MG53 protein bionic nano-drug, preparation method thereof and application of MG53 protein bionic nano-drug in post-myocardial infarction repair

Abstract

The invention discloses an MG53 protein bionic nano-drug and a preparation method thereof, nano mesoporous silica is used as a carrier of MG53 protein, the MG53 protein is loaded in silica mesopores through electrostatic interaction, and the surface of the mesoporous silica is coated with an erythrocyte membrane; the invention further discloses application of the MG53 protein bionic nano-drug in preparation of drugs for treating and / or preventing myocardial infarction and cardiac function recovery after myocardial infarction and application of the MG53 protein bionic nano-drug in preparation of drugs for treating and / or preventing heart injury. The protein bionic nano-drug provides a new method for intracellular delivery of high-molecular-weight protein, is expected to provide a new drug and an effective protection measure for myocardial infarction protection, and provides a new idea for in-vivo treatment of MG53 protein.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to an MG53 protein bionic nanomedicine, a preparation method thereof, and an application thereof in post-myocardial infarction repair. Background Art

[0002] Acute myocardial infarction (AMI) is one of the leading causes of death in humans. Currently, interventional therapy or coronary artery bypass surgery can help restore blood supply to patients, but about 30% of patients with myocardial infarction who have been treated will still suffer from heart failure within 5 years. Cardiomyocytes are highly differentiated cells that generally cannot divide and proliferate. Their death will lead to a decrease in the number of cardiomyocytes, thereby causing ventricular remodeling and eventually developing into heart failure. Therefore, repairing damaged cardiomyocytes and reducing their death is crucial for preventing and treating heart failure after myocardial infarction.

[0003] Mitsugumin53 (MG53) is a protein mainly secreted by muscle, belonging to the Tripartitemotif (TRIM) family, and is abundantly expressed in myocardium and skeletal muscle. MG53 protein has been shown to have significant protective effects on a variety of heart diseases, including myocardial ischemia-reperfusion injury, drug-induced myocardial injury, and heart failure. MG53 protein has the advantages of target specificity, high biological activity, and low toxicity and side effects, but like most protein drugs, it is easily degraded in the body and easily cleared by the immune system, which gives it a short half-life. Existing literature has confirmed that the half-life of recombinant MG53 protein in the blood is only about 1.4h. Moreover, the MG53 protein has a large molecular weight and a limited number of surface charges, so it is difficult for it to penetrate the cell membrane and enter the cell, resulting in limited therapeutic effects. Therefore, efficient delivery of MG53 protein into cells is expected to further enhance its myocardial protective effect.

[0004] Cell membrane biomimetic nanocarriers wrap endogenous biological membranes on the surface of traditional synthetic nanomaterials, using endogenous cell membranes to improve the biocompatibility of nanocarriers, reduce their susceptibility to being engulfed by the immune system, and thus achieve longer in vivo circulation cycles and more precise organ targeting. Currently, cell membrane biomimetic nanocarriers have shown significant advantages in the fields of early diagnosis and targeted treatment of diseases. However, there are few reports on nanocarriers that deliver MG53 protein to myocardial cells. The development of a nanocarrier that prolongs the half-life of MG53 protein and enhances the intracellular delivery of MG53 protein to myocardial cells is of great significance for the treatment of myocardial infarction. Summary of the invention

[0005] The purpose of the present invention is to solve the above problems and provide a MG53 protein bionic nanomedicine and a preparation method thereof and application thereof in post-myocardial infarction repair.

[0006] In order to achieve its purpose, the present invention adopts the following technical solution:

[0007] The first aspect of the present invention provides a MG53 protein bionic nanomedicine, which uses nano-mesoporous silica as a carrier of MG53 protein. The MG53 protein is loaded inside the silica mesopores through electrostatic action, and the surface of the mesoporous silica is coated with a red blood cell membrane; preferably, the pore size of the nano-mesoporous silica is ≥5nm, preferably 5-10nm.

[0008] Preferably, in the MG53 protein bionic nanomedicine, the red blood cell membrane is coated on the surface of mesoporous silica by physical extrusion.

[0009] The second aspect of the present invention provides a method for preparing the above-mentioned MG53 protein bionic nanomedicine, comprising the following steps:

[0010] (1) taking nano-mesoporous silica, mixing it with MG53 protein solution, allowing MG53 protein to be loaded onto the mesoporous silica, and obtaining drug-loaded nano-silica particles mSiO2@MG53;

[0011] (2) preparing red blood cell membranes, mixing the red blood cell membranes with mSiO2@MG53 at a mass ratio of 0.25 to 2:1, and allowing the red blood cell membranes to wrap around the surface of the silica particles of mSiO2@MG53, thereby obtaining MG53 protein bionic nanomedicine; preferably, the mass ratio of the red blood cell membranes to mSiO2@MG53 is 0.25 to 1:1 or 0.3 to 0.6:1.

[0012] In the above-mentioned technical scheme of the preparation method, in the step (1), the mass ratio of nano-mesoporous silica to MG53 protein is 2-5:1, the reaction time is 4-12 hours, and the unloaded MG53 protein is removed by centrifugation.

[0013] The method for wrapping silica with erythrocyte membrane in step (2) is as follows: taking erythrocyte membrane and extruding it back and forth for multiple times using a liposome extruder to obtain erythrocyte membrane vesicles, preferably extruding 8-20 times; taking erythrocyte membrane vesicles and mSiO2@MG53 and mixing them evenly according to a mass ratio of 0.25 to 2:1, and after mixing evenly, passing through a liposome extruder containing a 200nm polycarbonate membrane, extruding them multiple times until the erythrocyte membrane is wrapped around the outer surface of the silica particles, preferably extruding 8-20 times;

[0014] Preferably, when preparing red blood cell membrane vesicles, the red blood cell membrane is passed through polycarbonate membrane liposome extruders with different pore sizes in sequence to reduce the size of the red blood cell membrane to match the size of mSiO2@MG53, first passing through a large-pore polycarbonate membrane and then passing through a small-pore polycarbonate membrane; preferably, it is extruded multiple times through a liposome extruder with a polycarbonate membrane with a pore size of 400nm and 200nm to obtain red blood cell membrane vesicles.

[0015] In the above-mentioned preparation method and technical scheme, nano-mesoporous silica is used Prepared by synthetic method;

[0016] The preferred preparation method is: stir a mixed solution of hexadecyltrimethylammonium bromide and triethylamine at 60° C. for 1 hour, add ethyl orthosilicate, react overnight, and wash the template with ammonium nitrate to obtain nano-mesoporous silica mSiO2.

[0017] In the above-mentioned technical solution of the preparation method, the red blood cell membrane is obtained by extracting the red blood cells using a hypotonic hemolysis method; preferably, the hypotonic hemolysis method uses 0.25×PBS buffer or pure water for extraction.

[0018] The third aspect of the present invention provides the use of the above-mentioned MG53 protein bionic nanomedicine in the preparation of a drug for treating and / or preventing myocardial infarction and restoring cardiac function after myocardial infarction.

[0019] In the above-mentioned application technology scheme, the drug significantly reduces myocardial fibrosis after myocardial infarction and reduces the area of ​​myocardial infarction.

[0020] The fourth aspect of the present invention provides the use of the above-mentioned MG53 protein bionic nanomedicine in the preparation of a drug for treating and / or preventing cardiac damage, wherein the cardiac damage includes cardiac cell or myocardial tissue damage caused by at least one of cardiovascular disease, cardiac ischemia / reperfusion injury, hypoxia injury, heart failure or a combination thereof.

[0021] The beneficial effects of the present invention are:

[0022] The present invention realizes efficient loading of the macromolecular protein MG53 based on the advantages of large specific surface area and controllable size of mesoporous silica. Red blood cells are the most abundant component in plasma. The red blood cell membrane is easy to extract and obtain, and the CD47 protein contained on the surface has the ability to escape the phagocytosis of the immune system, which makes it have an ultra-long half-life in the body.

[0023] The MG53 protein bionic nanomedicine of the present invention utilizes CD47 protein on the surface of erythrocyte membrane, which can significantly reduce the phagocytosis of exogenous proteins by immune cells and reduce the distribution in the liver and spleen; it can significantly prolong the in vivo circulation time of MG53 protein, and the half-life is extended from about 1.8 hours to 15.2 hours; it can significantly enhance the intracellular delivery to myocardial cells under hypoxic conditions; it can enhance the protective effect of MG53 on myocardial infarction; it can significantly improve cardiac function, reduce the area of ​​myocardial infarction, reduce the apoptosis of myocardial cells, and effectively promote the recovery of myocardial infarction. The protein bionic nanomedicine of the present invention provides a new method for the intracellular delivery of large molecular weight proteins, is expected to provide a new drug and an effective protective measure for protecting myocardial infarction, and provides a new idea for the in vivo treatment of MG53 protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The particle size (AB), Zeta potential (C) and membrane protein expression (D) of RBCs@mSiO2@MG53;

[0025] Figure 2 Fluorescence images of macrophages engulfing RBCs@mSiO2@MG53-FITC and mSiO2@MG53-FITC;

[0026] Figure 3 Fluorescence images (A) and quantitative images (B) of the phagocytosis of RBCs@mSiO2@MG53-Alexa Fluro647 and mSiO2@MG53-AlexaFluro647 by the liver and spleen;

[0027] Figure 4 Fluorescence intensity graph of blood at different time points after injection of RBCs@mSiO2@MG53-TARMA and mSiO2@MG53-TARMA through tail vein;

[0028] Figure 5 The intracellular delivery of RBCs@mSiO2@MG53-FITC and mSiO2@MG53-FITC to cardiomyocytes H9C2 in normal culture and H2O2 (100uM) treatment;

[0029] Figure 6 The effects of MG53 and RBCs@mSiO2@MG53 on cardiac function in mice with myocardial infarction;

[0030] Figure 7 The effects of MG53 and RBCs@mSiO2@MG53 on the myocardial infarction area in mice with myocardial infarction;

[0031] Figure 8The effects of MG53 and RBCs@mSiO2@MG53 on the myocardial fibrosis area in mice with myocardial infarction;

[0032] In the figure:

[0033] RBC ghost represents the directly extracted, incomplete red blood cell membrane;

[0034] RBC vesicles represent intact red blood cell membranes prepared by extrusion of directly extracted red blood cell membranes through a liposome extruder;

[0035] Rm@mSiO2 stands for RBCs@mSiO2, which refers to mesoporous silica wrapped by red blood cell membrane without entrapped MG53 protein;

[0036] Rm@mSiO2@MG53 stands for RBCs@mSiO2@MG53. DETAILED DESCRIPTION

[0037] The present invention will be further described below in conjunction with embodiments, but the present invention is not limited thereto.

[0038] The experimental methods in the following examples are conventional methods unless otherwise specified.

[0039] Main reagents and materials:

[0040] Hexadecyltrimethylammonium bromide: C19H42BrN, CAS registration number 57-09-0;

[0041] Triethylamine: C6H15N, CAS registration number 121-44-8;

[0042] Ethyl orthosilicate: CAS registration number 78-10-4;

[0043] TARMA dye: G-Biosciences, USA.

[0044] Fluorescein isothiocyanate (FITC): G-Biosciences, USA.

[0045] MG53 protein: Novoprotein, China.

[0046] Example 1 Preparation of MG53 protein bionic nanomedicine (RBCs@mSiO2@MG53)

[0047] 1. Preparation of drug-loaded mesoporous silica nanocarrier (mSiO2@MG53)

[0048] Dissolve 6g of hexadecyltrimethylammonium bromide and 0.18g of triethylamine in 60ml of water and stir at 60°C for 1 hour. Then add 20ml of ethyl silane and stir overnight to react. Then, wash 6 times with an ethanol solution of ammonium nitrate (wherein the concentration of ammonium nitrate is 0.6wt%) to remove the template and obtain a mesoporous silica (mSiO2) nanocarrier. Take the prepared mSiO2 and prepare it into a suspension with a content of 5mg / ml using PBS buffer. Then take 1ml of ultrasound for 15min to evenly disperse the nanosilica, and then react with 1ml of MG53 protein (2mg / mL, the solvent is ddH2O) at room temperature for 6h, centrifuge and pour off the supernatant to remove the unloaded MG53 protein, and the resulting precipitate is mSiO2@MG53.

[0049] 2. Preparation of red blood cell membrane

[0050] Blood from C57BL / 6 mice was collected, centrifuged at 800g for 5 minutes, and washed with PBS buffer solution until the plasma was completely removed to obtain red blood cells. The red blood cells were then treated with 0.25×PBS buffer on an ice bath for 30 minutes, then centrifuged at 12000g for 15 minutes, and washed three times with ice PBS buffer to obtain the purified red blood cell membrane, which was stored at -80°C for later use. Red blood cell membranes can be obtained using different conventional preparation methods.

[0051] 3. Preparation of MG53 protein bionic nanomedicine (RBCs@mSiO2@MG53)

[0052] Take the previously purified red blood cell membrane and ultrasonicate it in an ice bath for 5 minutes, and squeeze it back and forth 15 times through a liposome extruder with a 400nm and 200nm polycarbonate membrane to obtain red blood cell membrane vesicles, and use the BCA protein assay kit to determine the concentration. Take the previously prepared red blood cell membrane vesicles and mSiO2@MG53 according to a mass ratio of 0.5:1 and mix them evenly. After mixing evenly, pass through a liposome extruder containing a 200nm polycarbonate membrane, squeeze 15 times, and collect the solution. Centrifuge at 10000rpm for 10min, pour off the supernatant to remove the unwrapped cell membrane, and resuspend it with 1×PBS buffer to obtain mesoporous silica wrapped with red blood cell membrane and loaded with MG53 protein, that is, MG53 protein biomimetic nanomedicine (RBCs@mSiO2@MG53).

[0053] Figure 1This is a transmission electron microscope image of the prepared RBCs@mSiO2@MG53, and the results show that the size of the inner core mesoporous silica is 90nm. The dynamic light scattering results show that the size after the red blood cell membrane is wrapped is about 130nm, and the surface potential is -14.8mV. The Western Blot experiment proved that after the red blood cell membrane is wrapped, the CD47 protein is retained on the surface of the MG53 protein bionic nanomedicine.

[0054] Example 2 RBCs@mSiO2@MG53 detection

[0055] 1. Phagocytosis of RBCs@mSiO2@MG53 by macrophages in vitro

[0056] mSiO2@MG53 and RBCs@mSiO2@MG53 were labeled with fluorescein isothiocyanate (FITC) to obtain FITC-labeled nanodrugs mSiO2@MG53-FITC and RBCs@mSiO2@MG53-FITC.

[0057] RAW264.7 macrophages were cultured at 0.5 × 10 5 The cells were seeded in the culture chamber at a density of EZslide was incubated at 37°C overnight. Then mSiO2@MG53-FITC or

[0058] RBCs@mSiO2@MG53-FITC, make the concentration of MG53 protein in each well equal, the final concentration of MG53 protein in each well is 50μg / mL, and incubate with macrophages at 37℃, 5% CO2 for 24h. Wash three times with PBS buffer, 5min each time. Then fix the cells with 4% paraformaldehyde for 15 minutes, wash three times with PBS buffer, and add DAPI (4',6-diamidino-2-phenylindole) dye solution to stain at room temperature for 5 minutes. The cells are finally observed under laser confocal microscope.

[0059] Figure 2 These are the results of the macrophage phagocytosis experiment on bionic nanomedicines: compared with mSiO2@MG53, the phagocytosis of RBCs@mSiO2@MG53 by macrophages was significantly reduced, indicating that MG53 bionic nanomedicine can reduce its phagocytosis by the immune system.

[0060] 2. Phagocytosis of RBCs@mSiO2@MG53 by the immune system

[0061] Alexa Fluor 647-labeled mSiO2@MG53 or RBCs@mSiO2@MG53 were injected at a dose of 5 mg / kg of MG53 protein (5 mg of MG53 protein per kg of body weight per mouse). The mice were killed 24 hours later, and their livers and spleens were taken out and imaged using a small animal in vivo imaging device under the same conditions to observe the distribution of the nanomedicine.

[0062] Figure 3 These are the results of the phagocytosis of mSiO2@MG53 and RBCs@mSiO2@MG53 by the liver and spleen in mice. The results show that the liver and spleen phagocytize less RBCs@mSiO2@MG53, which can increase the circulation time in the body and increase delivery to target organs.

[0063] 3. Determination of the in vivo half-life of MG53 protein biomimetic nanomedicine

[0064] 6-8 weeks old male C57BL / 6J mice were injected with TARMA dye-labeled RBCs@mSiO2@MG53 or mSiO2@MG53 through the tail vein at an injection volume of 2mg / kg of MG53 protein (2mgMG53 protein per kg body weight per mouse). At different time points, 20uL of blood was collected through the tail, and then 30uL of PBS buffer was added to the blood. The fluorescence intensity was then measured using an ELISA reader.

[0065] Figure 4 The metabolic curves of mSiO2@MG53 and RBCs@mSiO2@MG53 in mice show that the half-life of mSiO2@MG53 is 0.25 hours; the half-life of RBCs@mSiO2@MG53 is 15.2 hours, which is longer than the circulation period of mSiO2@MG53 in the body, indicating that the constructed MG53 bionic nanomedicine can optimize its pharmacokinetics.

[0066] Figure 2-4 The results collectively indicate that RBCs@mSiO2@MG53 biomimetic nanomedicine can reduce phagocytosis by the immune system, have a longer circulation time in the body, and enhance delivery to target organs, which is a greater advantage than the MG53 protein alone.

[0067] IV. Delivery of MG53 protein biomimetic nanomedicine to cardiomyocytes

[0068] H9C2 cardiomyocytes were cultured at 0.5 × 10 5Cells were seeded into 24-well plates at a density of 100 cells / well and incubated for 24 hours. Then FITC-labeled MG53 protein or RBCs@mSiO2@MG53 was added to the cardiomyocytes to make the concentration of MG53 protein in each well equal, and the final concentration of MG53 protein in each well was 4μg / mL. H2O2 treatment group: 100uM hydrogen peroxide was added at the same time as MG53 or RBCs@mSiO2@MG53. After incubation for 12 hours, the cells were washed three times with PBS buffer and then fixed with 4% paraformaldehyde. The cell nuclei were stained with DAPI for 5 minutes and then observed with a confocal microscope.

[0069] Figure 5 The results of the delivery of MG53 protein and RBCs@mSiO2@MG53 bionic nanodrug to cardiomyocytes: no matter in the normal group or the hydrogen peroxide-induced injury group, RBCs@mSiO2@MG53 bionic nanodrug can be taken up by cardiomyocytes, and compared with MG53 protein, it can enhance its intracellular delivery to cardiomyocytes.

[0070] 5. Protective effect of MG53 protein bionic nanomedicine on myocardial infarction

[0071] Myocardial infarction (MI) model was established in 6-8 week old male C57BL / 6J mice by ligating the left anterior descending artery. The sham group (Sham) underwent the same thoracotomy on mice, but the coronary artery was not ligated. The mice in the treatment group were injected with RBCs@mSiO2@MG53 or MG53 through the tail vein, with an injection volume of 1 mg / kg of MG53 protein (meaning that the injection volume for each mouse is 1 mg MG53 protein per kilogram of body weight). The injection was once every two days for two consecutive weeks. The model group or sham group was injected with an equal volume of normal saline as a control (Saline group in the figure). After 28 days, the cardiac function was evaluated by small animal ultrasound. Subsequently, the mice were killed and the heart tissue was collected. The heart tissue was fixed in 4% paraformaldehyde, dehydrated, embedded, and sliced, and the area of ​​myocardial infarction was observed by Masson staining.

[0072] Figure 6 The effects of MG53 protein and RBCs@mSiO2@MG53 on cardiac function were shown. The results showed that both MG53 protein and RBCs@mSiO2@MG53 bionic nanodrug treatment could improve the cardiac function of mice with myocardial infarction, but the protective effect of RBCs@mSiO2@MG53 bionic nanodrug was more significant.

[0073] Figure 7Masson staining was used to evaluate the infarct size of the myocardium of mice after treatment with MG53 protein and RBCs@mSiO2@MG53. The results showed that both MG53 protein and RBCs@mSiO2@MG53 could reduce the infarct size of the myocardium of mice. In contrast, the infarct size of mice treated with RBCs@mSiO2@MG53 was smaller.

[0074] Figure 8 Masson staining was used to evaluate the myocardial fibrosis area of ​​mice after treatment with MG53 protein and RBCs@mSiO2@MG53. The results showed that both MG53 protein and RBCs@mSiO2@MG53 could reduce myocardial fibrosis in mice. In contrast, the fibrosis area of ​​mice treated with RBCs@mSiO2@MG53 was smaller.

[0075] Figure 6-8 The results showed that MG53 protein and RBCs@mSiO2@MG53 can enhance the cardiac function of mice with myocardial infarction, reduce the area of ​​myocardial infarction and myocardial fibrosis. In contrast, RBCs@mSiO2@MG53 has a more significant protective effect on myocardial infarction in mice.

[0076] In summary, the MG53 bionic nanomedicine described in the present invention can significantly reduce the phagocytosis of MG53 protein by the immune system, prolong its half-life in the body, enhance the intracellular delivery to cardiomyocytes, and improve the protective effect of MG53 protein on myocardial infarction.

Claims

1. A MG53 protein bionic nanomedicine, characterized in that: Nano-mesoporous silica is used as a carrier of MG53 protein. MG53 protein is loaded inside the mesopores of silica through electrostatic action, and the surface of the mesoporous silica is coated with red blood cell membrane; preferably, the pore size of the nano-mesoporous silica is ≥5nm, preferably 5-10nm.

2. The MG53 protein bionic nanomedicine according to claim 1, characterized in that: The red blood cell membrane is coated on the surface of the mesoporous silica by physical extrusion.

3. The method for preparing the MG53 protein bionic nanomedicine according to claim 1, characterized in that: The steps include: (1) taking nano-mesoporous silica, mixing it with MG53 protein solution, allowing MG53 protein to be loaded onto the mesoporous silica, and obtaining drug-loaded nano-silica particles mSiO2@MG53; (2) preparing red blood cell membranes, mixing the red blood cell membranes with mSiO2@MG53 at a mass ratio of 0.25 to 2:1, and allowing the red blood cell membranes to wrap around the surface of the silica particles of mSiO2@MG53, thereby obtaining MG53 protein bionic nanomedicine; preferably, the mass ratio of the red blood cell membranes to mSiO2@MG53 is 0.25 to 1:1 or 0.3 to 0.6:

1.

4. The preparation method according to claim 3, characterized in that: In the step (1), the mass ratio of nano-mesoporous silica to MG53 protein is 2-5:1, the reaction time is 4-12 hours, and the unloaded MG53 protein is removed by centrifugation.

5. The preparation method according to claim 3, characterized in that: The method for wrapping silica with red blood cell membrane in step (2) is as follows: taking red blood cell membrane and extruding it back and forth for multiple times using a liposome extruder to obtain red blood cell membrane vesicles, preferably extruding 8-20 times; taking red blood cell membrane vesicles and mSiO2@MG53 and mixing them evenly according to a mass ratio of 0.25 to 2:1, and after mixing evenly, passing through a liposome extruder containing a 200nm polycarbonate membrane, extruding them multiple times until the red blood cell membrane is wrapped around the outer surface of the silica particles, preferably extruding 8-20 times; Preferably, when preparing red blood cell membrane vesicles, the red blood cell membrane is passed through polycarbonate membrane liposome extruders with different pore sizes in sequence to reduce the size of the red blood cell membrane to match the size of mSiO2@MG53, first passing through a large-pore polycarbonate membrane and then passing through a small-pore polycarbonate membrane; preferably, it is extruded multiple times through a liposome extruder with a polycarbonate membrane with a pore size of 400nm and 200nm to obtain red blood cell membrane vesicles.

6. The preparation method according to claim 3, characterized in that: Nano-mesoporous silica Prepared by synthetic method; The preferred preparation method is: stir a mixed solution of hexadecyltrimethylammonium bromide and triethylamine at 60° C. for 1 hour, add ethyl orthosilicate, react overnight, and wash the template with ammonium nitrate to obtain nano-mesoporous silica mSiO2.

7. The preparation method according to claim 3, characterized in that: The erythrocyte membrane is obtained by extracting erythrocytes using a hypotonic hemolysis method; preferably, the hypotonic hemolysis method uses 0.25×PBS buffer or pure water for extraction.

8. Use of the MG53 protein bionic nanomedicine according to claim 1 in the preparation of a drug for treating and / or preventing myocardial infarction and restoring cardiac function after myocardial infarction.

9. The use according to claim 8, characterized in that: The drug significantly alleviates myocardial fibrosis after myocardial infarction and reduces the area of ​​myocardial infarction.

10. Use of the MG53 protein bionic nanomedicine according to claim 1 in the preparation of a drug for treating and / or preventing cardiac damage, wherein the cardiac damage includes cardiac cell or myocardial tissue damage caused by at least one of cardiovascular disease, cardiac ischemia / reperfusion injury, hypoxia injury, heart failure or a combination thereof.

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