CN117815396A - Medicine for treating myocardial ischemia reperfusion injury - Google Patents
Medicine for treating myocardial ischemia reperfusion injury Download PDFInfo
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- CN117815396A CN117815396A CN202410250485.3A CN202410250485A CN117815396A CN 117815396 A CN117815396 A CN 117815396A CN 202410250485 A CN202410250485 A CN 202410250485A CN 117815396 A CN117815396 A CN 117815396A
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly discloses a medicine for treating myocardial ischemia reperfusion injury, which comprises UCP2 genes, protein or an accelerant thereof, a medically acceptable carrier and an iron death inhibition composition for inhibiting cell death caused by iron-dependent lipid peroxidation. The invention is realized byUcp2‑/‑The transgenic mice and related cell molecular biology method show whether UCP2 reduces MI/RI by inhibiting iron death, and for the first time, the UCP2 can improve myocardial ischemia reperfusion injury, provides a new drug action target for preventing and treating myocardial ischemia reperfusion injury, and has very important clinical transformation value.
Description
Technical Field
The invention belongs to the technical field of medicaments, and particularly relates to a medicament for treating myocardial ischemia reperfusion injury.
Background
Functional cardiomyocyte death is an important pathophysiological basis for myocardial ischemia reperfusion injury (Myocardial ischemia/reperfusion injury, MI/RI). In particular to a pathological process that after partial or complete acute occlusion of coronary artery, when recanalization is obtained again for a certain time, the ischemic cardiac muscle is recovered to normal perfusion, but the tissue injury is rather progressive and aggravated. The myocardial ultrastructural, energy metabolism, cardiac function and electrophysiology changes caused by ischemia are more prominent after vascular recanalization, and even serious arrhythmia can occur to cause sudden death. In the prior art, the generation mechanism is mainly related to the mass production of oxygen free radicals in cells, the overload of calcium ions, the inflammatory action of white blood cells, the deficiency of high-energy phosphate compounds and the like. In addition to the heart, ischemia reperfusion injury can also be seen in brain, lung, liver, pancreas, kidney, gastrointestinal tract and other organs.
The method is used for carrying out deep research on specific pathological mechanisms of myocardial ischemia reperfusion injury, exploring potential myocardial treatment targets, and has important clinical transformation significance. Among them, iron death, a programmed cell death mode characterized by intracellular iron overload and lipid metabolism abnormality, is closely related to MI/RI, but its underlying mechanism is not yet clear. There is no study in the prior art of the reduction of MI/RI by mitochondrial uncoupling protein 2 (Uncoupling protein, ucp 2) by inhibiting iron death.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a medicament for treating myocardial ischemia reperfusion injury, and mainly provides UCP2 treatment targets for relieving myocardial ischemia reperfusion injury and improving prognosis of patients with myocardial infarction.
The technical scheme adopted by the invention is as follows:
in a first aspect, the present invention provides a medicament for treating myocardial ischemia reperfusion injury comprising a UCP2 gene, protein or an enhancer thereof and a pharmaceutically acceptable carrier, and further comprising an iron death suppressing composition for suppressing cell death due to iron-dependent lipid peroxidation.
With reference to the first aspect, the present invention provides a first embodiment of the first aspect, wherein the UCP2 gene or protein is derived from a mouse, rat or human.
With reference to the first aspect, the present invention provides a second embodiment of the first aspect, wherein the promoter comprises a promoted microRNA, a promoted transcription regulatory factor, or a promoted targeting small molecule compound.
With reference to the first aspect, the present invention provides a third embodiment of the first aspect, the promoter comprising an adeno-associated viral vector comprising the amino acid sequence as set forth in SEQ ID NO:1, and a gene sequence shown in the specification.
The UCP2 gene sequence in the invention is shown as SEQ ID NO:1 is shown as follows:
ATGGTTGGTTTCAAGGCCACAGATGTGCCCCCAACAGCCACTGTGAAGTTCCTGGGGGCTGGGACAGCTGCCTGCATTGCAGATCTCATCACTTTCCCTCTGGATACCGCCAAGGTCCGGCTGCAGATCCAAGGGGAGAGTCAAGGGCTAGTGCGCACCGCAGCCAGCGCCCAGTACCGTGGCGTTCTGGGTACCATCCTAACCATGGTGCGCACTGAGGGTCCACGCAGCCTCTACAATGGGCTGGTCGCCGGCCTGCAGCGCCAGATGAGCTTTGCCTCCGTCCGCATTGGCCTCTACGACTCTGTCAAACAGTTCTACACCAAGGGCTCAGAGCATGCAGGCATCGGG
AGCCGCCTCCTGGCAGGTAGCACCACAGGTGCCCTGGCCGTGGCTGTAGCCCAGCCTACAGATGTGGTAAAGGTCCGCTTCCAGGCTCAGGCCCGGGCTGGTGGTGGTCGGAGATACCAGAGCACTGTCGAAGCCTACAAGACCATTGCACGAGAGGAAGGGATCCGGGGCCTCTGGAAAGGGACTTCTCCCAATGTTGCCCGTAATGCCATTGTCAACTGTGCTGAGCTGGTGACCTATGACCTCATCAAAGATACTCTCCTGAAAGCCAACCTCATGACAGATGACCTCCCTTGCCAC
TTCACTTCTGCCTTCGGGGCCGGCTTCTGCACCACCGTCATCGCCTCCCCTGTTGATGTGGTCAAGACGAGATACATGAACTCTGCCTTGGGCCAGTACCACAGCGCAGGTCACTGTGCCCTTACCATGCTCCGGAAGGAGGGACCCCGCGCCTTCTACAAGGGGTTCATGCCTTCCTTTCTCCGCTTGGGATCCTGGAACGTAGTGATGTTTGTCACCTATGAGCAGCTCAAAAGAGCCCTAATGGCTGCCTACCAATCTCGGGAGGCACCTTTCTGA
with reference to the third embodiment of the first aspect, the present invention provides a fourth embodiment of the first aspect, wherein the adeno-associated viral vector is AAV9 virus.
With reference to the first aspect, the present invention provides a fifth embodiment of the first aspect, the iron death suppressing composition comprising one or more of deferoxamine, deferiprone, ciclopirox chelate iron, antioxidant and Ferrostatin-1 inhibitor.
The beneficial effects of the invention are as follows:
the invention provides a pharmaceutical composition which can improve cardiac function after myocardial ischemia reperfusion by preparing myocardial cell iron death based on up-regulating UCP2 expression in mouse heart, and can cooperate with iron death inhibition to obviously reduce myocardial infarction area, myocardial pathological injury and myocardial fibrosis level, obviously reduce iron level and lipid peroxidation level and obviously increase antioxidation level, thereby achieving the effect of alleviating MI/RI.
Drawings
FIG. 1 is an electrocardiogram of three states after modeling of a mouse MI/RI model in accordance with an embodiment of the present invention;
FIG. 2 is a first verification graph of the mouse MI/RI model modeling in accordance with an embodiment of the present invention;
FIG. 3 is a second verification graph of the mouse MI/RI model modeling in accordance with an embodiment of the present invention;
FIG. 4 is a third verification graph of the mouse MI/RI model modeling in accordance with an embodiment of the present invention;
FIG. 5 is a fourth verification graph of the mouse MI/RI model modeling in accordance with an embodiment of the present invention;
FIG. 6 is a graph I of the results of a first experiment illustrating the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 7 is a graph II of the results of a first experiment illustrating the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 8 is a graph III of the results of a first experiment illustrating the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 9 is a graph IV of the results of a first experiment illustrating the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 10 is a graph five showing the results of a first experiment illustrating the effect of UCP2 on MI/RI in the examples of the present invention;
FIG. 11 is a graph I of the results of a second experiment illustrating the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 12 is a second graph of experimental results showing the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 13 is a third graph of the results of a second experiment illustrating the effect of UCP2 on MI/RI in an embodiment of the present invention;
FIG. 14 is a graph IV showing the results of a second experiment illustrating the effect of UCP2 on MI/RI in the examples of the present invention;
FIG. 15 is a graph five showing the results of a second experiment illustrating the effect of UCP2 on MI/RI in the examples of the present invention;
FIG. 16 is a graph six showing the results of a second experiment illustrating the effect of UCP2 on MI/RI in the examples of the present invention;
FIG. 17 is a graph seven showing the results of a second experiment illustrating the effect of UCP2 on MI/RI in the examples of the present invention;
fig. 18 is a graph one illustrating the first experimental result of UCP2 in reducing MI/RI by inhibiting iron death;
fig. 19 is a graph two illustrating the results of a first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
fig. 20 is a third experimental result graph illustrating that UCP2 reduces MI/RI by inhibiting iron death;
fig. 21 is a graph four showing the results of a first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
fig. 22 is a graph five illustrating the first experimental results of UCP2 in reducing MI/RI by inhibiting iron death;
FIG. 23 is a graph six illustrating the results of a first experiment in which UCP2 reduces MI/RI by inhibiting iron death;
fig. 24 is a graph seven illustrating the first experimental result of UCP2 in reducing MI/RI by inhibiting iron death;
fig. 25 is a graph eight illustrating the first experimental results of UCP2 in reducing MI/RI by inhibiting iron death;
FIG. 26 is a graph nine illustrating the results of a first experiment in which UCP2 reduces MI/RI by inhibiting iron death;
fig. 27 is a graph ten illustrating the results of the first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
fig. 28 is a graph eleven showing the results of a first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
fig. 29 is a graph twelve showing the results of a first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
FIG. 30 is a graph thirteen of the results of the first experiment illustrating that UCP2 reduces MI/RI by inhibiting iron death;
FIG. 31 is a graph fourteen showing the results of the first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
fig. 32 is a graph fifteen illustrating the results of a first experiment in which UCP2 reduced MI/RI by inhibiting iron death;
FIG. 33 is a graph I illustrating the results of a second experiment in which UCP2 reduces MI/RI by inhibiting iron death;
FIG. 34 is a second experimental result graph illustrating reduction of MI/RI by UCP2 through inhibition of iron death;
FIG. 35 is a third graph illustrating the results of a second experiment in which UCP2 reduces MI/RI by inhibiting iron death;
FIG. 36 is a fourth graph illustrating the results of a second experiment in which UCP2 reduces MI/RI by inhibiting iron death;
FIG. 37 is a fifth graph illustrating the results of a second experiment in which UCP2 reduces MI/RI by inhibiting iron death;
FIG. 38 is a graph six illustrating the results of a second experiment in which UCP2 reduces MI/RI by inhibiting iron death;
FIG. 39 is a panel of results of mouse WB detection of p53 and TfR1 protein expression levels in examples one;
FIG. 40 is a set of graphs II showing the results of mouse WB detection of protein expression levels of p53 and TfR1 in the examples;
FIG. 41 is a set of three graphs showing the results of mouse WB detection of protein expression levels of p53 and TfR1 in the examples;
FIG. 42 is a set of graphs four showing the results of mouse WB detection of protein expression levels of p53 and TfR1 in the examples;
FIG. 43 is a set of five graphs showing the results of mouse WB detection of p53 and TfR1 protein expression levels in examples.
Detailed Description
The invention is further illustrated by the following description of specific embodiments in conjunction with the accompanying drawings.
For the purposes of making the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments.
Thus, the following detailed description of the embodiments of the present application, as provided in the accompanying drawings, is not intended to limit the scope of the application, as claimed, but is merely representative of selected embodiments of the application. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.
Example 1:
the embodiment discloses a medicament for treating myocardial defect reperfusion injury, which comprises UCP2 gene, protein or promoter thereof and a medically acceptable carrier.
Specifically, the medicine comprises a substance for promoting UCP2 gene expression by taking AAV9 adenovirus as a vector and an iron death inhibition composition, wherein AAV9 adenovirus comprises a nucleotide sequence shown in SEQ ID NO:1, and a gene sequence shown in the specification.
To verify the feasibility of the agent, and UCP2 reduced MI/RI by inhibiting iron death, it was confirmed experimentally in this example.
1. Experimental method
Step (1) constructing a mouse MI/RI model
Wild type (WT is used for description) and Ucp-/-C57 BL/6 mice are used as objects, a slipknot is adopted to ligate the left anterior descending branch of the coronary artery for 30min at the same time, a corresponding MI/RI model is built by a reperfusion method for 2h, and whether the model is successfully built is evaluated through an electrocardiogram result and left ventricular wall color change.
Step (2) studying the expression profile of UCP2 after MI/RI in wild type mice
The MI/RI model constructed for WT mice was collected from myocardial tissue of the mice, and UCP2 protein and mRNA expression levels were detected by Western Blotting (WB) and Real-time fluorescent quantitative polymerase chain reaction (Real-time quantitative PCR, RT-qPCR). The change of UCP2 protein and mRNA after MI/RI is known by the step, and the correlation is judged by comparing the mouse samples of the sham operation group to determine whether the mouse samples are influenced by MI/RI.
Step (3) study of the protective Effect of UCP2 on the heart in MI/RI by way of Ucp 2-/-transgenic mice
Based on construction of WT mice and Ucp-/-mice MI/RI models, the extent of myocardial injury was determined for both mice by echocardiography, myocardial injury marker levels (LDH and CK), 2,3,5-triphenyltetrazolium chloride (2, 3,5-triphenyltetrazolium chloride, TTC) staining, hematoxylin-eosin (H & E) staining, masson staining, sirius Red (Sirius Red) staining, and comparative studies were performed to determine the effect of UCP2 in MI/RI.
On this basis, verification comparison was then performed in the mouse MI/RI model of Ucp2+/+ alone. Step (4) studying the effect of UCP2 on cardiac iron death in MI/RI mice
The role of UCP2 in MI/RI was determined and its corresponding mechanism was studied. The correlation between UCP2 and iron death was mainly determined. Specifically, based on construction of WT mice and Ucp 2-/-mice MI/RI models, the corresponding kits are adopted to detect the levels of total iron, fe2+, lipid Peroxide (LPO), malondialdehyde (MDA), superoxide dismutase (Superoxide dismutase, SOD) and Glutathione (GSH) in myocardial tissues of each group; dihydroethidium (DHE) detects reactive oxygen species (Reactive oxygenspecies, ROS) levels in myocardial tissue; WB, RT-qPCR detects iron death biomarker glutathione peroxidase 4 (Glutathione peroxidase, gpx 4), ferritin heavy chain-1 (Ferritin heavy chain, fth 1), long chain Acyl-coa synthetase 4 (Acyl-CoA synthetase long chainfamily member 4, acsl 4), transferrin (TF) protein and mRNA levels; immunofluorescence measures protein expression levels of iron death markers GPX4 and ACSL4 to study the effect of UCP2 on iron death.
Step (5) study on whether the heart protection effect of UCP2 on MI/RI mice is through inhibiting the iron death pathway of cardiac muscle cells
After determining the effect of UCP2 on iron death, the correlation and mechanism of action were determined by administering WT and Ucp-/-mice intraperitoneally with iron death inhibitor Ferrostatin-1 (Fer-1) and iron death inducer Erastin (Era) 1h prior to MI/RI procedures.
The detection content is as follows: detecting the levels of total iron, fe2+ and LPO, MDA, SOD, GSH in each group of myocardial tissues by adopting corresponding kits; DHE detects ROS levels in myocardial tissue; WB, RT-qPCR to detect iron death biomarkers GPX4, FTH1, ACSL4, TF protein and gene levels; immunofluorescence detection of protein expression levels of iron death markers GPX4 and ACSL 4; detection of myocardial injury marker levels (LDH and CK); TTC staining, H & E staining, masson staining, sirius red staining, and whether UCP2 can inhibit iron death and relieve MI/RI were studied.
Step (6) preliminary exploration of molecular mechanism of UCP2 for inhibiting myocardial cell iron death and relieving MI/RI
After determining that UCP2 alleviates MI/RI by inhibiting iron death, the deep mechanism is explored. Protein and gene expression of p53 and transferrin receptor 1 (Transferrin receptor, tfr 1) was analyzed by employing WB and RT-qPCR.
The experimental results are as follows:
reference is made to fig. 1 to the electrocardiogram (n=6) of the mice before ischemia, during ischemia, and during reperfusion. After ligating WT mice and Ucp 2-/-mice with slipknots for left anterior descending branches of coronary arteries, left ventricular wall cyanosis of mice can be seen, and an electrocardiogram shows that ST segment is obviously elevated; after 30min of ischemia, the ligature is loosened to reperfusion of blood, myocardial tissue in the left ventricular wall ischemia region is seen to turn red, and an electrocardiogram shows that ST segment falls back by more than 1/2, which indicates that MI/RI model construction is successful.
Referring to part 2, where P <0.01, change in UCP2 protein expression level after WT mice MI/RI (n=3), part 4 is change in UCP2 mRNA level after WT mice MI/RI (n=6). From the figure, it can be determined that mRNA levels and protein expression levels of UCP2 were significantly up-regulated after WT mice MI/RI compared to sham, indicating that overexpression of UCP2 was caused after mice MI/RI, and that there was a correlation.
Referring to the WT mice and Ucp 2-/-mice of fig. 3 for changes in UCP2 protein expression levels in myocardial tissue (n=3), and the WT mice and Ucp 2-/-mice of fig. 5 for changes in UCP2 mRNA levels after MI/RI (n=6), the results showed that UCP2 protein and mRNA expression were not detected in Ucp 2-/-mice compared to WT mice, indicating that UCP2 has been successfully knocked out in Ucp 2-/-mice.
The effect of UCP2 on MI/RI will be described with reference to FIGS. 6-17. N=6 in fig. 6-10, # P <0.05 compared to wt+i/R group, # P <0.05, # P <0.01 compared to Ucp2-/- +i/R group; +P <0.05, ++P <0.01 compared to WT
In FIG. 6, evaluation of mouse cardiac function from post MI/RI echocardiography, it is believed that UCP2 knockout does not affect mouse left ventricular function.
Referring to parts 7 and 8, wherein both left ventricular ejection fraction (Left ventricular ejection fraction, LVEF) (%) and left ventricular short axis shortening rate (Left ventricularfraction shortening, LVFS) (%) were significantly reduced in both MI/RI post-WT mice and Ucp-/-mice hearts; and Ucp-/-mice after MI/RI have more serious left ventricular function, LVEF (%) and LVFS (%) of the heart of Ucp-/-mice I/R group are significantly lower than those of WT mice I/R group, and the result shows that UCP2 protein can significantly relieve MI/RI.
Referring to FIG. 9 and FIG. 10, it can be seen that the myocardial tissue LDH and CK activity changes in mice after MI/RI. Since various myocardial enzymes such as LDH and CK are released when myocardial cells are necrotic, measuring the levels of the myocardial enzymes such as LDH and CK in serum helps to evaluate the degree of myocardial injury. As a result, it was found that the activity of LDH and CK was low in the sham groups of WT mice and Ucp 2-/-mice, and there was no significant difference. However, myocardial tissue injury was significantly aggravated in Ucp-/-mice following MI/RI, and LDH and CK activities exhibited in Ucp-/-mice I/R group were significantly higher than in WT mice I/R group. The results also demonstrate that Ucp-/-mice lacking UCP2 protein have higher myocardial injury than WT mice after MI/RI, and UCP2 protein can significantly alleviate MI/RI.
In fig. 11-17, where n=6, P <0.05, P <0.01 is compared to wt+i/R groups; # P <0.05, # P <0.01 compared to Ucp2-/- + I/R groups; +P <0.05, ++P <0.01 is compared to WT.
In fig. 11 and 12, it can be seen from TTC staining pictures and corresponding histograms that in WT mice and Ucp-/-mice hearts after MI/RI, myocardial infarction areas were significantly higher than in the corresponding sham group, and Ucp 2-/-mice I/R group had significantly higher myocardial infarction areas than WT mice I/R group.
Refer to the section of fig. 13, i.e. the H & E stained picture. The sham group of WT mice and Ucp-/-mice has clear myocardial structure, complete fibroblasts and orderly arrangement. WT mice after MI/RI have hearts, disordered myocardial structures, irregular myocardial fiber arrangement, swelling and necrosis of myocardial cells, and local infiltration of inflammatory cells. Whereas the heart of the Ucp-/-mouse I/R group was more severely damaged than the WT mouse I/R group.
Referring to fig. 14 and 15, i.e., masson stained pictures and collagen volume fractions, and fig. 16 and 17, i.e., sirius red stained pictures and collagen volume fractions, it can also be seen that there is a significant increase in fibrosis of cardiac muscle tissue in WT mice and Ucp-/-mice after MI/RI; however, the myocardial fibrosis degree of the Ucp-/-mouse group I/R is significantly higher than that of the WT group I/R.
As demonstrated by the above-described staining patterns with respect to FIGS. 11-17, UCP2 protein significantly alleviates MI/RI.
Referring to fig. 18-38, UCP2 protein decreased MI/RI by inhibiting iron death, fig. 18-32 where P <0.05, P <0.01 compared to wt+i/R group; # P <0.05, # P <0.01 compared to Ucp2-/- + I/R groups; +P <0.05, ++P <0.01 compared to WT
FIG. 18 and FIG. 19 are parts, total iron and Fe2 + Content (n=6). Total iron and Fe in myocardial tissue of MI/RI-post-MI WT mice and Ucp-/-mice compared to the corresponding sham group 2+ The average of the levels increased significantly, however, the total iron and Fe of the I/R group of Ucp 2-/-mice 2+ Levels were significantly higher than WT mice I/R group.
Referring to fig. 20-23, parts LPO, MDA, SOD and GSH levels (n=6). Lipid Peroxide (LPO) and Malondialdehyde (MDA) levels were significantly increased in both WT mice and Ucp-/-mouse myocardial tissue following MI/RI, and superoxide dismutase (Superoxide dismutase, SOD) and Glutathione (GSH) levels were significantly reduced compared to the corresponding sham group; however, the LPO and MDA levels were significantly higher in the Ucp-/-mouse I/R group than in the WT mouse I/R group, and the SOD and GSH levels were significantly lower than in the WT mouse I/R group.
Referring to the parts of fig. 24-28, GPX4, FTH1, ACSL4 and TF protein expression levels (n=3). Referring to the parts of fig. 29-32, mRNA levels of Gpx4, fth1, acsl4, and Tf (n=6). Protein and mRNA levels of both glutathione peroxidase 4 (Glutathione peroxidase 4, GPX 4), ferritin heavy chain-1 (Ferritin heavy chain 1, FTH 1) were significantly reduced and protein and mRNA levels of long chain Acyl-CoA synthetase 4 (Acyl-CoA synthetase long chainfamily member 4, ACSL4), transferrin (TF) were significantly increased in MI/RI post-WT mice and Ucp-/-mouse myocardial tissue; whereas the protein and mRNA levels of GPX4, FTH1 were significantly lower in the Ucp-/-mouse I/R group than in the WT mouse I/R group, the protein and mRNA levels of ACSL4, TF were significantly higher than in the WT mouse I/R group.
Referring to the parts of fig. 33-38, where n=6, P <0.05, P <0.01 is compared to wt+i/R groups; # P <0.05, # P <0.01 compared to Ucp2-/- + I/R groups; +P <0.05, ++P <0.01 is compared to WT.
Part of fig. 33 and 34, immunofluorescence detected protein levels of GPX4 in myocardial tissue, and part of fig. 35 and 36, immunofluorescence detected protein levels of ACSL4 in myocardial tissue. Immunofluorescence detection of protein expression levels of GPX4 and ACSL4 also showed consistent results with WB.
The portion of fig. 37 and 38, i.e., ROS levels. Reactive oxygen species (Reactive oxygen species, ROS) levels were significantly increased in myocardial tissue of WT mice and Ucp-/-mice following MI/RI; while Ucp-/-mice had significantly higher ROS levels than WT mice.
In summary, iron death of myocardial tissue of WT mice after I/RI was significantly reduced after intraperitoneal injection of Fer-1, as evidenced by a significant increase in iron levels (total iron, fe2+, FTH1, TF) (corresponding to the portions of fig. 18, 19, 24, 26, 28, 30, 32), lipid peroxidation levels (LPO, MDA, ROS, ACSL 4) (corresponding to the portions of fig. 20, 21, 24, 27, 31, portions of fig. 19-22) and antioxidant levels (SOD, GSH, GPX 4) (corresponding to the portions of fig. 22, 23, 24, 25, 29, portions of fig. 18 and 19) in myocardial tissue of WT mice I/r+fer-1.
And Ucp-/-mice have I/R+Fer-1 groups with myocardial tissue iron levels and lipid peroxidation levels significantly higher than WT mice I/R+Fer-1 groups and antioxidant levels significantly lower than WT mice I/R+Fer-1 groups. After the Erastin is injected into the abdominal cavity, the iron death of myocardial tissue of the WT mice after MI/RI is obviously increased, the iron level and lipid peroxidation level of myocardial tissue of the I/R+ Era group of the WT mice are obviously increased, and the antioxidation level is obviously reduced; whereas Ucp-/-mice had a myocardial tissue iron level of group I/R+ Era and lipid peroxidation level significantly higher than that of the WT mice group I/R+ Era and antioxidant levels significantly lower than that of the WT mice group I/R+ Era.
Subsequently, analysis of the heart structure and function of mice revealed that, after intraperitoneal injection of Fer-1, myocardial tissue injury of WT mice after MI/RI was significantly reduced, as shown by significantly reduced LDH and CK activities (corresponding to fig. 9, 10), myocardial infarction areas (fig. 11, 12), myocardial pathological injury (fig. 13), and myocardial fibrosis levels (fig. 14-17) of the myocardial tissue of WT mice I/r+fer-1 group; the index of the myocardial tissue of the Ucp-/-mouse I/R+Fer-1 group is obviously higher than that of the WT mouse I/R+Fer-1 group.
After the Erastin is injected into the abdominal cavity, the damage of myocardial tissue of the WT mice after MI/RI is obviously aggravated, and the LDH and CK activities, myocardial infarction areas, myocardial pathological damage and myocardial fibrosis levels of myocardial tissue of the I/R+ Era groups of the WT mice are obviously increased; whereas the above index for myocardial tissue from group I/R+ Era of Ucp-/-mice is significantly higher than that of group I/R+ Era of WT mice. The results show that UCP2 can inhibit the iron death pathway of cardiac muscle cells to relieve MI/RI of mice.
Referring to fig. 39-43, for illustrating the molecular mechanism of UCP2 inhibition of iron death in cardiomyocytes to alleviate MI/RI, P <0.05, P <0.01 is compared to wt+i/R group; # P <0.05, # P <0.01 compared to Ucp2-/- + I/R groups; +P <0.05, ++P <0.01 is compared to WT.
Fig. 39-fig. 41, parts, i.e., WB, detect protein expression levels of p53 and TfR1 (n=3).
The mRNA levels of p53 and Tfr1 were detected in the parts of fig. 42 and 43, i.e., RT-qPCR (n=6). Both p53 and TfR1 protein and mRNA levels were significantly up-regulated in WT mouse I/R group and Ucp 2-/-mouse I/R group compared to the corresponding sham group. Protein and mRNA levels of p53 and TfR1 of myocardial tissue of WT mice after MI/RI are significantly reduced after intraperitoneal injection of Fer-1; whereas the protein and mRNA levels of myocardial tissue p53 and TfR1 were significantly higher in the Ucp-/-mice I/R+Fer-1 group than in the WT mice I/R+Fer-1 group. Protein and mRNA levels of p53 and TfR1 of myocardial tissue of WT mice after MI/RI are significantly up-regulated after intraperitoneal injection of Erastin; whereas the protein and mRNA levels of myocardial tissue p53 and TfR1 were significantly higher in the Ucp-/-mouse group I/R+ Era than in the WT mouse group I/R+ Era.
This step demonstrates that up-regulation of UCP2 expression in the mouse MI/RI model can inhibit the mechanism of iron death in cardiac myocytes to alleviate MI/RI, which is associated with activation of UCP2 inhibition of the p53/TfR1 signaling pathway.
The invention is not limited to the alternative embodiments described above, but any person may derive other various forms of products in the light of the present invention. The above detailed description should not be construed as limiting the scope of the invention, which is defined in the claims and the description may be used to interpret the claims.
Claims (6)
1. A medicament for treating myocardial ischemia reperfusion injury, which is characterized in that: comprising UCP2 gene, protein or its promoter and a pharmaceutically acceptable carrier, and also comprises an iron death suppressing composition for suppressing cell death caused by iron-dependent lipid peroxidation.
2. A medicament for treating myocardial ischemia reperfusion injury as claimed in claim 1, wherein: the UCP2 gene or protein is derived from mice, rats or humans.
3. A medicament for treating myocardial ischemia reperfusion injury as claimed in claim 1, wherein: the promoter comprises a promoting microRNA, a promoting transcription regulating factor or a promoting targeting small molecule compound.
4. A medicament for treating myocardial ischemia reperfusion injury as claimed in claim 1, wherein: the promoter comprises an adeno-associated viral vector comprising a sequence as set forth in SEQ ID NO:1, and a gene sequence shown in the specification.
5. A medicament for treating myocardial ischemia reperfusion injury as claimed in claim 4, wherein: the adeno-associated viral vector is AAV9 virus.
6. A medicament for treating myocardial ischemia reperfusion injury as claimed in claim 1, wherein: the iron death suppressing composition includes one or more of deferoxamine, deferiprone, ciclopirox chelate iron, an antioxidant and a Ferrostatin-1 inhibitor.
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