CN116370639A - Pharmaceutical application of Glo I agonist in myocardial ischemia and reperfusion myocardial injury - Google Patents
Pharmaceutical application of Glo I agonist in myocardial ischemia and reperfusion myocardial injury Download PDFInfo
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- CN116370639A CN116370639A CN202310277809.8A CN202310277809A CN116370639A CN 116370639 A CN116370639 A CN 116370639A CN 202310277809 A CN202310277809 A CN 202310277809A CN 116370639 A CN116370639 A CN 116370639A
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Abstract
The invention belongs to the technical field of biological medicines, and relates to a medicinal application of a glyoxalase I (Glo I) agonist in myocardial ischemia and reperfusion myocardial injury, wherein the medicinal application is for treating, preventing or relieving the myocardial ischemia and reperfusion myocardial injury. In addition, the invention verifies that MGO is an important factor of ischemia reperfusion myocardial injury, and then researches myocardial injury mechanism of MGO in ischemia reperfusion injury, wherein the mechanism shows the relevance of reduced expression amount and activity of Glo I to ischemia reperfusion injury, and finally proves the heart protection effect of Glo I agonist on myocardial ischemia and reperfusion injury.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a pharmaceutical application of glyoxalase I (Glo I) agonist in myocardial ischemia and reperfusion myocardial injury.
Background
Acute myocardial infarction is ischemic cardiomyopathy caused by acute persistent ischemia and hypoxia of coronary artery, and at present, coronary bypass operation, thrombolysis and the like are the most common methods for clinically restoring coronary blood flow of heart and treating acute myocardial infarction. However, oxidative stress, calcium overload, and metabolic disturbances caused by sudden energy and oxygen supply during reperfusion therapy lead to myocardial cell injury and increased myocardial infarction area, which is called myocardial ischemia reperfusion injury. In the experimental myocardial infarction model, it was found that the increased infarct size of reperfusion injury may account for 50% of the final myocardial infarction size. During the treatment of patients with acute myocardial infarction, it was found that administration was effective only in the early stage of ischemia or before reperfusion, and treatment in the late stage of reperfusion hardly had any more myocardial protection effect [1] Thus, the early pathophysiological mechanism of targeting MIRI is the main strategy for MIRI myocardial protection class drug development. Early pathophysiological mechanisms of MIRI are complex, and changes in calcium ion homeostasis, activation of inflammatory signaling pathways, metabolic substrate utilization transfer, mitochondrial dysfunction, etc. are all important causes of cardiac dysfunction and myocardial tissue injury. At present, drugs in clinical transformation tests such as adenosine, nitrite, PKC delta inhibitors, MPTP opening inhibitors and the like mainly play a role in heart protection by inhibiting the early injury process or activating the protection process, but no drugs which are consistent with the curative effect of preclinical researches (reducing the myocardial infarction area of reperfusion injury) are available, and non-myocardial protection drugs such as beta-blockers, glucagon-like peptide 1 analogues and the like also fail to obviously improve the prognosis effect of clinical patients, so that the development of heart protection drugs administered before reperfusion or at early stage of reperfusion is still a main medical requirement in the myocardial infarction direction.
Disclosure of Invention
In order to solve the technical problems, the invention discovers that the MGO accumulation in the cardiac muscle is an important injury factor of acute myocardial ischemia and ischemia reperfusion injury, glyoxalase I (Glo I) can accelerate MGO metabolism by increasing the activity of the Glo I enzyme, reduce myocardial cell apoptosis and protect myocardial tissues and heart functions, and provides an application of a novel mechanism for protecting ischemia reperfusion injury cardiac muscle, namely a novel application of a Glo I agonist in preparing myocardial ischemia reperfusion myocardial protection drugs and a novel pharmacological action.
The invention provides application of a Glo I agonist in preparing a medicament for preventing, relieving and/or treating myocardial ischemia and reperfusion myocardial injury.
Further, the Glo I agonist refers to a substance which activates Glo I to Glo I enzyme activity by more than 130% in real time.
Still further, the Glo I agonists include, but are not limited to, xanthone C-glucoside, bardoxolone, sulforaphane, and the like.
Further, the application is the application of the Glo I agonist in preparing a medicament for preventing, relieving and/or treating acute myocardial ischemia;
the acute myocardial ischemia includes but is not limited to coronary artery acute, persistent ischemia, acute myocardial infarction; the acute myocardial infarction is myocardial necrosis caused by acute myocardial ischemia.
Further, the application is the application of the Glo I agonist in preparing a medicament for preventing, relieving and/or treating acute myocardial ischemia reperfusion injury;
the acute myocardial ischemia reperfusion injury is the injury of heart structure and function caused by opening coronary artery by thrombolysis, bypass, coronary artery stent and other modes after acute myocardial infarction.
Further, the application refers specifically to that a single Glo I agonist drug preparation or a drug prepared by combining with a pharmaceutically acceptable diluent or carrier is used for preventing, relieving and/or treating myocardial ischemia and directly related diseases thereof, reperfusion myocardial injury, wherein the myocardial ischemia and directly related diseases thereof comprise but are not limited to cryptogenic coronary heart disease, angina pectoris type, myocardial hard death type, ischemic cardiomyopathy or sudden death type diseases and the like.
Furthermore, the invention also provides a pharmaceutical composition (Glo I agonist pharmaceutical preparation), which comprises the Glo I agonist and other medicines, wherein the Glo I agonist is prepared into a pharmaceutical preparation with single chemical component or is prepared into a compound pharmaceutical preparation by combining with the other medicines; the pharmaceutical preparation can be prepared into various dosage forms according to related requirements of pharmacy and clinical requirements and applied to clinic, and the dosage forms of the pharmaceutical preparation comprise, but are not limited to, tablets, capsules, injections, oral liquids, granules and the like.
Methods and requirements for using Glo I agonist pharmaceutical formulations for preventing, alleviating and/or treating myocardial ischemia are as follows:
the Glo I agonist pharmaceutical formulations of the present invention for preventing, alleviating and/or treating myocardial ischemia may be used alone or in combination with other active ingredients, including for the preparation of products, including pharmaceuticals, reagents, foods, etc., for the prevention, diagnosis, detection, protection, treatment and study of myocardial ischemia and directly related diseases thereof, and in particular pharmaceuticals.
In particular aspects, the Glo I agonist drugs of the present invention for use in the preparation of anti-myocardial ischemia and reperfusion injury can be used alone or in combination with a number of other chemicals. Whether or not the chemicals have biological activity or function of treating a disease, including auxiliary functions such as synergistic amplification, antagonism or alleviation of side effects of Glo I agonist drugs used to prepare anti-myocardial ischemia and reperfusion myocardial injury, etc., the chemicals are one or more of a pharmaceutically acceptable carrier, food, natural product, chemically synthesized drug or human drug, etc.; preferably comprising one or more of a pharmaceutically acceptable carrier or food, etc.; further preferred are pharmaceutically acceptable carriers.
As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically acceptable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic or absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol or ethanol, and the like, and combinations thereof. In many cases, it is desirable to include an isotonic agent, for example, one or more of a sugar, a polyalcohol such as mannitol, sorbitol, or sodium chloride, and the like in the composition. The pharmaceutically acceptable carrier may also contain minor amounts of auxiliary substances, such as one or more of wetting or emulsifying agents, preservatives or buffers, and the like, which enhance the useful life or efficacy of the Glo I agonist pharmaceutical formulations for the preparation of anti-myocardial ischemia and reperfusion myocardial injury.
From a specific classification, the pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, and comprises one or more excipients such as starch or water; a lubricant such as one or more of glycerin or magnesium stearate, etc.; disintegrants such as microcrystalline cellulose and the like; fillers such as one or more of starch or lactose, etc.; a binder such as one or more of pregelatinized starch, dextrin, cellulose derivative, alginate, gelatin, or polyvinylpyrrolidone, etc.; osmotic pressure regulators such as one or more of glucose, sucrose, sorbitol, mannitol, etc.; diluents such as water and the like; disintegrants such as one or more of agar, calcium carbonate or sodium bicarbonate, etc.; absorption promoters such as quaternary ammonium compounds and the like; surfactants such as cetyl alcohol and the like; an adsorption support such as one or more of kaolin or saponite, etc.; a lubricant such as one or more of talc, calcium stearate, magnesium stearate, polyethylene glycol, or the like; in addition, other adjuvants such as one or more of flavoring agent or sweetener can be added into the composition.
For example, the active ingredient is used to prepare a Glo I agonist pharmaceutical formulation against myocardial ischemia and reperfusion injury by dissolving, suspending or emulsifying in a suitable aqueous solvent (e.g., one or more of distilled water, physiological saline, or green's solution, etc.) or in an oily solvent (e.g., one or more of vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, or propylene glycol, etc.), which may contain a dispersing agent (e.g., one or more of polysorbate 80, polyoxyethylene hardened castor oil 60, polyethylene glycol, benzyl alcohol, chlorobutanol, phenol, etc.), an osmotic pressure regulator (e.g., one or more of sodium chloride, glycerol, D9-mannose, D-sorbitol, or glucose, etc.), to prepare an injectable formulation. In this case, additives such as a solubilizing agent (e.g., one or more of sodium salicylate, sodium acetate, etc.), a stabilizer (e.g., human serum albumin, etc.), an analgesic (e.g., benzyl alcohol, etc.), etc. may be added, if necessary.
The Glo I agonist pharmaceutical formulations described herein for use in the preparation of an anti-myocardial ischemia and reperfusion myocardial injury may also be used in combination in a composition, particularly in combination with or similar to a composition for use in the treatment of animals, particularly mammals, including humans or other animals, with other chemicals such as drugs. The mammal comprises one or more of human, mouse, rat, sheep, monkey, cow, pig, horse, rabbit, dog, chimpanzee, baboon, marmoset, macaque or rhesus monkey, preferably one or more of human, mouse, rat, monkey, pig, rabbit or dog, more preferably one or more of human, rat or monkey. For example, the Glo I agonist pharmaceutical formulations of the present invention for use in the preparation of an anti-myocardial ischemia and reperfusion myocardial injury may be incorporated into a pharmaceutical composition suitable for administration to a subject. Generally, the pharmaceutical composition comprises a Glo I agonist pharmaceutical formulation of the invention for use in preparing an anti-myocardial ischemia and reperfusion myocardial injury and a pharmaceutically acceptable carrier.
The Glo I agonist pharmaceutical formulations for use in the preparation of anti-myocardial ischemia and reperfusion myocardial injury may be formulated in a variety of forms using conventional production methods well known in the art, for example by admixing the active ingredient with one or more carriers and thereafter formulating the same into the desired dosage form.
For use in patients, the dosage of the Glo I agonist pharmaceutical formulation of the present invention for use in the preparation of an anti-myocardial ischemia and reperfusion myocardial injury is 10 to 500mg/kg, which is usually determined according to the age and weight of the patient or user and the physical condition or condition of the patient's symptoms.
In the application scheme of the invention, metabolic disorder and oxidative stress in the myocardial ischemia reperfusion process can cause MGO accumulation, and the reduction of the expression and activity of the Glo I agonist in myocardial cells in the ischemia reperfusion or hypoxia reoxygenation process is also an important reason for the MGO accumulation. Accumulated MGO can promote ischemia reperfusion or hypoxia reoxygenation myocardial cell apoptosis through RAGE receptor pathway, damage heart structure, influence heart function and increase myocardial infarction area, and is a novel pathological mechanism of ischemia reperfusion injury.
The invention has the beneficial effects that:
1. the present invention provides a correlation of Glo I agonists with myocardial ischemia, demonstrating that Glo I agonists reduce myocardial apoptosis by accelerating the metabolism of MGO, protecting myocardial tissue and cardiac function.
2. The invention provides a pharmaceutical preparation which contains a Glo I agonist and a pharmaceutically acceptable carrier, can be applied to myocardial ischemia and reperfusion myocardial injury, and has great potential in the aspect of treating acute myocardial infarction based on the novel pharmacological action proved by the invention.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is the accumulation of free MGO in hypoxic reoxygenated cardiomyocytes;
FIG. 2 is the accumulation of bound MGO in hypoxic reoxygenated cardiomyocytes;
FIG. 3 shows the accumulation of MGO in ischemia reperfusion myocardial tissue;
FIG. 4 is a toxicity test of MGO on myocardial cells;
FIG. 5 shows the effect of MGO on promoting apoptosis of cardiomyocytes;
FIG. 6 shows that the decrease in GLO1 expression level and activity are responsible for the accumulation of MGO in ischemia reperfusion injury;
FIG. 7 shows that MGO activates RAGE pathway by interacting with RAGE receptor through MG-H1, causing apoptosis;
FIG. 8 is that a Glo I agonist increases Glo I activity;
FIG. 9 is that a Glo I agonist reduces MGO accumulation, affects RAGE pathway activation, and reduces cardiomyocyte apoptosis;
fig. 10 shows that Glo I agonists reduce the area of myocardial ischemia reperfusion injury myocardial infarction, protecting cardiac structure and function.
Detailed Description
The invention is described below by means of specific embodiments. The technical means used in the present invention are methods well known to those skilled in the art unless specifically stated. Further, the embodiments should be construed as illustrative, and not limiting the scope of the invention, which is defined solely by the claims. Various changes or modifications to the materials ingredients and amounts used in these embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
Metabolic disorders are important pathological mechanisms in the early stages of myocardial ischemia and reperfusion, accompanied by the production of toxic metabolites such as active aldehydes. The active aldehyde has wide chemical activity, can interact with nucleophilic groups on macromolecular substances such as nucleic acid, phospholipid, protein and the like to generate covalent bonding, form irreversible modification, influence the biological functions of macromolecules and promote the occurrence of diseases. Methylglyoxal (MGO), also known as Methylglyoxal, is an endogenous dicarbonyl aldehyde with high reactivity, which is mainly produced by degrading glycolytic intermediate products, namely glyceraldehyde-3-phosphate (GA 3P) and dihydroxyacetone phosphate (DHAP) through a non-enzymatic pathway, and acetone oxidation, amino acid decomposition and lipid peroxidation are also important production pathways of MGO, and MGO is mainly attenuated by metabolism of a glyoxalase system. Clinical studies have found that the levels of MGO in the plasma of patients admitted to a hospital for myocardial infarction and receiving reperfusion therapy rise significantly within hours after surgery and are closely related to the prognosis of the patient, suggesting that MGO may be an important factor in ischemia reperfusion myocardial injury.
Increased production of MGO and decreased metabolism are key factors in the development of MIRI by the accumulation of MGO, which may provide new therapeutic opportunities for MIRI. Current methods for reducing the accumulation of MGO mainly include direct quenching of MGO, blocking or reducing the formation of MGO, and promoting the metabolism of MGO. The chemical aminoguanidine, which directly quenches the MGO, was discontinued from clinical trials due to possible toxicity risks, and carnosine limited its use in humans due to the rapid hydrolysis of it by carnosine enzymes. The main in vivo enzymatic detoxification system of MGO is the Glutathione (GSH) dependent glyoxalase system, which is present in the cytoplasm of all mammalian cells and is capable of metabolizing MGO to non-toxic D-lactic acid. The enzyme system is mainly composed of glyoxalase I (Gloi), glyoxalase II (Gloi II) and a catalytic amount of GSH. Glo i catalyzes the conversion of spontaneously formed hemithioacetals of GSH and MGO to S-D-lactosyl glutathione, which is then hydrolyzed by Glo ii to D-lactic acid and GSH. Under normal conditions of the body, about 99% of the MGO is metabolised by the glyoxalase system for detoxification. The improvement of Glo I autoreactive activity through Glo I agonists is a more immediate and efficient therapeutic measure.
Thus, in some embodiments of the present invention, it was first demonstrated by experiments that MGO is an important factor in ischemia reperfusion myocardial injury, then the myocardial injury mechanism of MGO in ischemia reperfusion injury was studied, which demonstrated the reduced expression level and activity of Glo I in association with ischemia reperfusion injury, and finally the cardioprotective effect of Glo I agonists on myocardial ischemia and reperfusion injury.
Example 1
MGO accumulation in ischemia reperfusion injury
1.1 accumulation of MGO in hypoxic reoxygenated cardiomyocytes
The experimental method comprises the following steps: sterilizing young mice with 75% alcohol, shearing the chest with ophthalmic scissors, squeezing heart, taking out, washing in ice D-hanks for 3 times, and cleaning blood and other tissues; shearing heart tissue with ophthalmic scissors, adding 10m collagenase II, digesting for 5min at 37 ℃, centrifuging at 200rpm, and discarding the supernatant again; adding 10mL collagenase II again, digesting at 37 ℃ for 60min, centrifuging at 200rpm, taking the supernatant, adding an equal amount of myocardial cell culture solution to stop digestion, adding 10mL collagenase II into the remainder again, digesting at 37 ℃ for 60min, centrifuging at 200rpm, and taking the supernatant; centrifuging at 700rpm/5min at normal temperature after digestion is stopped, discarding supernatant, adding myocardial cell culture solution, mixing, sieving the whole culture medium, and placing in 75 culture bottle for 90min; counting the cell suspension after differential adherence by using a cell counting plate, inoculating a confocal small dish by using a hole/inoculating mode, and performing starvation treatment after 48 hours; and (5) changing the liquid for 36-48 hours. Reoxygenation was then carried out for 12 hours after the anoxic treatments for different times (0, 4,8, 12 hours), all dishes were added with MG O fluorescent probes before anoxic for the indicated MGO content.
Experimental results: as shown in fig. 1, the fluorescence intensity was gradually increased with increasing hypoxia time, and the fluorescence intensity was strongest in the H12H group, suggesting that the free MGO content in the H/R group was higher than in the CON group, suggesting that free MGO accumulated with increasing hypoxia time.
1.2 accumulation in hypoxic reoxygenated cardiomyocytes in combination with MGO (FIG. 2)
The experimental method comprises the following steps: h9c2 cells are inoculated into a 6-well plate, 6 x 10 times 5 cells are arranged in each well, CON group is subjected to normal oxygen culture, H/R group is subjected to oxygen deficiency for 12H and reoxygenation for 12H, the cells in the well plate are collected into different EP pipes, protein is extracted by cracking, protein concentration is normalized by a BCA method, and MG-H1 and CML/CEL protein content is detected by an immunoblotting method.
Experimental results: as shown in FIG. 2, the significant increase in MG-H1 and CML/CEL protein levels in the H/R group compared to the CON group suggests that the combined MGO levels in the H/R group are higher than in the CON group, again suggesting the accumulation of MGO during hypoxia reoxygenation.
1.3 accumulation of MGO in ischemia reperfusion myocardial tissue (FIG. 3)
The experimental method comprises the following steps: adult male wistar rats were fasted for 12 hours prior to surgery and fixed on an operating table after anesthesia. The pen-type venous indwelling needle is used for tracheal intubation, and after the tracheal intubation is completed, the tracheal intubation is connected with an animal breathing machine, and the parameters are as follows: a respiratory rate of 85; the respiration ratio is 1:1; tidal volume was 18mL. Sterilizing the chest skin and alcohol cotton, and cutting the skin between 3-4 intercostals on the left side of the chest. Separating muscle to expose rib, separating muscle under the third rib with hemostatic forceps, picking rib with hemostatic forceps in left hand, cutting the third rib with right hand knife, clamping and breaking the cut rib with hemostatic forceps, placing into face opener, and peeling centrifugal envelope with hemostatic forceps. The thymus is clamped and pulled out by hemostatic forceps. And 6-0 # threads are penetrated between the left auricle and the pulmonary artery cone, the left anterior descending branch is ligated, the silk thread is tensioned, myocardial ischemia is formed, the ligation part is loosened after 1h, the blood flow of the left anterior descending branch is restored, the air in the thoracic cavity is extruded, and the thoracic cavity is closed to suture the muscle and the skin. Heart ultrasonic detection and TTC detection are respectively carried out at 8 hours and 10 hours of reperfusion, left ventricular tissues are taken for tissue homogenization to extract proteins, and immunoblotting is used for detecting the expression content of AGEs and MG-H1 proteins.
Experimental results: TTC staining revealed that MI/R groups showed significant infarct areas (FIG. 3B), and H & E staining revealed that Sham groups were well-aligned in myocardium, abundant and uniform in cytoplasm, and normal in stroma; the MI/R group had partially lost cardiomyocyte nuclei, lacunae pattern of cardiomyocytes, myocardial tissue disturbance, and disappeared cardiomyocytes, instead of fibrous scar tissue (FIG. 3C). Ultrasound results showed that MI/R group had reduced stroke volume SV, ejection fraction EF, short axis shrinkage FS and cardiac output CO compared to Sham group (fig. 3D). The results show that the heart function and the myocardial tissue of the MI/R group rats are obviously damaged, which indicates that the modeling is successful. Furthermore, immunoblotting results showed a significant increase in the MGO adducts MG-AGEs and MG-H1 in the myocardial tissue homogenate of MI/R group over the Sham group (FIG. 3E), suggesting an increase in the bound MGO content.
Example 2
Myocardial injury effects of MGO in ischemia reperfusion injury
2.1 toxicity test of MGO against myocardial cells (FIG. 4)
Experimental method and results: h9c2 cells are inoculated into a 96-well plate, 7000 cells are planted in each well, the cell adherence state and the growth state are observed, and the cells are completely adhered and grown to about 80-90% of the area of the bottle bottom for subsequent treatment. The experiment is divided into a normoxic group and an anoxic group, the anoxic time is 12h, the reoxygenation time is 6h and 12h, and the MGO concentration is set to 0, 10, 100, 500, 1000, 2500, 5000 and 10000 mu M. The specific treatment is as follows:
(1) Normoxic group: diluting MGO to corresponding concentration by using high sugar complete culture medium, adding 100 mu m L of MGO diluent into each hole, culturing for 12h by normal oxygen, changing liquid, respectively culturing for 6h by normal oxygen, discarding the culture medium after 12h, adding 90 mu L of complete culture medium and 10 mu L of CCK-8 mixed solution into each hole, placing the culture plate into an incubator for incubation for 1-4 hours, and measuring absorbance at 450nm by using an enzyme-labeled instrument.
(2) Hypoxia reoxygenation group: diluting MGO to corresponding concentration by using low-sugar serum-free culture medium, adding 100 mu L of MGO diluent into each hole, carrying out hypoxia for 12 hours, changing liquid, respectively reoxygenating the culture medium after 6 hours and 12 hours, adding 90 mu L of complete culture medium and 10 mu L of CCK-8 mixed solution into each hole, placing the culture plate into an incubator for incubation for 1-4 hours, and measuring absorbance at 450nm by using an enzyme-labeled instrument.
H9c2 cardiomyocytes were treated with different concentrations of MGO, either 24H in normoxic or 12H in hypoxic conditions, and reoxygenated for 12H, and their viability was checked with CCK-8, with the MGO having a higher IC50 (600. Mu.M) for H9c2 cardiomyocytes in normoxic than for in hypoxic conditions (250. Mu.M).
2.2MGO pair promotes apoptosis of cardiomyocytes (FIG. 5)
The experimental method comprises the following steps: inoculating H9c2 cells into a six-hole plate, adding MGO (0, 200, 400, 600 mu M) with different concentrations for treatment, collecting culture mediums into flow tubes respectively, digesting the cells with pancreatin without EDTA in an incubator for 15-30min, stopping digestion completely after cell digestion, collecting the cells in the flow tubes containing the corresponding culture mediums, centrifuging at 800rpm for 5min. The supernatant was discarded and the cells were washed twice with PBS, each at 800rpm, and centrifuged for 5min. The supernatant was discarded, the cells were resuspended in 100. Mu.L of 1 XBindingBuffer, 5. Mu.L of LPI and 5. Mu.L of LannexinV-FITC solution were added, incubated at room temperature in the dark for 15min, and flow cytometry analysis was performed using a CytoFLEX flow cytometer. Cells in the well plate were harvested into different EP tubes, protein was extracted by lysis, protein concentration was normalized by BCA method, and the expression levels of CleavedCaspase-3 and CleavedCase-9 proteins were detected by immunoblotting.
Experimental results: as shown in fig. 5, the proportion of apoptosis of H9c2 cardiomyocytes treated at 400 μm and 600 μm was significantly up-regulated compared to the CON group (fig. 5A and B). Furthermore, immunoblotting results showed that apoptotic proteins clearedcaspase-3 and clearedcaspase-9 were significantly up-regulated in the 400 μm and 600 μm GO treated groups compared to the CON group (fig. 5C and D). The above results demonstrate that exogenous administration of MGO stimulation can cause apoptosis of H9c2 cardiomyocytes.
Example 3
Myocardial injury mechanism in ischemia reperfusion injury by MGO
3.1 decrease in Glo I expression level and Activity decrease are responsible for MGO accumulation in ischemia reperfusion injury (FIG. 6)
The experimental method comprises the following steps: cells were inoculated into six well plates, reoxygenated for 12 hours after differential time (0, 4,8, 12 h) of hypoxia treatment, the cells in the well plates were harvested into different EP tubes, lysed to extract protein, and protein concentration normalized by BCA method. The enzymatic activity of Glo I in the cell lysate was evaluated using an in vitro enzyme reaction system for the metabolism of Glo I and the expressed content of Glo I protein was detected using immunoblotting.
Experimental results: the H9c2 cardiomyocytes were subjected to hypoxia reoxygenation treatment, and as shown in fig. 6, glo I expression was gradually down-regulated and activity was gradually reduced as hypoxia time was newly increased.
3.2MGO activates RAGE pathway by MG-H1 interacting with RAGE receptor, causing apoptosis (FIG. 7)
The experimental method comprises the following steps: H9C2 cells were seeded in six well plates, reoxygenated for 12 hours after differential time (0, 4,8, 12H) hypoxia treatment, the cells in the well plates were harvested into different EP tubes, lysed to extract protein, normalized for protein concentration by BCA method, and assayed for RAGE protein expression content using immunoblotting. Inoculating the extracted primary myocardial cells into a confocal dish at 6 x 10-5 cells/hole, and performing starvation treatment after 48 hours; and (5) changing the liquid for 36-48 hours. Following a hypoxia 12H reoxygenation 12H treatment, cells in the dishes were immunofluorescent stained for RAGE and MG-H1, and confocal imaging was used to show changes in the degree of co-localization of MG-H1 with RAG E.
Experimental results: hypoxia reoxygenation of H9c2 cardiomyocytes was performed, as shown in FIG. 7, with increasing hypoxia time and increasing RAGE protein expression, the Glo I expression was gradually down-regulated. The primary cardiomyocytes were subjected to hypoxia reoxygenation, and immunofluorescence results showed that with increasing hypoxia time, expression of RAGE and MG-H1 in the cells increased and co-localization ratio of the two increased.
Example 4
Cardioprotection of glo I agonists against myocardial ischemia and reperfusion injury
4.1 xanthone C-glucoside (MGF) is a Glo I enzyme-activated agonist (FIG. 8)
The experimental method comprises the following steps: 100mM GSH was prepared with deionized water and 40% (6.48M) methylglyoxal solution was diluted to 100mM with buffer. 1420. Mu.L of detection buffer, 40. Mu.L of 100mM GSH and 40. Mu.L of 100mM MGO were mixed to form a substrate mixture, incubated at room temperature for 15 minutes, standard Glo I was diluted to 0.4 ng/. Mu.L with buffer, 50. Mu.L of Glo I standard and 50. Mu.L of varying concentrations of MGF were added to 96 well plates, incubated at 37℃for half an hour, and 150. Mu.L of substrate mixture was added to initiate the reaction. Absorbance values were continuously read at 240nm for 5 minutes, and Glo I enzyme activation of MGF was calculated as follows:
experimental results: the activation effect of the Glo I enzyme of MGF is more than or equal to 130 percent.
4.2MGF reduced myocardial apoptosis by reducing MGO accumulation, affecting RAGE pathway activation (FIG. 9)
The experimental method comprises the following steps: adult male wistar rats were randomly divided into Sham groups, sham+mgf (80 MG/kg, i.p.) groups, MI/R groups, MI/r+mgf (80 MG/kg, i.p.) groups, vehicle or MGF was intraperitoneally injected 1H before myocardial ischemia, left anterior descending branches were ligated for 1H, the rats were dissected after 10H reperfusion, left ventricular anterior wall tissues were homogenized, proteins were extracted, and levels of MG-H1, RAGE, gloI, clear Caspase-3, and clear Caspase-9 protein expression were examined using immunoblotting. Left ventricular anterior chamber wall tissue was paraffin embedded and then TUNEL stained.
First, the level of MG-H1 protein in myocardial tissue homogenates was examined, and immunoblotting results showed that the up-regulation of MG-H1 expression in myocardial tissue in MI/R group compared to Sham group, and the down-regulation of MG-H1 expression in MI/R+MGF group, showed that MGF decreased the level of MGO (FIGS. 9A and C). Protein levels of RAGE, gloI and apoptotic proteins and levels of GloI activity in the myocardial tissue homogenates were then examined and showed that MGF significantly inhibited expression of RAGE in ischemic myocardial tissue (figures 9B and D) and significantly down-regulated protein levels of GloI and activity of GloI in ischemic myocardial tissue compared to Sham group where expression of RAGE was significantly increased (figures 9B, E and F).
Experimental results: the above results demonstrate that MGF has cardioprotective effects during myocardial ischemia reperfusion by up-regulating GloI expression and GloI activity levels, increasing MGO metabolism, decreasing MGO levels, and reducing apoptosis caused by RAGE activation.
4.3MGF significantly reduced myocardial ischemia reperfusion injury in animal myocardial infarction area, protecting heart structure and function (FIG. 10)
The experimental method comprises the following steps: adult male wistar rats were randomly divided into Sham groups, sham+mgf (80 mg/kg, i.p.) groups, MI/R groups, MI/r+mgf (80 mg/kg, i.p.) groups, vehicle or MGF was intraperitoneally injected 1h before myocardial ischemia, left anterior descending branch was ligated for 1h, and heart ultrasound was performed on the rats after reperfusion for 8h, and 10h myocardial tissue sections were stained for TTC (fig. 6A). The anterior chamber wall of the left ventricle was paraffin embedded and H & E stained.
Experimental results: as the ultrasound results of fig. 10 show, the MI/R group has statistically significant decreases in stroke volume SV, ejection fraction EF, short axis systolic rate FS, and cardiac output CO, the left ventricular end systole inner diameter and the left ventricular end diastole inner diameter increase, and the systolic and end diastole left ventricular wall thickness decrease, but no significant difference. The MI/R+MGF group was significantly increased compared to MI/R group S V, EF, FS and CO, with statistical significance, with reduced left ventricular end systole and left ventricular end diastole inner diameters, and increased systolic and end diastole left ventricular wall thicknesses, but no significant differences. TTC staining results show that MI/R+MGF groups have significantly reduced infarct size compared with MI/R groups. H & E staining results show that MI/R group myocardial tissue disorder and myocardial cell disappearance are replaced by fibrous scar tissue, MI/R+MGF group myocardial is orderly arranged, cytoplasm is rich and uniform, and stroma is normal. The results suggest that the MGF can significantly improve myocardial ischemia reperfusion injury heart function, reduce myocardial infarction area and lighten myocardial ischemia reperfusion myocardial tissue injury.
Claims (6)
1. The application of glyoxalase I agonist in preparing medicine for treating myocardial ischemia and reperfusion myocardial injury.
2. Application of glyoxalase I agonist in preparing medicine for preventing or relieving myocardial ischemia and reperfusion myocardial injury.
3. The use according to any one of claims 1 or 2, wherein the glyoxalase i agonist activates glyoxalase i on-line; the activating of glyoxalase I means that the enzyme activity of glyoxalase I is improved by more than 130%.
4. Pharmaceutical formulation, characterized in that it comprises a drug as defined in any one of claims 1 to 3, in association with a pharmaceutically acceptable diluent or carrier.
5. The pharmaceutical formulation of claim 4, wherein the pharmaceutical formulation is used to combat myocardial apoptosis, reduce myocardial infarction area, and alleviate reduced cardiac function.
6. The use according to claim 3, wherein the glyoxalase i agonist is at least one of bardoxolone, sulforaphane, xanthone C-glucoside.
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