CN117243967B - Application of Met-tRNAiMet or tRNAiMet in preparation of medicines for treating myocardial hypertrophy and heart failure - Google Patents
Application of Met-tRNAiMet or tRNAiMet in preparation of medicines for treating myocardial hypertrophy and heart failure Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
- A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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Abstract
The invention relates to the technical field of biological medicine, in particular to application of Met-tRNAiMet or tRNAiMet in preparation of a medicament for treating myocardial hypertrophy and heart failure. Through exogenous supplementation of Met-tRNAiMet, the number of Met-tRNAiMet in the heart of the mice can be effectively increased, the cardiac ejection fraction of heart failure model mice can be obviously improved, the hypertrophy of cardiac myocytes can be reduced, and the integral stress response of the cardiac myocytes due to ischemia and hypoxia can be relieved, so that the cardiac function can be enhanced. The anti-myocardial hypertrophy and heart failure medicine can obviously change the heart function of heart failure animals and has the effect of effectively resisting myocardial hypertrophy and heart failure.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to application of Met-tRNAiMet or tRNAiMet in preparing a medicament for treating myocardial hypertrophy and heart failure.
Background
Heart failure and myocardial hypertrophy are not isolated diseases, which are often caused by potential heart defects, mainly in the elderly, where many people are receiving treatment for other medical problems at the same time. Thus, many heart failure and cardiac hypertrophy patients are accompanied by complications associated with underlying heart problems or causes thereof (e.g., angina pectoris, hypertension, diabetes, smoking-induced pulmonary diseases) and age-related problems (e.g., osteoarthritis), the presence of many complications increasing the likelihood of drug intolerance (e.g., ACE inhibitors and renal dysfunction) and the occurrence of drug interactions (e.g., nonsteroidal anti-inflammatory drugs and ACE inhibitors), complicating management of heart failure and cardiac hypertrophy.
Disclosure of Invention
The present invention is directed to solving at least one of the technical problems existing in the related art. Therefore, the inventor finds that the anti-myocardial hypertrophy and heart failure medicine can obviously change the heart function of heart failure animals and plays an effective role in resisting myocardial hypertrophy and heart failure.
In one aspect, the invention provides the use of Met-tRNAiMet or tRNAiMet in the manufacture of a medicament for the treatment of myocardial hypertrophy and heart failure.
Furthermore, the acting target for treating myocardial hypertrophy and heart failure is Met-tRNAiMet or tRNAiMet;
the Met-tRNAiMet expression mode is as follows: adenovirus expression vector mediated in vivo expression or Met-tRNAiMet in vitro synthesis followed by cardiac in situ injection;
the in vitro synthesis of Met-tRNAiMet was performed in a manner selected from the group consisting of: in vitro transcription, chemical synthesis or cell extraction.
Further, the adenovirus expression vector-mediated in vivo expressed Met-tRNAiMet material is an expression vector transformant in which a myocardial specific promoter and Met-tRNAiMet gene sequence are linked.
Further, met-tRNAiMet is human Met-tRNAiMet or mouse Met-tRNAiMet;
the sequence of Met-tRNAiMet is SEQ ID NO.1.
Further, the myocardial specific promoter is cTNT, alpha-MHC, MLC-2v, ANF or SERCA2a.
Further, the expression vector transformant includes an adeno-associated virus expression vector pAAV9.
In another aspect, the present invention provides a medicament for treating myocardial hypertrophy and heart failure, which comprises a pharmaceutically active ingredient; the pharmaceutically active ingredient comprises a substance that highly expresses Met-tRNAiMet targeted to cardiac myocytes.
Further, the substance highly expressing Met-tRNAiMet targeted to myocardial cells is an expression vector transformant in which a myocardial specific promoter and Met-tRNAiMet gene sequence are linked.
Further, met-tRNAiMet is human Met-tRNAiMet or mouse Met-tRNAiMet;
the myocardial specificity promoter is cTNT, alpha-MHC, MLC-2v, ANF or SERCA2a;
the expression vector transformant was the adeno-associated virus expression vector pAAV9.
In another aspect, the present invention provides a transformant for treating myocardial hypertrophy and heart failure, comprising: expression vector transformants linked to a myocardial specific promoter and a Met-tRNAiMet gene sequence.
The above technical solutions in the embodiments of the present invention have at least one of the following technical effects:
the inventor of the invention discovers that the ribosome translation of heart failure model mice myocardial cells is reduced, the reduction of the translation level of the myocardial cells can be the cause of myocardial hypertrophy and heart failure development, and the combination of Met-tRNAiMet plays a role in the translation initiation process, and the exogenous supplementation of Met-tRNAiMet can effectively increase the quantity of Met-tRNAiMet in heart of the mice, obviously improve the cardiac ejection fraction of heart failure model mice, reduce the myocardial cell hypertrophy and relieve the integral stress response of the myocardial cells caused by ischemia and hypoxia, thereby realizing the enhancement of cardiac function. The anti-myocardial hypertrophy and heart failure medicine can obviously change the heart function of heart failure animals and has the effect of effectively resisting myocardial hypertrophy and heart failure.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
In order to more clearly illustrate the invention or the technical solutions of the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the invention, and other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a ribosome map of the whole heart of a C57 mouse in experimental example 2 of the present invention after TAC surgery is completed.
FIG. 2 is a graph showing the ratio of ribosomal multimers to ribosomal monomers in cardiomyocytes in the mice of the experimental group and in the sham-operated group of experimental example 2 according to the present invention.
FIG. 3 shows the proportion of ribosomal polymers in cardiomyocytes in the mice of the operation group and the sham operation group in experimental example 2 according to the present invention.
FIG. 4 is a graph showing changes in p-EIF2α, PERK and H3 in cardiomyocytes in the mice of the operation group and the sham operation group in experimental example 2 of the present invention.
FIG. 5 is a schematic flow chart of the injection of pAAV9-cTNT-CAT or control pAAV9 virus into TAC mice in Experimental example 2 of the present invention.
FIG. 6 is the results of cardiac ultrasound in four groups of mice in Experimental example 2 of the present invention.
FIG. 7 shows the ejection fraction results of four groups of mice in Experimental example 2 of the present invention.
FIG. 8 is a short axis rate result of four groups of mice in experimental example 2 of the present invention.
FIG. 9 is a cardiac plane staining analysis of four groups of mice in Experimental example 2 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The following examples are illustrative of the invention but are not intended to limit the scope of the invention.
In the description of the embodiments of the present invention, it should be noted that the terms "center", "longitudinal", "lateral", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc. indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, are merely for convenience in describing the embodiments of the present invention and simplifying the description, and do not indicate or imply that the apparatus or elements referred to must have a specific orientation, be configured and operated in a specific orientation, and thus should not be construed as limiting the embodiments of the present invention. Furthermore, the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.
In describing embodiments of the present invention, it should be noted that, unless explicitly stated and limited otherwise, the terms "coupled," "coupled," and "connected" should be construed broadly, and may be either a fixed connection, a removable connection, or an integral connection, for example; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium. The specific meaning of the above terms in embodiments of the present invention will be understood in detail by those of ordinary skill in the art.
In embodiments of the invention, unless expressly specified and limited otherwise, a first feature "up" or "down" on a second feature may be that the first and second features are in direct contact, or that the first and second features are in indirect contact via an intervening medium. Moreover, a first feature being "above," "over" and "on" a second feature may be a first feature being directly above or obliquely above the second feature, or simply indicating that the first feature is level higher than the second feature. The first feature being "under", "below" and "beneath" the second feature may be the first feature being directly under or obliquely below the second feature, or simply indicating that the first feature is less level than the second feature.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the embodiments of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
The conception of the invention is as follows: the inventor of the invention discovers that restoring heart translation and maintaining basic functions of cardiac muscle cells are probably new targets for treating myocardial hypertrophy and heart failure through researches. According to the problems and defects existing in the field objectively, the inventor finds out the relation between Met-tRNAiMet serving as a translation initiating element and myocardial hypertrophy and translation decline in heart failure process in the early test exploration process, further develops an anti-myocardial hypertrophy and heart failure drug taking Met-tRNAiMet as a drug target through a molecular experiment, and simultaneously carries out animal experiments to prove that the anti-myocardial hypertrophy and heart failure drug based on Met-tRNAiMet can obviously change the heart function of heart failure model animals and play an effective role in resisting myocardial hypertrophy and heart failure. The invention focuses on the source problem of myocardial hypertrophy and heart failure development: protein translation is reduced and cardiomyocytes are insufficient to fulfill basal functions. Treatment with Met-tRNAiMet effects on translation initiation rates is expected to restore damaged cardiomyocytes by a radical treatment.
In one aspect, the invention provides the use of Met-tRNAiMet or tRNAiMet in the manufacture of a medicament for the treatment of myocardial hypertrophy and heart failure.
It should be noted that the expression "tRNAiMet" refers to tRNAiMet when chemically synthesized or when not entering cells; when transcribed or enters a cell, it is Met-tRNAiMet. The active ingredient of the finally obtained medicine for treating heart failure and myocardial hypertrophy is Met-tRNAiMet. It should be noted that heart failure and heart failure have conventional technical meanings known to those skilled in the art, and are all the common technical meanings expressed by the term "heart failure".
The inventor of the invention discovers that the ribosome translation of heart failure model mice myocardial cells is reduced, the reduction of the translation level of the myocardial cells is probably the reason of myocardial hypertrophy and heart failure development, and the combination of Met-tRNAiMet plays a role in the translation initiation process, and the exogenous supplementation of Met-tRNAiMet can effectively increase the quantity of Met-tRNAiMet in heart of the mice, obviously improve the cardiac ejection fraction of heart failure model mice, relieve the integral stress response of the myocardial cells caused by ischemia and hypoxia, thereby realizing the enhancement of cardiac function. The anti-myocardial hypertrophy and heart failure medicine can obviously change the heart function of heart failure model animals, and plays an effective role in resisting myocardial hypertrophy and heart failure.
Based on the change of myocardial hypertrophy and heart failure progress center muscle cell translation efficiency, the inventor speculates that Met-tRNAiMet is very likely to play a crucial role in restoring the myocardial cell basic protein translation efficiency, and develops related experiments. Experiments of the inventor of the invention find that myocardial hypertrophy and heart failure mice have significantly reduced myocardial cell translation level, and over-expression of Met-tRNAiMet related to translation initiation in heart failure model mice can resist myocardial hypertrophy and heart failure, and the logic association between the former and the latter is presumed to be as follows: in heart failure model mice, the reduction of myocardial cell translation level may play an important role in the processes of myocardial hypertrophy and heart failure, but if only one translation initiation factor Met-tRNAiMet is added, the translation of the heart can be recovered, the transportation of the heart to the blood of the organism is satisfied, and the subsequent functional study is needed. In functional studies the inventors of the present invention found that Met-tRNAiMet overexpression was able to treat myocardial hypertrophy and heart failure. It is suggested that the decrease in the level of cardiomyocyte translation may be responsible for the development of myocardial hypertrophy and heart failure, and that the heart may be protected by exogenous replacement of Met-tRNAiMet.
In some embodiments of the invention, the target for treating myocardial hypertrophy and heart failure is Met-tRNAiMet or tRNAiMet; the Met-tRNAiMet expression mode is as follows: adenovirus expression vector mediated in vivo expression or Met-tRNAiMet in vitro synthesis followed by cardiac in situ injection; the in vitro synthesis of Met-tRNAiMet was performed in a manner selected from the group consisting of: in vitro transcription, chemical synthesis or cell extraction. Therefore, the medicinal effect component of the medicament for treating myocardial hypertrophy and heart failure takes Met-tRNAiMet as a medicament target point, and plays a role in treating myocardial hypertrophy and heart failure by expressing Met-tRNAiMet in a high degree, so that the quantity of the mice cardiac Met-tRNAiMet can be specifically increased, the cardiac ejection fraction of heart failure model mice is obviously improved, and the integral stress response of myocardial cells caused by ischemia and hypoxia is relieved, thereby realizing the enhancement of cardiac function.
In some embodiments of the invention, the pharmaceutical ingredients of the medicament for treating myocardial hypertrophy and heart failure comprise directly injecting a heart-targeted Met-tRNAiMet nucleic acid substance, and a coronary artery targeting or myocardial cell targeting sequence can be added in front of Met-tRNAiMet to achieve the effect of specifically increasing heart expression to achieve the therapeutic effect. Other means, such as targeting of certain targets to cardiac nanocarriers and delivery vehicles, may also be employed, as may the goal of enhancing cardiac Met-tRNAiMet expression levels.
In some embodiments of the invention, the adenovirus expression vector-mediated in vivo expressed material is an expression vector transformant in which the myocardium-specific promoter and Met-tRNAiMet gene sequence are linked.
In some embodiments of the invention, met-tRNAiMet is human Met-tRNAiMet or mouse Met-tRNAiMet; the sequence of Met-tRNAiMet is SEQ ID NO.1.
In some embodiments of the invention, the Sequence ID of human Met-tRNAiMet in NCBI is: z69292.1.
In some embodiments of the invention, the myocardial specific promoter is cTNT, alpha-MHC, MLC-2v, ANF or SERCA2a.
In some embodiments of the invention, cTNT is cTNT as described in "Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution"; the Gene ID of the alpha-MHC is: 17888; the Gene ID of MLC-2v is: 17906; the Gene ID of ANF is: 4878; the Gene ID of SERCA2a is: 11938.
in some embodiments of the invention, the expression vector transformant comprises the adeno-associated viral expression vector pAAV9. The AAV9 adenovirus recombinant vector selected by the invention has the highest heart targeting specificity at present, can drive the target gene to express in vivo for a long time and has no immunogenicity, and other serotypes of adenovirus can have similar or equivalent therapeutic effects, and are not repeated herein.
In some embodiments of the present invention, the preparation method of the drug for treating myocardial hypertrophy and heart failure comprises the following steps: the Met-tRNAiMet sequence was repeated twice, and cTNT-Met-tRNAiMet double-stranded nucleotide was synthesized by using total gene synthesis technique, and cloned into expression vector transformant of Met-tRNAiMet gene sequence.
In some embodiments of the invention, the sequence of human Met-tRNAiMet from position 187 to position 586 (SEQ ID NO. 1) is repeated twice and ligated into pAAV vector to increase expression efficiency. The pAAV vector was supplied by well-known Gekko Co. It should be noted that, the sequence from 187 to 586 of human Met-tRNAiMet may have similar or equivalent therapeutic effects without repeating the sequence or repeating the sequence multiple times.
In some embodiments of the invention, the medicament for treating myocardial hypertrophy and heart failure further comprises: pharmaceutically acceptable auxiliary materials.
In some embodiments of the invention, the medicament for treating myocardial hypertrophy and heart failure further comprises: reagents for buffering, culturing and/or propagating the expression vector of the Met-tRNAiMet gene sequence.
It can be understood that the person skilled in the art can add various pharmaceutically acceptable auxiliary agents/auxiliary materials into the anti-myocardial hypertrophy and heart failure medicament according to objective requirements to prepare various dosage forms, thereby being convenient for sale or popularization.
In another aspect of the present invention, there is provided a medicament for treating myocardial hypertrophy and heart failure, comprising a pharmaceutically active ingredient; the pharmaceutically active ingredient comprises a substance that highly expresses Met-tRNAiMet targeted to cardiac myocytes. It should be noted that the medicines for treating myocardial hypertrophy and heart failure and the substances highly expressing Met-tRNAiMet targeted to myocardial cells are consistent with the above description, and will not be described in detail herein.
In some embodiments of the invention, the agent that highly expresses Met-tRNAiMet targeted to myocardial cells is an expression vector transformant that has linked thereto a myocardial specific promoter and a Met-tRNAiMet gene sequence.
In some embodiments of the invention, met-tRNAiMet is human Met-tRNAiMet or mouse Met-tRNAiMet; the myocardial specificity promoter is one of cTNT, alpha-MHC, MLC-2v, ANF or SERCA2a; the expression vector transformant was the adeno-associated virus expression vector pAAV9.
In another aspect of the invention, the invention provides a recombinant adenovirus comprising: expression vector transformants linked to a myocardial specific promoter and a Met-tRNAiMet gene sequence.
The expression vector transformant in which the myocardial specific promoter and the Met-tRNAiMet gene sequence were ligated was identical to the above description, and will not be described in detail here.
The invention will be further illustrated with reference to specific examples, which are given for the purpose of illustration only and are not to be construed as limiting the invention.
Examples
The following examples or experimental examples relate to the following instruments, reagents and consumables, and sources of biological materials:
1) Instrument and equipment
NanoPhotometer NP80 nucleic acid analyzer, E-gel imager gel analyzer, tanon 5200 gel imager, thermo ST16R low temperature bench centrifuge.
2) Reagent and consumable
2,2-Tribromoethanol (from sigma), sucrose RNASE and DNASE Free (from VWR), superSignal West Pico PLUS chemiluminescent developer from thermo; met-tRNAi Met The sequence fragment was synthesized by Beijing De Orthosiphon BioCo, and AAV9 viral vector packaging and purification was synthesized by Gekko gene technologies Co.
3) Sources of biological materials
C57 background mice were purchased from beijing velutinin inc.
Experimental example 1
Construction of recombinant adenoviruses
The recombinant adenovirus expression vector selects AAV9 adenovirus vector with high expression level of cardiac muscle cells, and adds cTNT cardiac muscle cell promoter.
1. Construction of pAAV9-cTNT-Met-tRNAiMet vector
Based on the base Sequence of the cardiomyocyte-specific promoter cTNT (Gene ID: 7139) and Met-tRNAiMet (Sequence ID: Z69292.1). Wherein the Met-tRNAiMet sequence is repeated twice. The double-stranded nucleotide of cTNT-Met-tRNAiMet is synthesized by adopting a total gene synthesis technology and cloned to a pAAV vector to form a pAAV-cTNT-Met-tRNAiMet plasmid, and the double-stranded nucleotide is synthesized by Beijing aoping biotechnology Co.
2. Plasmid transformation
pAAV-cTNT-Met-tRNAiMet plasmid was added to 100. Mu.L DH 5. Alpha. Competent cells and left on ice for 30 min; after heating at 42 ℃ for 45 seconds, the mixture was left on ice for 2 minutes; 1 ml of antibiotic-free LB medium is added, and shake culture is carried out for 1 hour at 37 ℃ and 100 RPM; white monoclonal colonies were selected for identification by culturing on amp+ LB plate medium.
3. Plasmid small lifter
Monoclonal colonies were picked and inoculated into 5ml of amp+ medium and shake-cultured at 37℃for 12 hours at 100 RPM. Plasmid extraction using the low endotoxin plasmid minibody midbody kit of the Magen organism comprises the following specific operation steps:
1) The medium was discarded and the residual liquid was gently tapped on absorbent paper. 600 μl Buffer E1/RNaseA was added and the bacteria were resuspended sufficiently by high speed vortexing.
2) Adding 600 mul Buffer E2 into the heavy suspension, and mixing the mixture for 6 to 8 times in a reverse way. And standing for 2 minutes at room temperature, and mixing the materials for 2-3 times in a reverse way.
3) 600 μl Buffer E3 is added to the lysate, and the solution is immediately inverted for 10-15 times.
4) Centrifuge at 13,000 Xg for 10 minutes at room temperature.
5) Transferring the supernatant to a 4-15 ml centrifuge tube, and adding Buffer E4 (550 mu l) with 1/3 times of the volume into the supernatant. And (5) reversing and uniformly mixing for 6-8 times.
6) HiPure EF Mini Column is sleeved in the collection tube. Transfer 750 μl of mixed liquor to the column. Centrifuge for 15-60 seconds at 10,000Xg.
7) The filtrate was discarded, the column was returned to the collection tube and the remaining mixture was transferred to the column. Centrifuging for 15-60 seconds at 10,000Xg; this step was repeated until all the mixture was transferred to the column for centrifugation.
8) The filtrate was discarded and the column was returned to the collection tube. 650 μl Buffer E5 was added to the column. Centrifuge for 15-60 seconds at 10,000Xg.
9) The filtrate was discarded and the column was returned to the collection tube. 650 μl Buffer PW2 (diluted with absolute ethanol) was added to the column. Standing for 2 minutes, and centrifuging for 15-60 seconds at 10,000Xg.
10 Pouring out the filtrate and returning the column to the collection tube. 650 μl Buffer PW2 (diluted with absolute ethanol) was added to the column. Centrifuge for 15-60 seconds at 10,000Xg.
11 Pouring out the filtrate and returning the column to the collection tube. Centrifuge at 10,000 Xg for 2 min.
12 The column was placed in a sterilized 1.5ml centrifuge tube. And adding 30-100 mu l Buffer TE to the center of the membrane of the column. Standing for 2 min, and centrifuging at 10,000Xg for 1 min to elute DNA. The column was discarded and the plasmid was stored at-20 ℃.
4. Virus packaging, virus purification and virus titer determination; among them, virus packaging, virus purification and virus titer determination are served by gemfibrozil gene technologies, inc. In beijing, and the preparation method is in accordance with routine procedures in the art.
Experimental example 2
1. The effect of recombinant adenovirus obtained in Experimental example 1 on the treatment of myocardial hypertrophy was examined
TAC (aortic arch stenosis) surgery was performed using 8 week old C57 mice, with the following procedure:
(1) The mice were anesthetized with a mixture of 2% isoflurane and 0.5-1.0L/min pure oxygen.
(2) After the conventional skin preparation and disinfection operation, the mice are fixed on a foam plate in a supine position, are connected with a small animal breathing machine through a laryngeal trachea cannula, have a tidal volume of 0.1-0.3ml, have a breathing frequency of 125-150 times/min and are maintained under gas anesthesia during operation.
(3) The left side 2 nd intercostal space enters the chest device, the mouse chest device is opened, the thymus is passively separated and fixed, and the innominate artery and the left common carotid artery and the left subclavian artery are respectively searched towards the proximal end and the distal end along the aortic arch. A6-0 suture was placed between the innominate and left carotid artery, a 27G narrowing needle was placed parallel to the aortic arch, ligated and carefully withdrawn from the narrowing needle, the chest suture was closed, and the anesthesia machine was removed.
The myocardial cell translation efficiency of the mice of the operation group (labeled TAC in fig. 1 to 4) and the Sham operation group (labeled Sham in fig. 1 to 4) are shown in fig. 1 to 4, and the results shown in fig. 1 to 4 are that the whole hearts of the mice of the operation group and the Sham operation group examine the myocardial cell translation efficiency by drawing a ribosome map, and the results indicate that the cell translation ability after TAC operation is significantly decreased, the proportion of ribosomal multimer (Polysome) is decreased, and the ribosomal monomer (Monosome) is significantly increased.
3 weeks after TAC surgery, 30 mice from the surgery group were selected and divided into three groups of 10 mice each, one of which was pAAV-cTNT-Met-tRNAiMet (labeled as tac+aav9-tRNAiMet in fig. 6 to 8) obtained by micro-intravenous injection of experimental example 1, the second group was pAAV9 virus (labeled as tac+aav9-control in fig. 6 to 9) by micro-intravenous injection of the control, the third group was untreated (labeled as TAC in fig. 6 to 9), and virus titer 1×10 11 vg/g only; 10 Sham mice were selected as no treatment and served as controls (labeled as Sham in fig. 5-8). After 2 weeks, the experimental emphasis is reached, and cardiac functions of the four groups of mice are detected by using cardiac ultrasound, and the results are shown in fig. 5 to 8, and the results show that: tac+aav9-tRNAiMet treatment significantly restored cardiac contractility, i.e., met-tRNAiMet treatment significantly improved cardiac function in TAC mice.
2. The effect of the recombinant adenovirus treatment obtained in Experimental example 1 on myocardial cell ISR response (comprehensive stress response) was examined
After the ultrasonic detection of each group of mice is finished, RIPA lysate is adopted to lyse myocardial cells, and a Western blot method is used for detecting the key protein expression condition of ISR in the hearts of each group of mice. The results are shown in FIG. 9, and the results show that Met-tRNAiMet treatment is effective in alleviating cardiomyocyte-integrated stress.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. Application of Met-tRNAiMet or tRNAiMet in preparing medicament for treating myocardial hypertrophy and heart failure, wherein Met-tRNAiMet is human Met-tRNAiMet; the sequence of Met-tRNAiMet is SEQ ID NO.1.
2. The use of Met-tRNAiMet or tRNAiMet according to claim 1 for the manufacture of a medicament for the treatment of myocardial hypertrophy and heart failure wherein the target of action for the treatment of myocardial hypertrophy and heart failure is Met-tRNAiMet or tRNAiMet;
the Met-tRNAiMet expression mode is as follows: adenovirus expression vector mediated in vivo expression or Met-tRNAiMet in vitro synthesis followed by cardiac in situ injection;
the in vitro synthesis of Met-tRNAiMet was performed in a manner selected from the group consisting of: in vitro transcription, chemical synthesis or cell extraction.
3. Use of Met-tRNAiMet or tRNAiMet according to claim 2 in the manufacture of a medicament for the treatment of myocardial hypertrophy and heart failure, wherein the Met-tRNAiMet expressed in vivo mediated by an adenovirus expression vector is an expression vector transformant linked to a myocardial specific promoter and a gene sequence of Met-tRNAiMet.
4. The use of Met-tRNAiMet or tRNAiMet according to claim 3 for the manufacture of a medicament for the treatment of myocardial hypertrophy and heart failure wherein the myocardial specific promoter is cTNT, a-MHC, MLC-2v, ANF or SERCA2a.
5. Use of Met-tRNAiMet or tRNAiMet according to claim 3 for the manufacture of a medicament for the treatment of myocardial hypertrophy and heart failure wherein the expression vector transformant comprises the adeno-associated viral expression vector pAAV9.
6. The medicine for treating myocardial hypertrophy and heart failure is characterized by comprising a medicine active ingredient; the pharmaceutical active ingredient comprises a substance which highly expresses Met-tRNAiMet of a target cardiac muscle cell, wherein the Met-tRNAiMet is a humanized Met-tRNAiMet; the sequence of Met-tRNAiMet is SEQ ID NO.1, and the substance for high expression of Met-tRNAiMet targeted to myocardial cells is an expression vector transformant in which a myocardial specific promoter and a gene sequence of Met-tRNAiMet are linked.
7. The drug for treating myocardial hypertrophy and heart failure as claimed in claim 6, wherein said myocardial specific promoter is cTNT, α -MHC, MLC-2v, ANF or SERCA2a; the expression vector transformant was the adeno-associated virus expression vector pAAV9.
8. A transformant for treating myocardial hypertrophy and heart failure, comprising: an expression vector transformant linking the myocardium-specific promoter and the Met-tRNAiMet gene sequence, met-tRNAiMet being human Met-tRNAiMet; the sequence of Met-tRNAiMet is SEQ ID NO.1.
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