CN101200721A - Human myocardium protecting gene and uses thereof - Google Patents
Human myocardium protecting gene and uses thereof Download PDFInfo
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- CN101200721A CN101200721A CNA2007101545049A CN200710154504A CN101200721A CN 101200721 A CN101200721 A CN 101200721A CN A2007101545049 A CNA2007101545049 A CN A2007101545049A CN 200710154504 A CN200710154504 A CN 200710154504A CN 101200721 A CN101200721 A CN 101200721A
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Abstract
The present invention belongs to the biotechnological field and relates to a human myocardial protection gene heat shock transcription factor (HSF1) and a sieving method and a purpose thereof. The present invention adopts the method of ''death trap'' that the gene which resists myocardial cell death is sieved from human cardiac gene, and the human myocardial protection gene heat shock transcription factor 1 is cloned from the obtained gene. The result of transfection cell and animal experiment shows that the obtained human myocardial protection gene has the function of resisting cell death and also has the function of resisting ischemia, protecting myocardial cell and preventing and remedying the heart failure occurrence and development inside the heart of a living organism. The present invention can prepare for the medicine for remedying the ischemic heart disease and preventing the cardiac insufficiency and provides a novel target gene for the further function research and the gene engineering medicine development, which has important meaning for the early prevention and treatment of the heart failure and the research and the development of the related medicines and measures.
Description
Technical field
The invention belongs to biological technical field, relate to a kind of human myocardium protecting gene, specifically, relate to the human myocardium protecting gene heat shock transcription factor (HSF1) and screening method and purposes.
Background technology
Heart failure is a complex set of clinical syndrome, is most organic heart disease people's the serious stage, and 5 annual survival rates and malignant tumour are similar.The heart patient is in case appearance is in heart failure, and its 1 annual death rate is that 43%, 5 annual death rate reaches 75%, the serious harm human health.Epidemiologic data shows present global heart failure number of patients up to 2,250 ten thousand, and annual newly-increased case 2,000,000.The increase of quick aging of population and various Hazard Factor becomes ischemic heart disease to cause the modal cause of disease of heart failure, improving in developed country's myocardial infarction survival rate is the major cause that increases in heart failure, also is a major issue from infection, tuberculosis to cardiopathic transformation at developing country's epidemiology.Consistent with global fashion trend, ischemic heart disease is that China causes the modal cause of disease of heart failure, especially China's 1.3 hundred million hypertension populations of having an appointment, and still be in the present situation of low awareness, low treatment rate, low compliance rate, reaching now in the quite a while from now in China's ischemic heart disease all will be to cause major cause in heart failure, and in rising trend, be the significant problem that China's public health faces, caused white elephant to national economy.
Along with progressively illustrating and the research of ebm on a large scale heart failure is pathogenetic, the treatment pattern of heart failure is also being brought in constant renewal in and is being developed.From 20th century 50 to the eighties to correct abnormal hemodynamics, improve the long-term repair strategy of symptom after the nineties, to improve prognosis.Yet at present the therapeutic modality of heart failure all is that recovery extent is limited at the palliative treatment of impaired or necrotic myocardium.The myocardial cell is commonly considered as cell in latter stage at end, and function myocardial cell's forfeiture is the immediate cause that causes that myocardial contraction is low, cause heart failure.And anoxic to be multiple paathogenic factor cause cell injury, dead common link; cell survival and dead final result under the damage hormesis depend on running balance between its endogenous protection mechanism and the dead signal; how regulating the balance that it protects factor and dead signal extremely in early days in cell injury, exciting protective mechanism is the key issue of defencive function cardiac muscular tissue, prevention heart failure.
Development along with genetics and information biology, change the hope that gene function was once once becoming the treatment heart failure by genetic modification, yet mainly lay particular emphasis on the function of individual gene at present about the research of gene, and the function of organ-tissue to be several genes coordinate the mutually common result who regulates, and heart failure is a kind of clinical syndrome that multiple factor fellowship causes, and is that the therapeutic modality of target spot can not be obtained the ideal effect with the individual gene.Prior art is found out difference expression gene with the method for gene chip, again these genes (often hundreds and thousands of) is carried out the evaluation of function assessment, and the sensation of looking for a needle in a haystack is often arranged.Though can obtain the sequence information of a large amount of related genes, wherein to illustrating also few that function plays a crucial role.Vito P has reported the method for screening protective gene from induce dead culturing cell in 1996, claim the method for dead trap (Death Trap).Shang Weijian has the research that dead trapped gene method for screening is applied to heart disease.
Summary of the invention
The purpose of this invention is to provide a kind of human myocardium protecting gene, be specifically related to the gene that cell injury has protection cardiac muscle opposing anoxia-induced apoptosis extremely in early days.More specifically to the human myocardium protecting gene heat shock transcription factor (HSF1).
Further purpose of the present invention provides screening method of said gene and uses thereof.
The present invention adopts dead trap " method of (Death Trap), carry out the functional gene screening, from the human heart gene pool, filter out gene with opposing cardiomyocyte cell death, therefrom, clone the heat shock transcription factor 1 (HSF1) with sequence 1 structure.
HSF1 of the present invention confirms to have the effect of anti-cell death through cell experiment; Have opposing ischemic protection myocardial cell and the control effect that development takes place in heart failure through experimentation on animals result proof.
Purpose of the present invention is achieved through the following technical solutions,
1. adopt the gene of death trap functional gene sieve method screening protection cardiac muscle opposing anoxia-induced apoptosis and clone its cDNA;
2. further verify the gene that has myocardium protecting action among clone's the cDNA by cell and experimentation on animals;
3. illustrating substantially on the basis that screening-gene connects each other and act on, seek optimized interaction pattern, and can reach best myocardial preservation effect by cell and experimentation on animals checking;
4. according to the gene order prediction product form with myocardial preservation function of screening, can produce the gene transformation intestinal bacteria of secretory protein, and carry out cytokine activity screening, evaluation;
Relatively behind patient's myocardial ischemia serum and the relevant protection of heart expression of gene change, screening has the early prediction index that judging prognosis is worth, and carries out clinical verification.
The present invention has carried out cell experiment, with above-mentioned HSF1 gene transfecting cell, the result show 60% above transfection the cell of described gene can resist the death that anoxic causes, confirm that described HSF1 has the effect of anti-cell death.
The present invention has carried out experimentation on animals, at first, made heart ischemia/reperfusion injury model with the transgenic mice of heart HSF1 gene overexpression, the result shows, behind heart ischemia/reperfusion injury, the area of HSF1 transgenic mice myocardial necrosis has reduced more than 30% than non-transgenic mouse, and the quantity of apoptosis of cardiac muscle has then reduced more than 40%.Simultaneously, the present invention has confirmed that HSF1 comes heart is protected by heat shock protein(HSP) HSP27, HSP70 and HSP90 rather than HSP110.These provide protections also are embodied on the electrocardiogram(ECG of transgenic mice simultaneously--the faster recovery that ST-T changes behind the ischemia/reperfusion injury; In addition, the present invention has made pressure excess load model in heart failure with the transgenic mice of heart HSF1 gene overexpression and the mouse of heart HSF1 gene knockout.The result shows that the former has delayed in heart failure developing with the control group ratio, and shows simultaneously and can promote the newborn microvascular formation of heart, on the contrary the latter.Zooperal result has proved that the HSF1 gene also has opposing ischemic protection myocardial cell and the control effect that development takes place in heart failure in the heart of live body.
The present invention is applied to heart with the method for this direct function genescreen of dead trap, has more purpose and accuracy.Can carry out recombinant targetedly to the gene that screens, help searching out best gene therapy method more.
Use COS7 cell strain (available from U.S. ATCC company) to carry out genescreen in the present invention's experiment; The human heart gene pool is available from U.S. Life Technologies company; Adopt HSF1 transgenic mouse (Japanese mountain pass university use Medical Engineering Section) to carry out experimentation on animals.
The present invention is with human heart gene pool transfection culturing cell and use hydrogen peroxide to carry out death and induce, and has cloned the heat shock transcription factor (HSF1) in the gene that extracts from the cell strain of survival.Studies show that further HSF1 can not only anti-cell death; in the heart of live body, also has provide protection; but also when finding that HSF1 has the protein kinase A kt1 of cytoprotection by activation; suppressed to cause the activity of apoptotic kinases JNK and protein caspase3; thereby reduced cardiac cellular apoptosis, played the effect of myocardial preservation.
The present invention filters out genes involved from the heart tissue that is in different dead stages of cell or different severity of heart failure, and manual manufacture goes out the cDNA of these genes, these cDNA are imported in culturing cell or the animal hearts, observe connecting each other and acting on of they.Can provide new target gene for further functional study and genetically engineered drug exploitation.By " dead trap " functional gene method for screening; filter out in myocardial damage and have the new gene that reverses cardiac muscle death, protection cardiac muscle extremely in early days; and illustrate its interaction pattern, all significant to early prevention, treatment and the further relevant medicine of research and development and the means of heart failure.
The present invention has great importance to medicine and the means of seeking treatment ischemic heart disease and prevention cardiac insufficiency.
Description of drawings
Fig. 1 is technological line figure of the present invention.
Fig. 2 is pressure excess load model left ventricular ejection fraction measurement numerical value figure.
Fig. 3, the 4th, pressure excess load model new vessel number is measured numerical value figure.
Fig. 5 is getting in touch of existing between ASK1 and the HSF1.
Fig. 6 is the provide protection of HSF1 pair cell.
Embodiment
Embodiment 1
One, resists the gene of anoxia-induced apoptosis with death trap method screening protection cardiac muscle
With the rat heart inoblast is research object, by electroporation transfection human heart gene pool (pCMVSPORT heart cell expression cDNA library).Giving the lethality anoxic to transfectional cell after 48 hours stimulates inducing cell death, and the cell clone of survival may include the gene of protection cardiac muscle opposing anoxia-induced apoptosis.From the cell clone of survival, extract behind the subgene storehouse transfection cardiac fibroblast again, repeated experiments program 4 times.Screening changes the most tangible several genes from the cell clone of last survival, clones its cDNA.
Two, whether the cDNA of checking screening has myocardium protecting action and optimizes its interaction pattern
1. cytology level
With clone's cDNA transfection myocardial cell respectively, after giving the lethality anoxic and stimulating, observation of cell survival and death condition, which of clear and definite death trap method screening planted gene and has the protection myocardial cell and resist the effect that anoxic stimulates.
The present invention will have several genes of protection cell resistance anoxia-induced apoptosis with various combination mode cotransfection myocardial cell; after giving the stimulation of lethality anoxic; more different rotaring transfecting mode pair cell survivals and dead influence are optimized heterogeneic mutual integrated mode at cell levels.
967 ser autophosphorylation under physiological status of ASK1, test-results shows: when temperature raise, dephosphorylation took place in p967, and this moment, ASK1 activated (easily causing apoptosis).The result shows, will cultivate neonatal rat myocardial cell place 42 ℃ 2 hours, this moment, the activity of HSF1 was the highest, when being higher than 37 ℃, so more obvious when 42 ℃ of ASK1 express declines than 37 ℃, and always the expression of ASK1 does not have obvious variation.Above presentation of results, HSF1 activate and can suppress the ASK1 expression, and then apoptosis is reduced, the protection cardiac muscle.
Cultivate neonatal rat myocyte, 0.1M the hydrogen peroxide-induced apoptosis selects for use ROS as index, DCFH-DA mark ROS, streaming detects ROS, cell transfecting HSF1, result show that apoptosis of cardiac muscle obviously increases behind the adding H2O2, cell behind the transfection HSF1 is compared with transfectional cell not for H2O2 inductive apoptosis, the ROS level can reduce more than 20%, and for not adding the hydrogen peroxide-induced apoptotic cells, transfection HSF1 might not reduce intracellular ROS level.
Above-mentioned cell cultures result shows: HSF1 can suppress ASK1 to express, and suppresses the ROS level, the protection cardiac muscle.
2. animal level
Duplicate the rat acute myocardial infarction model; in coronary ligation at once, 30min behind the acute ischemia; 3h; 6h; the cDNA that 12h is independent respectively at the local asphyxia cardiac muscle or cotransfection is cloned; estimate heart function respectively at postoperative capable cardiac ultrasonic inspection in 1 month, 3 months, 6 months, the capable pathological examination of the muscular tissue of coring is observed morphological change, and the combination of estimating any gene or several genes in the animal level has the effect that protection cardiac muscle opposing acute anoxia stimulates.
Duplicate coronary artery constriction chronic myocardial ischemia model; the cDNA independent in the part or cotransfection is cloned; estimate heart function respectively at postoperative capable cardiac ultrasonic inspection in 1 month, 3 months, 6 months; the capable pathological examination of the muscular tissue of coring is observed morphological change, and the combination of estimating described gene or several genes in the animal level has the effect that protection cardiac muscle opposing chronic hypoxia stimulates.
Duplicate mouse mechanical pressure load inductive model in heart failure, the cDNA independent in the part or cotransfection is cloned, estimate heart function respectively at 1 week of postoperative, 2 weeks and the row cardiac ultrasonic inspection of 4 weeks, the capable pathological examination of the muscular tissue of coring is observed morphological change, and the combination of estimating described gene or several genes in the animal level has the control effect that development takes place in heart failure.
The result shows:
1. after the pressure excess load modelling success, wild mouse (NO) group left ventricular ejection mark (LVEF) is beginning decline the 3rd week, and the 4th week descended obviously, heart failure occurred; With the NO group relatively, knock out mice (KO) LVEF just descends since first week and reduces up to the 4th week, heart failure occurs, and gene transfection mouse (TG) group does not also descend up to the 4th all LVEF, occurs in heart failure.Its concrete measurement numerical value is seen Fig. 2.
2. after the pressure excess load modelling success, detect the new vessel number with immunohistochemical methods, can be observed at the 4th weekend, wild mouse (NO) group, the mouse of gene knockout (KO) group, number descends, but the mouse of gene transfection (TG) group increases.Measurement numerical value that it is concrete and chart are seen chart 3,4.
Above-mentioned experimentation on animals tentatively shows: HSF1 can promote new vessel to generate, and improves heart function.
Three, predict the product form according to the gene order with myocardial preservation function of screening; the gene transformation intestinal bacteria of secretory protein will wherein be produced; and carry out cytokine activity screening, evaluation, for further exploitation somatomedin and protein drug provide the target gene of source innovation.
Four, relatively behind patient's myocardial ischemia serum and the relevant protection of heart expression of gene change, screening has the early prediction index that judging prognosis is worth
1. collect 6h after healthy volunteer and the patients of acute myocardial infarction infarct, 12h, the serum specimen of 24h extracts genome cDNA.Protection gene order according to above-mentioned experiment screening designs and synthesizes probe respectively, and with serum specimen cDNA hybridization, the different time sections screening-gene changes in the expression of serum after observation healthy volunteer and the acute anoxia.
2. collect unexpected death and, extract genome cDNA because of the capable heart transplantation patient's of ischemic heart disease endstage cardiac insufficiency myocardium sample.With synthesising probing needle and the cDNA of cardiac muscular tissue hybridization, observe screening-gene and change in the expression of chronic hypoxia cardiac muscular tissue.Change by comparative analysis serum and the relevant protection of cardiac muscular tissue's sample expression of gene, screening may be as the extremely early stage index of judging the ischemic heart disease prognosis, and the step of going forward side by side is carried out the Clinical Follow-up checking.
SEQUENCE?LISTING
＜110〉Zhongshan Hospital Attached to Fudan Univ
＜120〉human myocardium protecting gene and uses thereof
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Claims (6)
1. the human myocardium protecting gene heat shock transcription factor is characterized in that having the structure of sequence 1.
2. the described human myocardium protecting gene heat shock transcription of claim 1 factor preparation method; it is characterized in that adopting the method for " dead trap "; carry out the functional gene screening; screening has the gene of opposing cardiomyocyte cell death from the human heart gene pool; from the gene with opposing cardiomyocyte cell death that is obtained, the clone has the heat shock transcription factor 1 of sequence 1 structure.
3. the human myocardium protecting gene heat shock transcription factor of claim 1 is preparing the purposes for the treatment of in the heart failure drugs.
4. the purposes of the human myocardium protecting gene heat shock transcription factor of claim 1 in preparation prophylaxis of heart failure medicine
5. the human myocardium protecting gene heat shock transcription factor of claim 1 is in the myocardium purposes of resisting in the anoxia-induced apoptosis medicine of preparation protection.
6. the human myocardium protecting gene heat shock transcription factor of claim 1 is resisted purposes in the ischemic medicine preparation protection myocardial cell.
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| CN 200710154504 CN101200721B (en) | 2006-09-18 | 2007-09-18 | Human myocardium protecting gene and uses thereof |
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| CN200610116174 | 2006-09-18 | ||
| CN200610116174.X | 2006-09-18 | ||
| CN 200710154504 CN101200721B (en) | 2006-09-18 | 2007-09-18 | Human myocardium protecting gene and uses thereof |
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| CN101200721B CN101200721B (en) | 2011-06-08 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105125572A (en) * | 2009-12-18 | 2015-12-09 | 箭头研究公司 | Organic compositions to treat hsf1-related diseases |
| CN111197059A (en) * | 2020-01-10 | 2020-05-26 | 复旦大学附属中山医院 | Adenovirus vector and application thereof in preparing medicine for preventing and treating heart failure |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3961019B2 (en) * | 1995-02-28 | 2007-08-15 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Gene transfer mediated angiogenesis therapy |
| WO2001026694A1 (en) * | 1999-10-08 | 2001-04-19 | Medgene Bioscience, Inc. | Gene therapy for cardiomyopathy |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105125572A (en) * | 2009-12-18 | 2015-12-09 | 箭头研究公司 | Organic compositions to treat hsf1-related diseases |
| CN111197059A (en) * | 2020-01-10 | 2020-05-26 | 复旦大学附属中山医院 | Adenovirus vector and application thereof in preparing medicine for preventing and treating heart failure |
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| CN101200721B (en) | 2011-06-08 |
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