CN108295249A - Applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage - Google Patents
Applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage Download PDFInfo
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- CN108295249A CN108295249A CN201810196277.4A CN201810196277A CN108295249A CN 108295249 A CN108295249 A CN 108295249A CN 201810196277 A CN201810196277 A CN 201810196277A CN 108295249 A CN108295249 A CN 108295249A
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- C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
- C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
- C12Y305/01098—Histone deacetylase (3.5.1.98), i.e. sirtuin deacetylase
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Abstract
The invention belongs to the function of gene and application field, a kind of application of the histon deacetylase (HDAC) Sirt1 of catalytic proteins lysine residue deacetylation in the drug for preparing treatment treating myocardial ischemia damage is disclosed.Present invention determine that deacetylase Sirt1 acts on p21 deacetylations the interaction between cardiac muscle cell cell cycle; to treat the drug for the treatment of myocardial ischemia damage in screening using Sirt1 as drug targets for the first time; especially it is used to prepare the drug for promoting Myocardial Regeneration treatment treating myocardial ischemia damage; and then a kind of drug for treating treating myocardial ischemia damage is provided, that is, it is directed to the adeno-associated virus of Sirt1.
Description
Technical field
The invention belongs to the function of gene and application field, it is related to a kind of catalytic proteins lysine residue deacetylation
Histon deacetylase (HDAC) Sirt1（Sirtuins1, abbreviation Sirt1）Application, more particularly to Sirt1 prepare treatment cardiac muscle
Application in the drug of ischemic injuries.
Background technology
Acute myocardial infarction（MI）Cause cardiac muscle cell dead rapidly, heart dysfunction then occurs.According to recent statistics
Number display, for China patient dead due to acute myocardial infarction AMI every year up to 2,500,000 people, it is dead former that heart infarction has been in China at present
Because of second.It will be helpful to increase the quantity of cardiac muscle cell by the method for Myocardial Regeneration, and then after being effectively improved myocardial infarction
Heart function.Although there are many stem cells of type to be transplanted for treating heart injury, thin about using embryo to do
The ethics problem of born of the same parents' tissue still has, and recipient needs lifetime immunity to inhibit to prevent cellular rejection.Nearest research
It has been proved that it may be the regenerated promising method of inducing heart that inducing cardiomyocytes, which reenter the cell cycle,.
P21 is by cell cycle protein dependent kinase inhibitor 1A（CDKN1A）Coding generates, can be by directly inhibiting
Cell cycle protein dependent kinase（CDK）, the proliferation of suppression of cell.Sirt1 is a kind of histone deacetylase enzyme, can make albumen
Lysine residue deacetylation in matter, participation includes regeneration, cell cycle regulating, DNA is repaired and the weights such as tumour occurs
Want biological process.In addition, Sirt1 itself, which has, reduces the bad reconstruct of ventricle, inhibits cardiac muscle cell apoptosis and weaken cardiac muscle stalk
The function of the cardioprotection of cardiac myocyte hypertrophy after plug.Previously studies have shown that p21 can inhibit cardiac muscle cell's period, and then hinder
Hold back Myocardial Regeneration；And deacetylase Sirt1 is by that can reduce p21 gene expression abundances to the deacetylation effect of p21 and eliminate p21
Induce the cell-cycle arrest generated.However, it is not immediately clear whether Sirt1 can be in cardiac muscle to the effect of p21 deacetylations
Cell cycle regulation influences Myocardial Regeneration in turn in cell.
Invention content
The purpose of the present invention is to provide a kind of DNA methylase inhibitors of catalytic proteins lysine residue deacetylation
Enzyme Sirt1（Sirtuins1, abbreviation Sirt1）Application.
Application of the present invention is applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage.
Further, application of the present invention is that Sirt1 is preparing the medicine for promoting Myocardial Regeneration to treat treating myocardial ischemia damage
Application in object.
The drug of the further feature of application according to the present invention, the treatment treating myocardial ischemia damage is to be directed to
The adeno-associated virus of Sirt1.
Stimulation terminal differentiation cardiac muscle cell reenter the cell cycle may be promote Myocardial Regeneration treatment myocardial ischemia
Property damage important method, but lack effective treatment means because cardiac muscle cell's cell cycle is indefinite at present.
Present invention determine that deacetylase Sirt1 is acted on p21 deacetylations and phase interaction between cardiac muscle cell's cell cycle
With to for the first time using Sirt1 as drug targets in the drug of screening treatment treating myocardial ischemia damage, especially be used to prepare promotion
Myocardial Regeneration treats the drug for the treatment of myocardial ischemia damage, and then provides a kind of drug for treating treating myocardial ischemia damage, that is, is directed to Sirt1
Adeno-associated virus.
It is confirmed by the methods of immunofluorescence, the p21 of acetylation makes cardiac muscle cell block in the period.In addition, by exempting from
The methods of epidemic disease co-precipitation, immunoblotting find that Sirt1 can be catalyzed the deacetylation of p21 in cardiac muscle cell.Meanwhile in vitro with
It is overexpressed the Adenovirus Transfection mouse primary cardiac muscle cell of Sirt1, as a result shows that cardiac muscle cell's increasing can be increased by being overexpressed Sirt1
It grows.Then, C57 mouse are infected as experimental subjects using Sirt1 adeno-associated virus, is established by ligation ramus descendens anterior arteriae coronariae sinistrae small
Mouse myocardial infarction model, the results showed that compared with empty viral group, Sirt1 adeno-associated virus infects C57 mouse cardiac myocytes proliferation
Showed increased, Apoptosis is substantially reduced, and myocardial infarct size significantly reduces, and remodeling ventricle and heart function are obviously improved.Finally, turning
In the cardiac muscle cell for having contaminated the acetylation p21 being overexpressed, it is overexpressed Sirt1 and carries out rescue experiment, it was demonstrated that p21 deacetylations participate in
The proliferation of the cardiac muscle cell of Sirt1 inductions.These results prompt Sirt1 to be catalyzed p21 deacetylations, have and promote cardiac muscle again
It is raw, the bad reconstruct of ventricle is reduced, the cardiac function effect after myocardial infarction is improved, and adeno-associated virus is utilized to be overexpressed Sirt1
Have the function of promoting Myocardial Regeneration treatment myocardial ischemic injury, for the novel targets of research treatment myocardial ischemic injury and new
Strategy provides theoretical foundation and Clinical Basis.
Description of the drawings
Figure 1A is shown in cardiac muscle cell that there are acetylation p21.
Figure 1B shows that p21 deacetylations promote cardiomyocyte proliferation in vitro.
Fig. 2 shows that Sirt1 is catalyzed p21 deacetylations.
Fig. 3 displays are overexpressed Sirt1 and promote cardiomyocyte proliferation.
Fig. 4 A-4F displays, which are overexpressed Sirt1, can improve the cardiac function of adult mouse heart after myocardial infarction.Wherein,
Fig. 4 A show that left ventricular end diastolic diameter, Fig. 4 B show that left room end systolic diameter, Fig. 4 C show left room short axis shortening rate, Fig. 4 D
Display Left Ventricular Ejection Fraction is used, Fig. 4 E display Masson stained myocardium infarct sizes, cardiac muscle cell apoptosis after Fig. 4 F infarct.
Fig. 5 shows that Sirt1 is catalyzed p21 deacetylations, promotes cardiomyocyte proliferation.
Specific implementation mode
Describe the specific experiment verification of application according to the present invention in detail below in conjunction with appended attached drawing.
1. experiment purpose
It explores whether the Sirt1 in cardiac muscle cell can be catalyzed p21 deacetylations, releases p21 to cardiac muscle cell's cell cycle
Inhibiting effect, and then promote cardiomyocyte proliferation.
2. experimental animal and raising
Experimental animal：C57BL/6J tire mouse（Gestational age is 16.5 days）, newborn mice（1 day age）, adult mice（28 day age）.By south
Square medical university's Experimental Animal Center provides.This is tested all zooperies and obtains Nanfang Medical Univ experimental animal committee member
The approval of meeting, all operations are in strict accordance with U.S. National Institutes（NIH）“the guide for the care and
The regulation of use of Laboratory animals " executes.
Feeding environment：All experiment mices are raised in Hospital of Southern Medical University animal experimental center（SPF
Grade）.Mouse special feed is provided by Guangdong Province's Experimental Animal Center.
Rearing conditions：Room temperature is between 22-24 DEG C, and for humidity between 40-70%, it is 12 hours that light and shade, which replaces lighting hours,
Free water is ingested.
3. experimental method
（1）Explore whether p21 occurs acetylation in cardiac muscle cell expresses and whether the p21 of acetylation causes cardiac muscle cell all
Phase blocks.
By the method for co-immunoprecipitation detect acetylation p21 cardiac muscle cell statement situation.In 1 day age mouse cardiac muscle
P21 plasmids are transfected in cell respectively（p21-WT）, acetylation p21 plasmids（p21-KQ）, deacetylation p21 plasmids（p21-KR）With
It is overexpressed p21, acetylation p21, deacetylation p21, with EdU Immunofluorescence test cardiomyocyte proliferation situations.
（2）Explore whether Sirt1 is catalyzed p21 deacetylations.
By co-immunoprecipitation, western blotting method, whether detection Sirt1 interacts with p21, and catalysis p21 is gone
Acetylation.
（3）Explore the influence for being overexpressed Sirt1 to cardiac muscle cell.
With the adenovirus for being overexpressed Sirt1（Ad-Sirt1）1 day age mouse cardiac myocytes is transfected, Immunofluorescence test is passed through
The rate of dyeing of EdU, to observe the proliferative conditions of cardiac muscle cell.
（4）It explores and is overexpressed whether Sirt1 influences the recovery of cardiac function after myocardial infarction.
Mouse heart infarction model is established using the method that ramus descendens anterior arteriae coronariae sinistrae ligatures, the successful mark of model foundation is：
Visible left anterior descending branch feed region cardiac muscle becomes pale under direct-view and ECG ST section is raised.Respectively infarct 7 days, 14 days,
It is with left room contraction/relaxation latter stage internal diameter, left room short axis shortening rate and Left Ventricular Ejection Fraction with 2 dimension ultrasound detections within 21 days and 28 days
Index observing left ventricular function changes, and infarct dyes detection myocardial infarction area, the TUNEL dyeing detection hearts on the 28th day with Masson
Muscle cell apoptosis situation.
（5）Explore the proliferation whether Sirt1 catalysis p21 deacetylations promote cardiac muscle cell.
Transfection contains only p21 plasmids respectively in 1 day age mouse cardiac myocytes（p21-WT）, be overexpressed acetylation p21
（p21-KQ）Plasmid and the p21 for being overexpressed acetylation（p21-KQ）The adenovirus of plasmid+overexpression Sirt1（Ad-Sirt1）, lead to
The rate of dyeing for crossing Immunofluorescence test EdU, to observe different group cardiomyocyte proliferation situations.
4. experimental result
（1）P21 can be acetylation in cardiac muscle cell, and can generate inhibition after p21 acetylations to cardiac muscle cell's cell cycle and make
With, and then inhibit cardiomyocyte proliferation.
It is confirmed by co-immunoprecipitation method, p21 is 1 day age mouse in the expression quantity of 28 day age mouse cardiac myocytes
1.57 again（*p<0.05, n=3）, the p21 of acetylation is 2.01 times of 1 day age mouse in 28 day age mouse cardiac myocytes（*p<
0.05, n=3）, referring to Figure 1A.
In 1 day age mouse cardiac myocytes, transfection respectively contains only p21 plasmids（p21-WT）, be overexpressed deacetylation p21
（p21-KR）And the p21 of acetylation（p21-KQ）Then plasmid detects the rate of dyeing of EdU by immunofluorescence dyeing, with observation
The proliferative conditions of cardiac muscle cell, as a result show the rate of dyeing of tri- groups of EdU of p21-WT, p21-KR, p21-KQ be respectively 3.93%,
8.74%、2.38%（*p<0.05, n=4）, referring to Figure 1B.
In conjunction with Figure 1A -1B as a result, showing that P21 can be acetylation in cardiac muscle cell, and can be thin to cardiac muscle after p21 acetylations
Born of the same parents' cell cycle generates inhibiting effect.
（2）Sirt1 is catalyzed p21 deacetylations.
Injection is overexpressed the adenovirus vector of Sirt1 respectively（Ad-Sirt1）And empty carrier adenovirus（Ad-NC）To mouse
Heart is to be overexpressed Sit1, after transfecting 10 days, confirms to be overexpressed Sirt1 not only by the method for co-immunoprecipitation, immunoblotting
The expression quantity of p21 is reduced, and reduces p21 Acetylation Levels, the above result shows that Sirt1 is catalyzed p21 deacetylations, referring to
Fig. 2（*p<0.05, n=4）.
（3）It is overexpressed Sirt1 and promotes cardiomyocyte proliferation.
Injection is overexpressed the adenovirus of Sirt1 in 1 day age mouse cardiac myocytes（Ad-Sirt1）, contaminated by immunofluorescence
Color detects the rate of dyeing of EdU, to observe the proliferative conditions of cardiac muscle cell, as a result shows that being overexpressed Sirt1 increases cardiac muscle carefully
The EdU positive rates of born of the same parents promote cardiomyocyte proliferation, referring to Fig. 3（*p<0.05, n=4）.
（4）The cardiac function of adult mouse heart after myocardial infarction can be improved by being overexpressed Sirt1.
Mouse heart infarction model is established with the method that coronary artery left anterior descending branch ligatures, adeno-associated virus is injected in heart infarction marginal zone
（AAV-Sirt1 or AAV-NC）, shunk/relaxed with left room with 2 dimension ultrasound detections within 7 days, 14 days, 21 days and 28 days in infarct respectively
It is that index observing left ventricular function changes to open warp, left room short axis shortening rate and Left Ventricular Ejection Fraction in latter stage, the 28th day use of infarct
Masson dyeing detections myocardial infarction area, TUNEL dyeing detection cardiac muscle cell apoptosis situations, as a result prompt are overexpressed Sirt1
The cardiac function that adult mouse heart after myocardial infarction can be improved, referring to Fig. 4 A-4F（*p<0.05, n=4）.
（5）Sirt1 is catalyzed p21 deacetylations, and then the cardiomyocyte proliferation promoted.
Transfection contains only p21 plasmids respectively in 1 day age mouse cardiac myocytes（p21-WT）, be overexpressed acetylation p21
（p21-KQ）Plasmid and the p21 for being overexpressed acetylation（p21-KQ）The adenovirus of plasmid+overexpression Sirt1（Ad-Sirt1）, lead to
The rate of dyeing for crossing Immunofluorescence test EdU, to observe different group cardiomyocyte proliferation situations, as a result prompt p21-WT,
P21-KQ, p21-KQ+ Ad-Sirt1 EdU rate of dyeing be respectively 3.98%, 2.21%, 8.09%, prompt Sirt1 catalysis p21 go
Acetylation can promote cardiomyocyte proliferation, referring to Fig. 5（*p<0.05, n=4）.
The experimental results showed that, Sirt1 is catalyzed p21 deacetylations above, relieves p21 and makees to the inhibition in cardiac muscle cell's period
With, and then promote cardiomyocyte proliferation, being overexpressed Sirt1 using adeno-associated virus, there is promotion Myocardial Regeneration to treat myocardial ischemia
Property damage effect.
Claims (3)
- Applications of the 1.Sirt1 in the drug for preparing treatment treating myocardial ischemia damage.
- 2. applications of the Sirt1 in preparing the drug for promoting Myocardial Regeneration to treat treating myocardial ischemia damage.
- 3. application according to claim 1 or 2, it is characterised in that：The drug of the treatment treating myocardial ischemia damage is to be directed to The adeno-associated virus of Sirt1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810196277.4A CN108295249A (en) | 2018-03-09 | 2018-03-09 | Applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage |
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| CN201810196277.4A CN108295249A (en) | 2018-03-09 | 2018-03-09 | Applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage |
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Cited By (1)
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| CN114807139A (en) * | 2022-05-11 | 2022-07-29 | 上海海洋大学 | Regenerative micromolecule miRNA-XU2 and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114807139A (en) * | 2022-05-11 | 2022-07-29 | 上海海洋大学 | Regenerative micromolecule miRNA-XU2 and application thereof |
| CN114807139B (en) * | 2022-05-11 | 2023-11-24 | 上海海洋大学 | Regenerated small molecule miRNA-XU2 and application thereof |
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Application publication date: 20180720 |