CN110387358A - Target and application of the histone demethylase LSD1 as myocardial hypertrophy diagnosing and treating - Google Patents
Target and application of the histone demethylase LSD1 as myocardial hypertrophy diagnosing and treating Download PDFInfo
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- C12Y114/11027—[Histone H3]-lysine-36 demethylase (1.14.11.27)
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Abstract
The present invention relates to medical diagnosis and treatment technology field, in particular to target and application of the histone demethylase LSD1 as myocardial hypertrophy diagnosing and treating, when using drug occur inhibition of histone demethylase LSD1 (KDM1A) activity, and the change of patient's cardiac muscle LSD1 enzymatic activity or LSD1 expression, it then will lead to the promotion of cardiovascular system onset risk, such as: myocardial hypertrophy.The present invention is illustrated the diagnosing and treating target of myocardial hypertrophy and application for histone demethylase LSD1.
Description
Technical field
The present invention relates to medical diagnosis and treatment technology field, in particular to histone demethylase LSD1 is as cardiac muscle
The target of plump diagnosing and treating and application.
Background technique
The histone demethylase that histone demethylase LSD1 (KDM1A) is found as the first, Ke Yite
The opposite sex carries out demethylation for the site BAT H3K9me1/2 and the site WAT H3K4me1/2, and to the H3K9me3 in the site and
H3K4me3 does not have demethylation active.
Metzger's et al. research shows that: LSD1 can by H3K9 demethylations activity, release to adrenal gland
The inhibition of plain receptor pathway.Adrenocepter is the signal of interest access for adjusting myocardial hypertrophy.H3K9me3 specific histone
Demethylase JMJD2B can equally activate the transcriptional activity of adrenocepter.First is gone in H3K9me3 specific histone
Base enzyme JMJD2C is cooperateed with down with LSD1, and the expression of adrenocepter related gene is activated.
Various evidences show that LSD1 is possible therapeutic targets in cancer.It is reported that LSD1 mistake in kinds of tumors
Expression, including neuroblastoma, the breast cancer of ER feminine gender, bladder cancer, lung cancer and colorectal carcinoma (Schulte, J.H., et
al.Cancer Res2009,69(5),2065-71；Lim,S.,et al.Carcinogenesis 2010,31(3),512-
20；and Hayami,S.,et al.Int J Cancer 2011,128(3),574-86).It has been shown that being drawn by LSD1 inhibition
The H3K4 methylation level increase risen reactivates expression (Huang, Y., the et of tumor suppressor gene in cancer model
al.Clin Cancer Res 2009,15(23),7217-28).Further it has been found that LSD1 and estrogen and androgen receptor knot
The specific demethylation for causing inhibition H3K9 to indicate is closed, to increase expression of target gene (Metzger, E., et al.Nature
2005,437(7057),436-9；and Garcia-Bassets,I.,et al.Cell 2007,128(3),505-18).Cause
This can pass through permissive H3K4 and inhibition H3K9 by demethylation caused by LSD1 depending on being integrated to the co-factor of LSD1
Indicate and promotes cancer.Therefore, in many cancer types, the inhibition of LSD1 may be to express swelling for epigenetic silencing again
Tumor suppressor and the available strategy for lowering important cancer approach.
However, influence of the histone demethylase LSD1 to cardiac muscle then has no any report.
Summary of the invention
The present invention is had found by many experiments: isoprel can be weakened by being overexpressed histone demethylase LSD1
Caused myocardial hypertrophy, and LSD1 demethylation enzymatic activity is inhibited then to will lead to myocardial hypertrophy, the overexpression was preferably table
Up to 4 times or more；Using in myocardial hypertrophy model caused by aorta arch constriction operation, LSD1 expression changes, and
The raising of the 4th lysine di-methylation level of raising and histone H 3 of the 4th lysine monomethylization level of histone H 3,
And the 9th lysine di-methylation level of raising and histone H 3 of the 9th lysine monomethylization level of histone H 3
It increases.
The present invention is achieved through the following technical solutions:
Present invention firstly provides a kind of myocardial hypertrophies to diagnose target, and the target is histone demethylase LSD1.
And a kind of myocardial hypertrophy therapeutic targets, the target are histone demethylase LSD1.
The specific histone demethylase LSD1 activity is suppressed, then being judged as will lead to myocardial hypertrophy.
Also, it is horizontal that the histone demethylase LSD1 takes part in oxidative stress correlative protein expression in myocardial hypertrophy
Regulation.
More specifically, the raising and histone H 3 of the 4th lysine monomethylization level of histone H 3 are also embodied by
The raising of the 9th lysine monomethylization level of raising and histone H 3 of the 4th lysine di-methylation level and group egg
The raising of the 9th lysine di-methylation level of white H3.
Furthermore another object of the present invention is to provide histone demethylase LSD1 in preparation as a kind of cardiac muscle fertilizer
The application of thick diagnosis target target detectable substance.
And application of the histone demethylase LSD1 in preparation as a kind of detectable substance of myocardial hypertrophy therapeutic targets.
In the application, histone demethylase LSD1 activity is suppressed, then being judged as will lead to myocardial hypertrophy.
Specifically, in the application, histone demethylase LSD1 takes part in oxidative stress correlation egg in myocardial hypertrophy
The regulation of white expression.
More specifically, the raising and histone H 3 of the 4th lysine monomethylization level of histone H 3 are also embodied by
The raising of the 9th lysine monomethylization level of raising and histone H 3 of the 4th lysine di-methylation level and group egg
The raising of the 9th lysine di-methylation level of white H3.
Compared with the prior art, the beneficial effects of the invention include:
The prior art is only using histone demethylase LSD1 as therapeutic targets possible in cancer, from mechanism of action
It is difficult to that the target applied to cardiovascular field is selected to use.
Histone demethylase LSD1 can weaken myocardial hypertrophy caused by isoprel, and LSD1 is inhibited to go
Methylase activity then will lead to myocardial hypertrophy.LSD1 demethylation enzymatic activity is to the fertilizer of cardiac muscle caused by adrenocepter access
Thickness plays certain adjustment effect.
Detailed description of the invention
Fig. 1,1 cardiac volume detection schematic diagram of embodiment, wherein (left → right: control group；Isoproterenol group
(ISO)；OG-L002 group), isoproterenol group and OG-L002 group heart size significantly increase；
Fig. 2,1 cardiac chamber wall thickness detection schematic diagram of embodiment, wherein (left → right: control group；Isoproterenol group；
OG-L002 group), toy ultrasonic experiments prompt isoproterenol group and OG-L002 group heart chamber wall thickness to increase；
Fig. 3 expresses water using the mRNA of qPCR detection myocardial hypertrophy correlation factor ANP, α-MHC, MLC-2V in embodiment 1
Flat testing result；
Fig. 4, using the egg of Western Blot detection myocardial hypertrophy correlation factor ANP, α-MHC, MLC-2V in embodiment 1
White expression testing result；
Fig. 5, in embodiment 1 using Western Blot detection histone H 3 K4me1, H3K4me2, H3K9me1 and
The horizontal testing result of histone methylated modification of H3K9me2；
2 cardiac volume detection schematic diagram of Fig. 6 embodiment, wherein (left → right: control group；Sham-operation group；The arch of aorta
Ligation operation group (3), arch of aorta ligation group heart size significantly increase；
Using the mRNA of qPCR detection myocardial hypertrophy correlation factor ANP, α-MHC, MLC-2V and LSD1 in Fig. 7 embodiment 2
Expression testing result；
In Fig. 8 embodiment 2 using Western Blot detection histone H 3 K4me1, H3K4me2, H3K9me1 and
The horizontal testing result of histone methylated modification of H3K9me2；
Fig. 9, using the variation of Western Blot method detection LSD1 expression in embodiment 3；
Figure 10,3 cardiac volume detection schematic diagram of embodiment illustrate that LSD1 overexpression can inhibit isoprel to lure
The myocardial hypertrophy led；
Figure 11, using the expression of qPCR detection myocardial hypertrophy correlation factor Anp, MLC-2v mRNA in embodiment 3.
Specific embodiment
Below with reference to embodiment and attached drawing, the present invention is described in further detail, but the embodiment invented is not limited to
This.
Embodiment 1
Histone demethylase inhibitor can induce myocardial hypertrophy experiment
SD rat (140~180g) is divided into three groups: control group, isoproterenol group (ISO), LSD1 inhibition group (OG-
L002, Selleckchem), every group 8.Isoprel 2mg/kg is injected intraperitoneally in isoproterenol group daily；LSD1 inhibits
Agent group injects OG-L00250 μ g/kg daily；The physiological saline of control group injection same volume.
Wherein, the chemical structural formula of OG-L002 is as follows:
Administration after three weeks, puts to death SD rat, draws materials to its heart.
Experimental result referring to Figures 1 and 2 is visible: heart size detection schematic diagram such as Fig. 1, wherein left → right: control
Group；Isoproterenol group (ISO)；OG-L002 group, isoproterenol group and OG-L002 group heart size significantly increase；
Heart chamber wall Thickness sensitivity schematic diagram such as Fig. 2, wherein (left → right: control group；Isoproterenol group；OG-L002
Group), toy ultrasonic experiments prompt isoproterenol group and OG-L002 group heart chamber wall thickness to increase.
Also, correlation factor is measured by qPCR and Western Blot.
Using qPCR detection myocardial hypertrophy correlation factor ANP, α-MHC, MLC-2V mRNA expression testing result such as
Shown in Fig. 3；
Using the protein expression level inspection of Western Blot detection myocardial hypertrophy correlation factor ANP, α-MHC, MLC-2V
It is as shown in Figure 4 to survey result；
From the above it is found that showing as the up-regulation of plump factor expression level and the increase of heart chamber wall thickness, meaning
Have the generation of myocardial hypertrophy.
From aforementioned testing result: histone demethylase LSD1 can weaken cardiac muscle caused by isoprel
Plumpness, and LSD1 demethylation enzymatic activity is inhibited then to will lead to myocardial hypertrophy.From myocardial hypertrophy correlation factor result as it can be seen that LSD1
Demethylation enzymatic activity plays certain adjustment effect to myocardial hypertrophy caused by adrenocepter access.
Embodiment 2
Aortic coaractation refers to the aortostenosis in arterial duct or ligamentum arteriosum region.It is common mouse and rat
The common method of myocardial hypertrophy model.It is performed the operation in this example using aorta arch constriction, constructs myocardial hypertrophy in SD rat body
Model observes the influence of histone LSD1 and H3K4 and H3K9 methylation level.
SD rat (140~180g) is divided into four groups: control group, sham-operation group (Sham), arch of aorta ligation operation group
(TAC), every group 8.Arch of aorta ligation operation group is successfully established myocardial hypertrophy model, referring to Fig. 6 and Fig. 7.
From experimental result as it can be seen that arch of aorta ligation operation successfully result in heart size it is big become larger and the plump factor
The raising of expression illustrates that this method has been successfully established myocardial hypertrophy model, referring to Fig. 6 and Fig. 7；Histone demethylase LSD1
The reduction of expression, referring to Fig. 7；The raising of the 4th lysine monomethylization level of histone H 3 and histone H 3 the 4th rely
The raising of the 9th lysine monomethylization level of raising and histone H 3 of propylhomoserin di-methylation level and histone H 3 the 9th
The raising of position lysine di-methylation level, it is shown in Figure 8.
This example demonstrated myocardial hypertrophies and histone demethylaseLSD1 expression and dysfunction and myocardial hypertrophy Between causality.
Embodiment 3
From following experiment and as a result, it has been found that: isoprel can be weakened and lure by being overexpressed histone demethylase LSD1
The myocardial hypertrophy led.
SD rat (140~180g) is divided into four groups: the unloaded group (pEF1a) of control group, virus, LSD1 are overexpressed viral group
(pEF1a-LSD1), the viral group (ISO+pEF1a-LSD1) of isoprel+LSD1 overexpression, every group 8.
2mg/kg isoprel is injected intraperitoneally in isoproterenol group daily；The physiology salt of control group injection same volume
Water.It packs LSD1 and is overexpressed slow virus, direct in-situ is injected in cardiac muscle after ultracentrifugation is concentrated, while it is different to give intraperitoneal injection
Third adrenaline (ISO), draws materials after 3 weeks.Using the protein expression level discovery of Western Blot detection LSD1, Success in Experiment
Realize the overexpression (Fig. 6) of LSD1 protein level.It was found that the heart induced by isoprel can be weakened by being overexpressed LSD1
Flesh plumpness process (Fig. 7) detects myocardial hypertrophy correlation factor ANP, MLC-2V using qPCR, and discovery ISO combines LSD1 slow virus
The mRNA expression of ANP and MLC-2V does not increase (Fig. 8) in group (ISO+pEF1a-LSD1).
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of myocardial hypertrophy diagnoses target, which is characterized in that the target is histone demethylase LSD1.
2. a kind of myocardial hypertrophy therapeutic targets, which is characterized in that the target is histone demethylase LSD1.
3. histone demethylase LSD1 is preparing the application as a kind of myocardial hypertrophy diagnosis target target detectable substance.
4. application of the histone demethylase LSD1 in preparation as a kind of detectable substance of myocardial hypertrophy therapeutic targets.
5. target according to claim 1 or 2, which is characterized in that the histone demethylase LSD1 activity by
Inhibit, being then judged as will lead to myocardial hypertrophy or have a myocardial hypertrophy onset risk.
6. target according to claim 5, which is characterized in that the histone demethylase LSD1 takes part in myocardium fertilizer
The regulation of plump factor expression level in thickness.
7. target according to claim 5, which is characterized in that be also embodied by the 4th lysine monomethyl of histone H 3
The 9th one first of lysine of raising and histone H 3 of horizontal the 4th lysine di-methylation level of raising and histone H 3
The raising of the 9th lysine di-methylation level of raising and histone H 3 of baseization level.
8. application according to claim 3 or 4, which is characterized in that the histone demethylase LSD1 activity by
Inhibit, being then judged as will lead to myocardial hypertrophy or have a myocardial hypertrophy onset risk.
9. application according to claim 8, which is characterized in that the histone demethylase LSD1 takes part in myocardium fertilizer
The regulation of plump factor expression level in thickness.
10. application according to claim 8, which is characterized in that be also embodied by the 4th lysine monomethyl of histone H 3
The 9th one first of lysine of raising and histone H 3 of horizontal the 4th lysine di-methylation level of raising and histone H 3
The raising of the 9th lysine di-methylation level of raising and histone H 3 of baseization level.
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| CN111763671A (en) * | 2020-06-28 | 2020-10-13 | 上海市东方医院（同济大学附属东方医院） | siRNA of targeted histone demethylase KDM5B and application |
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| CN102952799A (en) * | 2012-05-17 | 2013-03-06 | 中国科学院北京基因组研究所 | Applications of gene and protein coded thereby to promotion of cell cytoplasm cleavage and cell proliferation as well as research and development of drugs |
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