CN106822899A - A kind of medicine by suppressing autophagy promotion Myocardial Regeneration - Google Patents
A kind of medicine by suppressing autophagy promotion Myocardial Regeneration Download PDFInfo
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- CN106822899A CN106822899A CN201710140765.9A CN201710140765A CN106822899A CN 106822899 A CN106822899 A CN 106822899A CN 201710140765 A CN201710140765 A CN 201710140765A CN 106822899 A CN106822899 A CN 106822899A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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Abstract
The invention discloses a kind of medicine by suppressing autophagy promotion Myocardial Regeneration.Research of the invention finds, it is related to autophagy in the reduction of growth course cardiac myocyte centerbody number, by Drug inhibition cardiac muscle cell's centerbody autophagy, the phenomenon that cell cannot regenerate caused by growth course is reduced due to cardiac muscle cell's centerbody number can be alleviated, and improve the uptake ratio of cardiac muscle cell EdU.Suppressing medicine or derivatives thereof of autophagy can promote the regeneration of cardiac muscle cell, and the disease treatment of cardiomyocyte cell death is caused so as to be expected to be applied to heart failure or other.
Description
Technical field
The invention belongs to field of medicaments, it is related to the new application of medicine, the medicine for more particularly to suppressing autophagy is promoting cardiac muscle
New opplication in terms of regeneration.
Background technology
Used as one of most important organ of human body, its major function is for blood flow provides pressure, by blood to heart
Transport body everywhere.The volume of heart constantly increases with growth course, and the propagation and hypertrophy of its cardiac myocyte are the hearts
Two big main paths of dirty development.Cardiac muscle cell gradually loses multiplication capacity after birth.Heart failure is widely present in global range
Serious, the high angiocardiopathy of fatal rate.After there is miocardial infarction or heart failure in adult, the loss of cardiac muscle cell's number
Almost irreversible, this is limited with the multiplication capacity of cardiac muscle of mammal cell closely related, therefore, disease or ischemic etc. because
The myocardial damage that element is caused is difficult to repair.Therefore, cardiomyocyte proliferation is always the focus studied in field.
Centerbody is made up of two pairs of mutually perpendicular barrel-like structure centrioles and ambient electron densification thing.It is used as one kind weight
During the organelle wanted participates in cell propagation, cell contains two centerbodies and is more conducive to carefully in the specific cell cycle
The division of born of the same parents.And in the research on cardiomyocyte proliferation ability, it was observed that such as DNA synthesis reduction, syncytiam and many times
Body cell ratio increases, the reduction of mitosis level and cytokinesis process are obstructed etc., and phenomenon is relevant with centerbody.So, for
In the research of cardiomyocyte proliferation regeneration, centerbody is probably an important research object.
Cell autophagy is removed degradation pathway and is played a role when cell is subject to hungry or other pressure as one kind, passes through
The protein of degraded macromolecular, organelle or dysfunction maintains the internal balance of cell.Recent studies have found that the embryo of mouse
Tire fibroblast autophagy can participate in adjusting centerbody number.But in cardiac muscle cell, the process whether there is also in
Unknown state.
The content of the invention
It is an object of the invention to explore the influence that autophagocytosis in cardiac muscle cell regenerates to cardiomyocyte proliferation, tool is found
There is the new application of the medicine for suppressing autophagocytosis.
Research discovery of the invention, is reduced in the number of growth course cardiac myocyte centerbody, and centerbody number
Reduce related to autophagy.By Drug inhibition cardiac muscle cell's centerbody autophagy, can alleviate in growth course due to cardiac muscle cell
Centerbody number reduces the phenomenon that caused cell cannot regenerate, and improves the uptake ratio of cardiac muscle cell EdU.
On the basis of experiment, the present invention proposes that the medicine for suppressing autophagy can promote the regeneration of cardiac muscle cell, so as to be expected to
Being applied to heart failure or other causes the disease treatment of cardiomyocyte cell death.
One complete autophagy process needs the participation of multiple steps, including the formation of autophagosome, autophagosome and lysosome
Fusion and autophagy lysosome content three processes of degraded.The medicine and its derivative of suppression autophagy may interfere with therein
One or more processes, so as to suppress the generation of autophagy.For example：
3-MA (3-Methyladenine, 3-MA) can be by suppressing the type III phosphatidyl in autophagy process
Inositol kinase (Phosphoinositide 3-Kinase) signal path, so as to check the generation of autophagosome.In addition, it is wet
Graceful penicillin (Wortmannin), LY294002 can block type III phosphatidyl inositol kinase signal path, so as to suppress certainly
The generation bitten.
Chloroquine (Chloroquine, CQ) can influence the fusion process of autophagosome and lysosome by improving lysosome pH value,
So that autophagy process is blocked.In addition, HCQ, Bava Lip river mycin A1 (Bafilomycin A), vincaleukoblastinum and Nuo Kaoda
Azoles (nocodazole) can also suppress merging for autophagosome and lysosome, so as to influence the generation of autophagy.
Eventually through the hydrolase content in lysosome after autophagosome and lysosome fusion, E46d and
Degradeds of the Pepstatin A to lysosome suppresses so that in a large amount of accumulations of Vesicle-Containing being degraded and lysosome, from
And reach the effect for suppressing autophagy.
The present invention speculates that suppressing the medicine and its derivative of autophagy may participate in the regeneration of cardiac muscle cell by testing
Journey, so that there is provided a kind of new approaches by suppressing autophagy promotion cardiac muscle mitochondria.
To suppress the medicine and its derivative of autophagy as active component, can be used to prepare the medicine for promoting cardiac muscle mitochondria
Thing preparation.The compound or molecule and pharmaceutically acceptable assistant agent that autophagy will be suppressed are made various forms of pharmaceutical preparations, use
In heart failure or other cause the disease treatment of cardiomyocyte cell death.
" the pharmaceutically acceptable assistant agent " including pharmaceutically acceptable carrier, excipient, diluent etc., they with
Active component (suppressing the compound or molecule of autophagy) is compatible.Pharmaceutical preparation is prepared to ability with pharmaceutically acceptable assistant agent
It is known for the those of ordinary skill of domain.The pharmaceutical preparation can be solid pharmaceutical preparation or liquid preparation.Preparation of the invention
Can in units of dosage form, such as tablet, capsule (including sustained release or delay release releasing pattern), suppository, pill, pulvis,
The various formulations such as paste, supensoid agent, granule, tincture, syrup, emulsion agent, suspension, injection and various slow release formulations,
So as to be adapted to various form of medication, for example orally, parenteral injection, mucous membrane, muscle, intravenous, subcutaneous, intraocular, intracutaneous or warp
Cross the form of medication of skin etc..
To sum up, present invention discover that cardiac muscle mitochondria can be promoted by suppressing autophagy, so as to suppress cardiac muscle cell's autophagy
Medicine be likely to become heart failure, miocardial infarction and other cause the therapeutic component of the disease of cardiomyocyte cell death.
Brief description of the drawings
Fig. 1 rat myocardial cell centerbody numbers mesoderm growing early stage situation of change, wherein, 0Ctr represents cardiac muscle cell
Centerbody is not contained in cell；1Ct contains a centerbody in representing cardiac muscle cell；2Ctr contains two in representing cardiac muscle cell
Centerbody；MCtr contains more than 2 centerbodies in representing cardiac muscle cell.
Centerbody and autophagosome common location ratio situation of change are counted during the Rat Development measured in Fig. 2 embodiments 2
Figure, * P<0.05.
In Fig. 3 embodiments 3 after CQ or 3-MA suppresses autophagy, the situation of change of cardiac muscle cell's centerbody number, * P<
0.05, * * P<0.01.
Suppress cardiac muscle cell's EdU uptake ratio situations of change, * P after autophagy in Fig. 4 embodiments 4<0.05.
Specific embodiment
Below by embodiment, the present invention will be further described, the scope of but do not limit the invention in any way.
The cardiac muscle cell of embodiment 1. centerbody number in growth course is reduced
By the use of γ-tubulin (γ tubulins) as centerbody label (γ-tubulin as centerbody master
Composition is wanted, is anchored in centriole ambient substance by NEDD1/GCP-WD), observe in rat myocardial cell in growth course
The situation of change of heart body.
The ventricular muscle cell of different days rat is separated using 0.1% trypsase and 0.08% clostridiopetidase A II.Culture 36
After hour, the fixed punching 7 minutes of -20 DEG C of pre- cold methanol is thin using γ tubulins and cardiac muscle after serum is closed 30 minutes afterwards
Born of the same parents' marker antibody mark center body and cardiac muscle cell, after laser confocal microscope is imaged, in counting in growth course
Heart body number.
Result is as shown in figure 1, rat during 1 day (P1) to 9 days (P9), contains two from after birth in cardiac muscle cell
The ratio of centerbody is down to 24% from 56%, and the cell proportion without centerbody rises to 32% from 4% in cell.
The common location ratio of centerbody and autophagosome increases in the growth course of embodiment 2.
MAP light chain 3 (Microtubule-associated protein 1light chain 3, LC3)
The formation of autophagosome is take part in, is positioned on autophagosome film, and be proved to be common autophagosome mark in mammalian cell
One of note albumen.The ventricular muscle cell of different days rat is separated also with 0.1% trypsase and 0.08% clostridiopetidase A II.
Culture 36 hours, the fixed punching 7 minutes of -20 DEG C of pre- cold methanol, after serum is closed 30 minutes afterwards, using γ tubulins, certainly
Bite body and cardiomyocyte markers thing antibody does immunocytochemistry, after laser confocal microscope is imaged, statistics was developed
The ratio of centerbody and autophagosome common location in journey.
During Rat Development we have found that the common location ratio of cardiac muscle cell's centerbody and autophagosome (LC3 marks) by
Cumulative many, during by P1 26% is increased to 52% (Fig. 2) during P7, illustrates during development, centerbody number reduce and
Autophagy is relevant.
Embodiment 3. suppresses cell autophagy and alleviates the reduction of cardiac muscle cell's centerbody number
In order to further verify whether autophagy participates in the reduction of centerbody number this process, we utilize medicine (CQ
And 3-MA) intraperitoneal injection is carried out to rat, the purpose of autophagy is suppressed to reach, so as to observe centerbody number be received in cell autophagy
Situation of change after to suppression.Chloroquine (Chloroquine, CQ), can influence autophagosome and lyase by improving lysosome pH value
The fusion process of body so that autophagy process is blocked.3-MA (3-Methyladenine, 3-MA) can suppress certainly
Type III phosphatidyl inositol kinase (Phosphoinositide 3-Kinase) signal path during biting, so as to check autophagy
The generation of body.
To the rat suckling mouse intraperitoneal injection of saline (as control) of different days, chloroquine (60mg/kg) and 3- methyl
Adenine (30mg/kg), injection separates ventricular muscle cell after 12 hours, is marked using γ tubulins, autophagosome and cardiac muscle cell
Note thing antibody does immunocytochemistry, after laser confocal microscope is imaged, counts different experiments group rat myocardial cell
The ratio situation of change of centerbody and autophagosome common location in growth course.Result shows, after autophagy is suppressed, with control group
It is significantly raised (Fig. 3) compared to ratio containing two centerbodies in cardiac muscle cell.
The uptake ratio of cardiac muscle cell EdU is improve after the suppression cell autophagy of embodiment 4.
The deoxyuridine of 5- acetenyls -2 ' (EdU) are a kind of thymidine analog, the energy when cell is bred
Enough insert in the DNA molecular for replicating, can effectively mark the cell in the S phases.Using this feature of EdU, to difference
The rat suckling mouse intraperitoneal injection of saline (as control) of age in days, chloroquine and 3-MA, separate cardiac muscle after 12 hours
Cell, and to EdU is added in culture medium, culture using cy5 dye markers EdU and utilizes cardiomyocyte markers thing antibody two days later
Immunocytochemistry is done, after laser confocal microscope is imaged, statistics different experiments group rat myocardial cell was being developed
The situation of change of EdU uptake ratios in journey.It was found that during cell autophagy is suppressed, compared to control group, injecting chloroquine
Uptake ratio with the cardiac muscle cell EdU of 3-MA is significantly improved (Fig. 4), implies that suppressing cell autophagy may promote the heart
The propagation of myocyte.
It is above-mentioned test result indicate that, in suckling mouse growth course, autophagy participates in regulation cardiac muscle cell centerbody number
During.Suppressing autophagy can effectively alleviate this process, and provide increasing growth course cardiac myocyte multiplication capacity
Certain reference.For clinical treatment miocardial infarction provides thinking.
Claims (5)
1. application of the medicine of autophagy or derivatives thereof in the medicine for promoting cardiac muscle mitochondria is prepared is suppressed.
2. application as claimed in claim 1, it is characterised in that described medicine for suppressing autophagy or derivatives thereof refers to following
One or more inhibited medicines during three or derivatives thereof：The formation of autophagosome, autophagosome and lyase
The fusion of body and the degraded of autophagy lysosome content.
3. application as claimed in claim 1, it is characterised in that described medicine for suppressing autophagy or derivatives thereof is selected from following medicine
One or more in thing and their derivative：3-MA, wortmannin, LY294002, chloroquine, HCQ,
Bava Lip river mycin A1, vincaleukoblastinum, nocodazole, E46d and Pepstatin A.
4. a kind of pharmaceutical preparation for promoting cardiac muscle mitochondria, comprising suppress medicine or derivatives thereof of autophagy as activity into
Point, and pharmaceutically acceptable assistant agent.
5. pharmaceutical preparation as claimed in claim 4, it is characterised in that medicine of the suppression autophagy or derivatives thereof is selected from down
One or more in row medicine and their derivative：3-MA, wortmannin, LY294002, chloroquine, hydroxyl chlorine
Quinoline, Bava Lip river mycin A1, vincaleukoblastinum, nocodazole, E46d and Pepstatin A.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112451529A (en) * | 2020-12-18 | 2021-03-09 | 忻佑康医药科技(南京)有限公司 | New pharmaceutical application of Kb-NB 142-70 |
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| EP1782849A2 (en) * | 1999-04-12 | 2007-05-09 | Theregen, Inc. | Three-dimensional stromal tissue |
| CN103505732A (en) * | 2012-06-21 | 2014-01-15 | 复旦大学 | Tumor treatment synergism combination drug |
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| CN112451529A (en) * | 2020-12-18 | 2021-03-09 | 忻佑康医药科技(南京)有限公司 | New pharmaceutical application of Kb-NB 142-70 |
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