardial hypertrophy and heart failure in a hypertension model. Wherein panel a shows that myocardial hypertrophy is alleviated following overexpression of Bach 2; panels B-E show that in the myocardial hypertrophy model, LV-s and LV-d were elevated compared to the normal group, whereas EF and FS were reduced compared to the normal group, and that overexpression of BACH2 clearly reversed cardiomyocyte injury caused by TAC.
FIG. 2 is a graph showing the trend of Bach2 expression with increasing ISO (isoproterenol) stimulation time in hypertension models, and the changes in ANP, BNP and Myh7, which are indicators of myocardial hypertrophy and heart failure after Bach2 is over-expressed.
FIG. 3 is a tissue slice and index map of Bach2 in diabetic myocardial injury model, which can significantly improve diabetic myocardial injury, while knockout Bach2 aggravates diabetic myocardial injury.
Wherein the A picture is a tissue slice picture that the heart fibrosis of the diabetic mouse is improved by in-situ overexpression of Bach2 in the heart of the diabetic mouse, and the heart fibrosis of the diabetic mouse is aggravated by in-situ knockout of Bach2 in the heart of the diabetic mouse; panel B shows that overexpression of Bach2 improves Ejection Fraction (EF) of the heart; panel C shows that overexpression of Bach2 improves left ventricular Fractional Shortening (FS); panel D shows that in situ knockout Bach2 worsens the Ejection Fraction (EF) of the heart; figure E shows that in situ knockout Bach2 worsens the left ventricular shortening score (FS).
FIG. 4 is a graph of protein and RNA expression of Bach2 and index changes associated with myocardial injury levels in human samples from a diabetic myocardial injury model;
wherein, the A picture shows that the expression of Bach2 in heart tissues of diabetic patients is reduced on the RNA level, but the expression of indicators of myocardial damage such as Mlkl, Tgf beta 1 and the like is increased; panels B and C show that expression of Bach2 was decreased but increased as an indicator of myocardial injury in heart tissue from diabetic patients at protein level; panel D is a significant down-regulation of protein expression by Bach2 in all of the left ventricle, interventricular septum, and right ventricle.
FIG. 5 is a graph showing the change of indices related to the degree of myocardial damage in a drug-induced myocardial damage model by in vitro intervention of BACH2 (plasmid-transfected overexpression).
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below with reference to the accompanying drawings:
the invention provides application of an immune-related transcription factor Bach2 in preparation of a medicine for protecting myocardial cells.
The invention provides application of an immune-related transcription factor Bach2 in preparation of medicaments for treating and preventing cardiovascular diseases.
The cardiovascular diseases include hypertension, diabetic myocardial damage, drug-induced myocardial damage, myocardial infarction and arrhythmia.
The application of the immune-related transcription factor Bach2 in preparation of a medicament for protecting myocardial cells; the medicine is used for promoting the expression of an immune-related transcription factor Bach 2.
The application of the immune-related transcription factor Bach2 in the preparation of medicaments for treating and preventing cardiovascular diseases is used for promoting the expression of the immune-related transcription factor Bach 2.
The invention is derived on the basis of basic experiments, and relates to application of a transcription factor Bach2 in protecting myocardial cells, including various cardiovascular disease models, such as hypertension, diabetic myocardial injury, drug-induced myocardial injury, myocardial infarction and the like.
a) A hypertension model: c57BL/6J male mice were used for 6 weeks to perform aortic arch narrowing surgery, resulting in a cardiac hypertrophy and heart failure model. On the basis, the heart in-situ overexpression Bach2 shows that Bach2 can improve indexes such as myocardial hypertrophy and heart failure. In a cell model, it is also proved that at different time points of the myocardial hypertrophy model, the expression of Bach2 is increased and then decreased, and the important protection effect is played on myocardial cells. The correlation between Bach2 expression and hypertension was also confirmed in human myocardial samples.
b) Diabetic myocardial injury model: after ordinary C57 mice are fed with high fat for four weeks, streptozotocin (40mg/kg) is injected into the abdominal cavity in small dose, and the injection is performed every other day for three times; after the molding is finished, the success of molding is indicated when the random blood sugar is higher than 16.7mmol/L after two consecutive days of detection. Bach2 was overexpressed in situ in the heart in diabetic mice, and Bach2 was found to significantly ameliorate myocardial damage caused by diabetes. Bach2 was also demonstrated in a cellular model to be able to alleviate cardiomyocyte injury caused by high glucose; bach2 is detected in a human heart sample to be reduced in the expression of diabetic heart and is negatively correlated with indexes such as blood sugar and the like.
c) Drug-induced myocardial injury model: the toxic and side effects of antipsychotic drugs and antitumor drugs are studied. Firstly, injecting an anti-tumor drug in a common C57 mouse at intervals to cause myocardial injury, and then carrying out heart in-situ overexpression Bach2 to observe that the myocardial injury symptom of the mouse is relieved.
d) Myocardial infarction: a mouse model of myocardial infarction (opening the chest, fully exposing the anterior descending branch of the left coronary artery, inserting a needle at the lower margin of the left auricle, and passing a suture through LAD to finish the blockage of LAD blood flow) is developed, and the overexpression of Bach2 is found to relieve the symptoms of myocardial infarction on the basis.
Example 1
A hypertension model: c57BL/6J male mice were used for 6 weeks to perform aortic arch narrowing surgery, resulting in a cardiac hypertrophy and heart failure model. Based on the above, the heart in situ overexpression Bach2 shows that Bach2 can improve indexes such as myocardial hypertrophy and heart failure (as shown in figure 1). Male mice were divided into four groups at 6 weeks using C57 BL/6J: sham (Con-Sham), TAC model (Con-TAC), Sham + Bach2 overexpression (OE-Sham), TAC model + Bach2 overexpression (OE-TAC), with 8 mice per group. The TAC model is an aortic arch constriction surgery to cause myocardial hypertrophy and heart failure, on the basis, heart in-situ overexpression Bach2 (AAV 9-Bach2 is injected into the heart in situ), the Con-TAC group mouse heart is found to show obvious myocardial hypertrophy under a hyposcope, and Bach2 can improve the change (as shown in a picture A in figure 1). WGA staining allowed staining of cardiomyocyte membranes, and in fig. 1 panel a it was observed that cardiomyocyte hypertrophy induced by the TAC model was significantly inhibited by Bach2 (green fluorescent cytofama Fluro). The left ventricular end systolic diameter (LV-s) and the left ventricular end diastolic diameter (LV-d) are important indexes for measuring the heart function, and the B graph and the C graph in the graph in FIG. 1 show that LV-s and LV-d in the model group are obviously increased, and Bach2 almost recovers to a normal level after being over-expressed. The left ventricular short axis shortening (FS) and Ejection Fraction (EF) are direct indicators of cardiac function, and fig. 1, D and E show that the levels of FS and EF in the model group are both significantly reduced, while the over-expression Bach2 can reverse myocardial damage caused by the TAC model.
The experimental results show that: the TAC model can remarkably induce myocardial hypertrophy and increase the volume of myocardial cells, but the index of myocardial hypertrophy after Bach2 is over-expressed is relieved (as shown in a graph in figure 1). In the myocardial hypertrophy model, LV-s and LV-d were elevated compared to the normal group, whereas EF and FS were reduced compared to the normal group, and overexpression of Bach2 clearly reversed cardiomyocyte injury by TAC (FIG. 1, panels B-E). In fig. 1, the following are identified: h & E: (haemattoxylin-eosin stating, hematoxylin-eosin staining); WGA: (Wheat gem agglutinin staining); LV-d (left ventricular end diastole end diameter); LV-s (left ventricular end systolic dimension, left ventricular end systole internal diameter); FS (Fraction shortening, left ventricular minor axis shortening rate); EF: (ejection fraction).
Example 2
With the prolonged ISO (isoproterenol) stimulation time in the hypertension model, it was found that Bach2 expression showed a tendency to increase early and decrease late. In addition, after Bach2 was overexpressed in primary cardiomyocytes in suckling mice, indicators of myocardial hypertrophy and heart failure, such as ANP (atriopeptin), BNP (brain natriuretic peptide) and Myh7 (myostatin heavy chain 7) were all significantly reduced, and Bach2 was further confirmed to be able to protect the heart from hypertension (see fig. 2).
Example 2 the results show that: the expression of Bach2 was found to rise significantly at 6h and then to exhibit a downward trend (as shown in panel a and B of fig. 2) with ISO stimulation of primary cardiomyocytes in suckling mice at different times. Bach2 is over-expressed in primary myocardial cells of suckling mice, and Bach2 shows that the indexes ANP, BNP, Myh7 and the like of myocardial hypertrophy and heart failure are remarkably inhibited (as shown in a C picture and a D picture in a figure 2). The icons in fig. 2: ISO: (isoproterine, isoproterenol); ANP (atriopeptin, atrial natriuretic peptide); BNP (rain natrietic peptide); myh7 (myostatin heavy chain 7, sarcoplasmic globulin heavy chain 7); beta-actin: (β -actin); ERK: (Extracellular Signal Regulated Kinase); actin (actinin). In FIG. C, con represents blank control, con + ISO represents ISO treatment model, and B2OE + ISO represents Bach2 overexpression plus ISO treatment. Bach2-OE in Panel D represents Bach2 overexpression and ISO (min) represents different times of treatment of cells with isoproterenol.
Example 3
Diabetic myocardial injury model: after ordinary C57 mice are fed with high fat for four weeks, streptozotocin (40mg/kg) is injected into the abdominal cavity in small dose, and the injection is performed every other day for three times; after the molding is finished, the success of molding is indicated when the random blood sugar is higher than 16.7mmol/L after two consecutive days of detection. The successfully modeled diabetic mice were randomly divided into four groups: the mice in the group are divided into a Vehicle-1 group (heart in situ injection of over-expressed control adeno-associated virus AAV9-Con), a BACH2 group (heart in situ injection of Bach2 over-expressed adeno-associated virus AAV9-Bach2), a Vehicle-2 group (heart in situ injection of knockout control adeno-associated virus AAV9-shNC) and a shBach2 group (heart in situ injection of Bach2 knockout adeno-associated virus AAV9-shBach2), and 10 mice in each group. Heart in situ overexpression Bach2 in diabetic mice found that Bach2 significantly ameliorated diabetic myocardial injury, while knockout Bach2 exacerbated diabetic myocardial injury (see fig. 3).
Example 3 the results show that: overexpression of Bach2 in situ in the heart of diabetic mice improved the fibrosis of the heart (FIG. 3, panel A) and the Ejection Fraction (EF) of the heart (FIG. 3, panel B), and left ventricular shortening Fraction (FS) (FIG. 3, panel C) of the diabetic mice compared to the control group (Vehicle-1 group). In contrast, heart in situ knock-out Bach2 in diabetic mice exacerbated fibrosis of the heart (as in panel a of fig. 3) and Ejection Fraction (EF) of the heart (as in panel D of fig. 3), left ventricular shortening Fraction (FS) (as in panel E of fig. 3) in diabetic mice compared to control (Vehicle-2) mice. The icons in fig. 3 are: h & E: (haemattoxylin-eosin stating, hematoxylin-eosin staining); sirius Red: (sirius red stain); and (3) IHC: (immunological chemistry staining); EF: (ejection fraction); FS: (Fraction shortening, left ventricular short axis shortening rate).
Example 4
In human samples, protein and RNA levels of Bach2 were detected to be reduced in both diabetic myocardial injury models and inversely correlated with the degree of myocardial injury (see FIG. 4). The inventors collected cardiac tissues of 7 control cardiac tissues (those without cardiovascular disease) and 5 Diabetic (DM) subjects, extracted RNA and protein, and detected the expression of Bach2 and the level of myocardial damage, and the results showed that the expression of Bach2 was significantly down-regulated in Diabetic (DM) heart, while myocardial damage was significantly increased, such as TGF β 1(transforming growth factor β 1), RIP1(receptor-interacting protein kinase 1), RIP3(receptor-interacting protein kinase 3), and MLKL (Mixed kinase lineage domain like protein) (fig. 4 a and B). In addition, 14 samples of paraffin tissues of the heart of control and diabetic subjects were collected, each sample including the Left Ventricle (LV), interventricular septum (IVS) and Right Ventricle (RV), and the immunohistochemical staining was used to count Bach2 expression.
The results show that: expression of Bach2 was reduced in heart tissues of diabetic patients at RNA level, but increased in indicators of myocardial damage such as Mlkl and Tgf β 1 (fig. 4, panel a). The same trend was shown in protein level (as in panels B and C of figure 4). Statistical analysis found that Bach2 protein expression was significantly down-regulated in either the left ventricle, ventricular septum or right ventricle (see panel D in fig. 4). The icons in fig. 4: DM: (diabetic mellitis, diabetes); TGF beta 1: (transforminggrowth factor β 1 ); RIP 1: (receptor-interacting protein kinase 1); RIP 3: (receptor-interacting protein kinase 3); MLKL: (Mixed linkage kinase domain like proteins); LV: (left ventricle); IVS: (interventricular septum); RV: (right ventricles).
Example 5
Drug-induced myocardial injury model: toxic and side effects of antipsychotic drugs and antitumor drugs are researched, wherein IBI308 is an antitumor drug targeting PD-1 and is originally named as Sintilimab (sintilimab), and IBI308 is used for modeling toxic and side effects of myocardial cell drugs in our experiments. Mouse and human myocardial cells HL-1 and AC16 were cultured in vitro, mouse primary myocardial cells were isolated, a myocardial injury model was generated by drug induction, BACH2 (plasmid transfection overexpression) was intervened in vitro, and BACH2 was found to significantly improve drug-induced myocardial injury (see FIG. 5). The results show that: the in vitro overexpression of Bach2 can slow down myocardial cell apoptosis caused by antitumor drugs, thereby protecting cardiac tissues and relieving symptoms.
Con + hIgG4 group in the experiment, which is a control group, was treated with control immunoglobulin; con + IBI308 group, control group treated with IBI 308; b2+ IgG4 group, which is a group treated with control immunoglobulin for Bach2 overexpression; group B2+ IBI 308: groups were treated with IBI308 for Bach2 overexpression. The icons in FIG. 5: NLRP 3: (Nucleotide-binding oligomerization domain, leucoine-rich repeat and pyrin domain-binding 3, Nucleotide-binding oligomerization domain); ASC: (Apoptosis-associated specific-like protein conjugation a CARD, Apoptosis-related granule-like protein); GSDMD: (Gasderm min D protein).
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (5)
1. An application of an immune-related transcription factor Bach2 in preparing the medicines for protecting myocardial cells.
2. An application of the immune-related transcription factor Bach2 in preparing the medicines for preventing and treating cardiovascular diseases is disclosed.
3. The use of an immune-related transcription factor Bach2 in the preparation of a medicament for the treatment and prevention of cardiovascular disease according to claim 2, wherein: the cardiovascular diseases include hypertension, diabetic myocardial injury, drug-induced myocardial injury, myocardial infarction and arrhythmia.
4. Use of an immune-related transcription factor Bach2 as defined in claim 1 in the preparation of a medicament for the protection of myocardial cells; the method is characterized in that: the medicine is used for promoting the expression of an immune-related transcription factor Bach 2.
5. The use of an immune-related transcription factor Bach2 in the preparation of a medicament for the treatment and prevention of cardiovascular disease according to claim 2, wherein: the medicine is used for promoting the expression of an immune-related transcription factor Bach 2.
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| 单圣帅等: "转录因子 BACH2 在冠心病患者外周血单个核细胞中的表达及意义", 《临床免疫学》 * |
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