CN111575363A - Research method for MS-275 acting on acute myocardial ischemia-reperfusion injury - Google Patents
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Abstract
The invention discloses a research method of MS-275 acting on acute myocardial ischemia reperfusion injury, which comprises the following steps: the method comprises the following steps: establishing an acute MI/RI model of the rat by performing anterior descending ligation on the left coronary artery of the SD male rat; step two: observing the effect of MS-275 in the MI/RI acute phase of rats; step three: the molecular mechanism of MS-275 on the protection of rat MI/RI was explored. The research achieves the following research purposes by establishing an acute MI/RI model of a rat and combining an internal experiment and an external experiment: 1) observing histone acetylation level, HDAC1 and microRNA-210(miR-210) expression in rat MI/RI acute-phase myocardial tissues; 2) MS-275, a novel HDACI type selective inhibitor, was demonstrated to have protective effects on rat MI/RI and its effects on histone acetylation level, HDAC1 and miR-210 expression in myocardial infarction area tissues after rat myocardial ischemia reperfusion; 3) the specific molecular mechanism of MS-275 for improving MI/RI of rats is revealed from the perspective of miRNA epigenetic regulation, and important theoretical and experimental basis is provided for treating MI/RI by HDACI.
Description
Technical Field
The invention relates to the technical field of medicine, in particular to a research method for acting on acute myocardial ischemia-reperfusion injury by MS-275.
Background
A large number of researches show that histone deacetylase is used as an important epigenetic modification regulatory factor and participates in the pathogenesis process of myocardial ischemia/reperfusion injury. The histone deacetylase inhibitor can interfere the function of HDACs, effectively reduce ischemia/reperfusion injury, and has a wide treatment prospect in the field of myocardial protection. However, the specific molecular mechanisms involved in this protective effect are less studied.
Disclosure of Invention
In order to overcome the problems, the invention provides a research method for the effect of MS-275 on acute myocardial ischemia-reperfusion injury.
The technical scheme adopted by the invention is as follows:
the research method of the effect of MS-275 on acute myocardial ischemia-reperfusion injury comprises the following steps:
the method comprises the following steps: establishing an acute MI/RI model of the rat by performing anterior descending ligation on the left coronary artery of the SD male rat;
step two: observing the effect of MS-275 in the MI/RI acute phase of rats;
step three: the molecular mechanism of MS-275 on the protection of rat MI/RI was explored.
Wherein, step one includes: SD male rats 72 were randomly divided into 4 groups of 18 per group: wherein the first group is a Sham group (Sham group) with only threading and no ligation; the second group was ischemic 30-minute group (I30 min group); the third group was a 30-minute ischemia reperfusion 60-minute group (I/R60min group); the fourth group was an ischemia 30-minute reperfusion 2-hour group (I/R120 min group); after the experiment is finished, the rat is sacrificed, the heart is separated, a tissue specimen in the myocardial infarction area is reserved, the myocardial infarction area and the change of the cell tissue morphology in the myocardial infarction area are observed through section staining, and the histone acetylation level, the expression change of HDAC1 and miR-210 are detected through technologies such as immunohistochemistry, histone acetylation detection kits, real-timePCR and the like.
Wherein, step two includes: SD male rats 90 were randomly divided into 3 groups of 30 per group: the first group is a Sham operation group (Sham group), which is not ligated by threading, and is injected with a solvent DMSO into the abdominal cavity 24 hours and 1 hour before the operation, respectively; the second group is myocardial ischemia/reperfusion group (I/R group), which is injected with a solvent DMSO into the abdominal cavity 24 hours and 1 hour before the operation respectively; the third group is myocardial ischemia/reperfusion + HDACI pretreatment group (I/R + MS-275 group), and MS-275(10mg/kg) was intraperitoneally injected 24 hours and 1 hour before the operation; ischemia/reperfusion time is 30min/120min, and hemodynamics and arrhythmia of rats in each group are monitored in the experimental process; after the experiment is finished, the rat is sacrificed, the heart is separated, a tissue specimen in the myocardial infarction area is reserved, the myocardial infarction area and the change of the cell tissue morphology in the myocardial infarction area are observed through section staining, and the histone acetylation level, the HDAC1 and the expression change of miR-210 are detected.
Wherein, step three includes: screening and identifying a downstream target gene FOXO3A of miR-210 by using methods such as bioinformatics, a dual-luciferase reporter gene system, interference over-expression and the like; MS-275 treats the H9c2 cell strain, and detects the level of miR-210 promoter zone protein H4ac, the expression of miR-210 and FOXO3A and the apoptosis condition before and after treatment; analyzing the correlation of miR-210 and FOXO3A expression in rat ischemia reperfusion myocardial infarction area tissues; the target gene resilience experiment proves that miR-210/FOXO3A mediates the myocardial protection effect of MS-275.
The invention has the following advantages:
the research achieves the following research purposes by establishing an acute MI/RI model of a rat and combining an internal experiment and an external experiment: 1) observing histone acetylation level, HDAC1 and microRNA-210(miR-210) expression in rat MI/RI acute-phase myocardial tissues; 2) MS-275, a novel HDACI type selective inhibitor, was demonstrated to have protective effects on rat MI/RI and its effects on histone acetylation level, HDAC1 and miR-210 expression in myocardial infarction area tissues after rat myocardial ischemia reperfusion; 3) the specific molecular mechanism of MS-275 for improving MI/RI of rats is revealed from the perspective of miRNA epigenetic regulation, and important theoretical and experimental basis is provided for treating MI/RI by HDACI.
Detailed Description
The present invention will be further described below, but the present invention is not limited to these.
Examples
The research method of the effect of MS-275 on acute myocardial ischemia-reperfusion injury comprises the following steps:
the method comprises the following steps: establishing an acute MI/RI model of the rat by performing left anterior descending coronary artery ligation on SD male rats: SD male rats 72 were randomly divided into 4 groups of 18 per group: wherein the first group is a Sham group (Sham group) with only threading and no ligation; the second group was ischemic 30-minute group (I30 min group); the third group was a 30-minute ischemia reperfusion 60-minute group (I/R60min group); the fourth group was an ischemia 30-minute reperfusion 2-hour group (I/R120 min group); after the experiment is finished, the rat is sacrificed, the heart is separated, a tissue specimen in the myocardial infarction area is reserved, the myocardial infarction area and the change of the cell tissue morphology in the myocardial infarction area are observed through section staining, and the histone acetylation level, the expression change of HDAC1 and miR-210 are detected through technologies such as immunohistochemistry, a histone acetylation detection kit, real-time PCR and the like.
Step two: the effect of MS-275 in the acute phase of MI/RI in rats was observed: SD male rats 90 were randomly divided into 3 groups of 30 per group: the first group is a Sham operation group (Sham group), which is not ligated by threading, and is injected with a solvent DMSO into the abdominal cavity 24 hours and 1 hour before the operation, respectively; the second group is myocardial ischemia/reperfusion group (I/R group), which is injected with a solvent DMSO into the abdominal cavity 24 hours and 1 hour before the operation respectively; the third group is myocardial ischemia/reperfusion + HDACI pretreatment group (I/R + MS-275 group), and MS-275(10mg/kg) was intraperitoneally injected 24 hours and 1 hour before the operation; ischemia/reperfusion time is 30min/120min, and hemodynamics and arrhythmia of rats in each group are monitored in the experimental process; after the experiment is finished, the rat is sacrificed, the heart is separated, a tissue specimen in the myocardial infarction area is reserved, the myocardial infarction area and the change of the cell tissue morphology in the myocardial infarction area are observed through section staining, and the histone acetylation level, the HDAC1 and the miR-210 expression change are detected;
step three: the molecular mechanism of MS-275 on the protection of rat MI/RI is explored: screening and identifying a downstream target gene FOXO3A of miR-210 by using methods such as bioinformatics, a dual-luciferase reporter gene system, interference over-expression and the like; MS-275 treats the H9c2 cell strain, and detects the level of miR-210 promoter zone protein H4ac, the expression of miR-210 and FOXO3A and the apoptosis condition before and after treatment; analyzing the correlation of miR-210 and FOXO3A expression in rat ischemia reperfusion myocardial infarction area tissues; the target gene resilience experiment proves that miR-210/FOXO3A mediates the myocardial protection effect of MS-275.
As a result: the LAD ligation and the release are carried out to successfully establish a rat MI/RI model; compared with the I30min group, the I/R120 min group can obviously reduce the level of the total histone H4ac in the tissues of myocardial infarction areas of rats (the vs I30min group of the I/R120 min group is 0.9745 +/-0.1247 vs 1.8090 +/-0.1796, P is less than 0.01), promote the protein expression of HDAC1 (P is 0.001), and inhibit the expression of miR-210 (the vs I30min group of the I/R120 min group is 4.5480 +/-0.7486 vs 12.4100 +/-1.9640, and P is less than 0.01).
MS-275 pre-ischemic pretreatment can obviously reduce the incidence rate of arrhythmia such as tachycardia, ventricular premature beat, ventricular fibrillation and the like caused by myocardial I/R of rats (P <0.01), obviously improve the function damage of ventricles and reduce the myocardial infarction area (I/R + MS-275 vs I/R group is 30.76 +/-2.0780 vs 46.80 +/-3.0590, and P < 0.01); compared with the I/R group, the level of H4ac in the myocardial tissue of rats in the I/R + MS-275 group is obviously increased (P <0.001), the level of HDAC1 is obviously reduced (P <0.001), the activity is obviously inhibited (I/R + MS-275 group vs I/R group is 3092 +/-189.7 vs 5163 +/-231.2, P is <0.001), and the expression level of miR-210 is obviously increased (I/R + MS-275 group vs I/R group is 9.9050 +/-0.8261 vs 4.5680 +/-0.6110, P is < 0.001).
Compared with the control group, the activity of HDAC1 in MS-275 group H9c2 cells is significantly reduced (MS-275 group vs control group is 1678 ± 156.9vs 3235 ± 205.5, P <0.001), miR-210 promoter region block protein H4ac level is significantly increased (MS-275 group vs control group is 2.3790 ± 0.2352vs1.0110 ± 0.0803, P <0.001), the expression of miR-210 is also significantly increased (MS-275 group vs control group is 2.9740 ± 0.4888vs 1.0170 ± 0.0982, P <0.01), and the apoptosis of H9c2 cells is significantly reduced (MS-275 group vs control group is 6.9250 ± 0.7471vs 13.9600 ± 0.9552, P < 0.001).
Bioinformatics prediction and dual-luciferase reporter gene detection suggest that FOXO3A may be a downstream target gene of miR-210; the interference of miR-210 in H9c2 cells can obviously increase the expression of FOXO3A (protein: Inhibitor vs INC is 3.2900 +/-0.5511 vs 1.0000 +/-0.0000, P is less than 0.01; mRNA: Inhibitor vs INC is 5.9050 +/-0.8525 vs 1.0230 +/-0.1064, P is less than 0.001), while the overexpression of miR-210 can obviously inhibit the expression of FOXO3A (protein: mimic vs MNC is 0.2667 +/-0.0596 vs 1.0000 +/-0.0000, P is less than 0.001; mRNA: mimic vs MNC is 0.2720 +/-0.0748 vs 0.9788 +/-0.0850, P is less than 0.001); compared with the I/R group, the expression of FOXO3A in myocardial tissues of rats with I/R + MS-275 is remarkably reduced (protein: I/R + MS-275 group vs I/R group is 0.1240 + -0.0239 vs 0.3340 + -0.0411, P is less than 0.01; mRNA: I/R + MS-275 group vs I/R group is 16.3300 + -2.4730 vs 33.1400 + -5.6750, P is less than 0.05), and the mRNA expression of FOXO3A is remarkably and negatively correlated with the expression of miR-210 (R is-0.6727, P is 0.0390); after interfering with miR-210 expression in MS-275 treated H9c2 cells, the effect of MS-275 in inhibiting apoptosis largely disappeared (MS-275+ inhibitor group vs MS-275+ INC group 13.5800 ± 1.0200vs 6.5950 ± 0.8586, P < 0.01); the over-expression of miR-210 in H9c2 cells can obviously inhibit apoptosis (Mimic + Plasmid control vs MNC + Plasmid control is 4.8730 + -0.4516 vs 12.5200 + -0.8256, P is less than 0.01), and after the expression of the target gene FOXO3A is restored, the apoptosis inhibition effect of miR-210 is reversed (Mimic + FOXO3A Plasmid vs Mimic + Plasmid control is 10.7500 + -0.8543 vs 4.8730 + -0.4516, P is less than 0.05).
And (4) conclusion: MS-275 pre-ischemic pretreatment can obviously reduce myocardial infarction area and arrhythmia incidence after I/R of rats, and obviously improve ventricular function, and has myocardial protection effect; the possible molecular mechanism is that MS-275 promotes miR-210 promoter histone H4ac, induces the expression of the latter to be increased, and further inhibits the apoptosis of the myocardial cells by regulating miR-210/FOXO3A axis.
It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (4)
- A research method for the effect of MS-275 on acute myocardial ischemia-reperfusion injury is characterized by comprising the following steps:the method comprises the following steps: establishing an acute MI/RI model of the rat by performing anterior descending ligation on the left coronary artery of the SD male rat;step two: observing the effect of MS-275 in the MI/RI acute phase of rats;step three: the molecular mechanism of MS-275 on the protection of rat MI/RI was explored.
- 2. The method of claim 1, wherein the MS-275 is administered to a subject suffering from acute myocardial ischemia reperfusion injury, wherein the subject is selected from the group consisting of: the first step comprises the following steps: SD male rats 72 were randomly divided into 4 groups of 18 per group: wherein the first group is a Sham group (Sham group) with only threading and no ligation; the second group was ischemic 30-minute group (I30 min group); the third group was a 30-minute ischemia reperfusion 60-minute group (I/R60min group); the fourth group was an ischemia 30-minute reperfusion 2-hour group (I/R120 min group); after the experiment is finished, the rat is sacrificed, the heart is separated, a tissue specimen in the myocardial infarction area is reserved, the myocardial infarction area and the change of the cell tissue morphology in the myocardial infarction area are observed through section staining, and the histone acetylation level, the expression change of HDAC1 and miR-210 are detected through technologies such as immunohistochemistry, a histone acetylation detection kit, real-time PCR and the like.
- 3. The method of claim 1, wherein the MS-275 is administered to a subject suffering from acute myocardial ischemia reperfusion injury, wherein the subject is selected from the group consisting of: the second step comprises the following steps: SD male rats 90 were randomly divided into 3 groups of 30 per group: the first group is a Sham operation group (Sham group), which is not ligated by threading, and is injected with a solvent DMSO into the abdominal cavity 24 hours and 1 hour before the operation, respectively; the second group is myocardial ischemia/reperfusion group (I/R group), which is injected with a solvent DMSO into the abdominal cavity 24 hours and 1 hour before the operation respectively; the third group is myocardial ischemia/reperfusion + HDACI pretreatment group (I/R + MS-275 group), and MS-275(10mg/kg) was intraperitoneally injected 24 hours and 1 hour before the operation; ischemia/reperfusion time is 30min/120min, and hemodynamics and arrhythmia of rats in each group are monitored in the experimental process; after the experiment is finished, the rat is sacrificed, the heart is separated, a tissue specimen in the myocardial infarction area is reserved, the myocardial infarction area and the change of the cell tissue morphology in the myocardial infarction area are observed through section staining, and the histone acetylation level, the HDAC1 and the expression change of miR-210 are detected.
- 4. The method of claim 1, wherein the MS-275 is administered to a subject suffering from acute myocardial ischemia reperfusion injury, wherein the subject is selected from the group consisting of: the third step comprises: screening and identifying a downstream target gene FOXO3A of miR-210 by using methods such as bioinformatics, a dual-luciferase reporter gene system, interference over-expression and the like; MS-275 treats the H9c2 cell strain, and detects the level of miR-210 promoter zone protein H4ac, the expression of miR-210 and FOXO3A and the apoptosis condition before and after treatment; analyzing the correlation of miR-210 and FOXO3A expression in rat ischemia reperfusion myocardial infarction area tissues; the target gene resilience experiment proves that miR-210/FOXO3A mediates the myocardial protection effect of MS-275.
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CN114758726A (en) * | 2022-04-26 | 2022-07-15 | 川北医学院附属医院 | Myocardial ischemia reperfusion influence factor data detection method |
CN117752309A (en) * | 2024-02-22 | 2024-03-26 | 天津医科大学第二医院 | method for evaluating protective effect of sevoflurane on myocardial ischemia reperfusion injury |
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CN117752309A (en) * | 2024-02-22 | 2024-03-26 | 天津医科大学第二医院 | method for evaluating protective effect of sevoflurane on myocardial ischemia reperfusion injury |
CN117752309B (en) * | 2024-02-22 | 2024-04-30 | 天津医科大学第二医院 | Method for evaluating protective effect of sevoflurane on myocardial ischemia reperfusion injury |
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