CN104174011B - Centrifugal force and shearing force response protein 1(RECS1) treating the function and application in myocardial hypertrophy - Google Patents
Centrifugal force and shearing force response protein 1(RECS1) treating the function and application in myocardial hypertrophy Download PDFInfo
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Abstract
The invention discloses a kind of centrifugal force and shearing force response protein 1(RECS1) treating the function and application in myocardial hypertrophy, belong to function and the application of gene.The present invention with RECS1 knock out mice and heartspecific RECS1 transgenic mice for experimental subject, the relation between the expression of RECS1 gene and myocardial hypertrophy is studied by aorta arch constriction surgical simulation myocardial hypertrophy disease model, result shows that RECS1 gene knockout significantly promotes myocardial hypertrophy, fibrosis, worsens cardiac function; RECS1 gene overexpression significantly suppress myocardial hypertrophy and fibrosis thereof, improves cardiac function, and namely have can cardioprotection function and suppress the effect of myocardial hypertrophy for RECS1 gene.Based on the effect of RECS1 gene, RECS1 can be used for preparing the medicine of cardioprotection function and/or prevention, alleviation and/or treatment myocardial hypertrophy, and the treatment for myocardial hypertrophy provides an effective new way.
Description
Technical field
The invention belongs to function and the application of gene, particularly a kind of centrifugal force and shearing force response protein 1(RECS1) treating the function and application in myocardial hypertrophy, the application specifically in preparation prevention, alleviation and/or treatment myocardial hypertrophy medicine.
Background technology
Cardiovascular system diseases is one of the number one killer in the current world, has been increased to the first place of various principal disease in the incidence rate of the current cardiovascular system diseases of China.Myocardial hypertrophy is very general in society, and myocardial hypertrophy is the overweight adaptations caused of continuous pressure or volume load, is the independent hazard factor of sudden death, myocardial infarction, congestive heart failure, can increases admission rate and mortality rate.Myocardial hypertrophy is regulated by many factors, and is a kind of dynamic process of complexity.Research show the pressure that continues and/or volume load excessive, can left ventricle aneurysm be increased, cause myocardial hypertrophy.The visible cardiac weight of its feature cardinal principle obviously increases, ventricular structure changes; Visible on cellular level, myocardial cell length and/or width increase, and muscle segment quantity increases, arrangement disorder, and collagen content increases, fibrous tissue hyperplasia, and cell arrangement disorder is loose; On molecular level, various born of the same parents' external stimulus signals such as transforming growth factor-β (TGF-β), Angiotensin II (AngII), Endothelin, catecholamine can be transduceed by activation signal, the expression of inducing embryo type gene, thus impel cell that loose character mutation occurs, finally cause cardiac myocyte hypertrophy.Left ventricular hypertrophy is the risk factor of generally acknowledged cardiovascular disease mortality rate, if untreated, it can cause contraction and Diastolic Heart failure also finally to cause heart failure.But existing research can not annotate the mechanism of myocardial hypertrophy completely.Therefore, find the specific molecular suppressing myocardial hypertrophy, for the generation development mechanism of setting forth myocardial hypertrophy further, there is great theory significance, can be clinical prevention myocardial hypertrophy and novel targets and New Policy are provided.
RECS1(responsivetocentrifugalforceandshearstressgene1) be blood shearing force response protein, belong to Bax and suppress son-1(BI-1) newcomer of family, i.e. Tmbim1(transmembraneBaxinhibitormotif-containingprotein1).BI-1 family is one group of repeatedly cross-film small molecular protein with biological functions such as anti-apoptotics, mainly comprises BI-1, Lifeguard, GAAP(Gorky and to fall ill protein) and RECS1 etc.Laminar shear stress makes the expression of RECS1 increase, and to keep the steady statue of vascular system, avoids blood vessel to be exposed to blood flow stress and various bioactive substance for a long time and the damage caused.Nojima laboratory reports the transcriptional expression of blood shear stress induction RECS1 the earliest, and clone obtains cDNA and the aminoacid sequence [1] of RECS1.People RECS1 is 1 311 amino acid whose 7 transmembrane proteins, has very high homology with Lifeguard and glutamate binding proteins.In cardiac hypertrophy, generally along with the apoptosis of inflammation and myocardial cell, the intracellular signal transduction path that NF-κ B signal path reacts mainly as mediating inflammatory.Research confirms that the activation of NF-κ B is that cardiac myocyte hypertrophy is necessary, and nearest research prompting NF-κ B signal path may play an important role [2,3] in the developing of myocardial hypertrophy; Fas gene is the short apoptogene received much concern, and during the early stage myocardial hypertrophy of the discovery such as Liu Jidong spontaneous hypertensive rat, myocardium Fas expresses and raises, and may participate in the generation [4] of later stage heart failure.The l cell of the stably express RECS1 agonistic antibody special to TNFR2 shows certain toleration to have report to show, display RECS1 may participate in the regulation and control [5] of TNF-alpha signal.RECS1 is in conjunction with TNFR1, and the nuclear transcription factor-kappa B suppressing overexpression TNFR1 to induce (NF-κ B) activation [6], thus negative regulation TNF-alpha signal.Easily suffer from aorta cystic medionecrosis when the mice of RECS1 gene knockout is old and performance has large artery trunks di, show that the growth that RECS1 may participate in modulating vascular is reinvented.Immunohistochemical analysis finds, the expression of the mouse aorta Matrix Metalloproteinase-9 (MMP-9) of RECS1 gene knockout significantly improves [7,8].Recent result of study display, RECS1 can reduce the expression of cell surface Fas, thus the apoptosis [9] that protection FasL (FasL) is induced.Therefore infer, RECS1 may play an important role in myocardial hypertrophy, the new thinking that the Therapy study of the heart disease caused for myocardial hypertrophy provides.
[list of references]
1、H.Yoshisue，K.Suzuki，A.Kawabatal,Atherosclerosis162，323(Jun,2002).
2、FreundC,Schmidt-UllrichR,BaurandA,etal.Requirementofnuclearfactor-NF-κBinangiotensinⅡandisoproterenol-inducedcardiachypertrophyinvivo.Circulation,2005,111(18):2319-2325.
3、YoungD,PopovicZB,JonesWK,etal.BlockadeofNF-kappaBusingIkappaBalphadominant-negativemiceamelioratescardiachypertrophyinmyotrophin-overexpressedtransgenicmice.JMolBiol,2008,381(3):559-568.
4, Liu Jidong, deer gram wind, Zhang Xin etc.Spontaneous hypertensive rat cardiac muscle fas gene expression and left ventricular hypertrophy Relational Data Mining.Hypertension magazine, 2003.
5, Cai Cifeng, Wu Mingjiang, Liao Zhiyong. Chinese biological chemistry and molecular biosciences journal 26,36(Jan, 2010)
6, Liao Zhiyong. Chinese biological chemistry and molecular biosciences journal 27,412(May, 2011).
7、ZhaoH,ItoA,SakaiN,MatsuzawaY,YamashitaS,NojimaH.RECS1isanegativeregulatorofmatrixmetalloproteinase-9productionandagedRECS1knockoutmicearepronetoaorticdilation.CirculationJournal.2006;70(5):615-24.
8、ZhaoH,ItoA,KimuraSH,YabutaN,SakaiN,IkawaM,OkabeM,MatsuzawaY,YamashitaS,NojimaH.RECS1deficiencyinmiceinducessusceptibilitytocysticmedialdegeneration.GenesGenetSyst.2006;81(1):41-50.
9、ShuklaS,FujitaK,XiaoQ,LiaoZ,GarfieldS,SrinivasulaSM.AshearstressresponsivegeneproductPP1201protectsagainstFas-mediatedapoptosisbyreducingFasexpressiononthecellsurface.Apoptosis.2011;16(2):162-73。
Summary of the invention
For solving defect and the deficiency of above-mentioned prior art; the object of the invention is to determine the expression of RECS1 and the mutual relation of myocardial hypertrophy; the application of a kind of RECS1 in the medicine of screening cardioprotection function and/or prevention, alleviation and/treatment myocardial hypertrophy is provided, provides one for the protection of the novelty teabag of the target gene RECS1 of cardiac function and/or prevention, alleviation and/or treatment myocardial hypertrophy.
Object of the present invention is achieved through the following technical solutions:
By test, the present invention determines that RECS1 expresses the relation between myocardial hypertrophy:
1, RECS1 gene knockout significantly promotes myocardial hypertrophy, fibrosis, worsens cardiac function
The present invention selects wild-type mice, RECS1 knock out mice is tested, and often kind of mice is divided into sham operated rats and operation group, often organizes 10 mices.Operation group gives aorta arch constriction operation, sham operated rats refuses aorta arch constriction, then by carrying out the mensuration of heart cardiac myocytes plumpness, fibrosis and cardiac function to each group of mice of sham operated rats and operation group, research RECS1 gene knockout is on the impact of the myocardial hypertrophy that aorta arch constriction is induced.Result shows that the RECS1 defect knocked out caused by RECS1 gene significantly worsens myocardial hypertrophy, fibrosis and cardiac function (Fig. 1, Fig. 2, Fig. 3, Fig. 7).
2, RECS1 gene overexpression significantly suppress myocardial hypertrophy and fibrosis thereof, improves cardiac function
The present invention selects heartspecific RECS1 transgenic mice and nontransgenic mice to test, and often kind of mice is divided into sham operated rats and operation group, often organizes 10 mices.Operation group gives aorta arch constriction operation, sham operated rats refuses aorta arch constriction, then by carrying out the mensuration of heart cardiac myocytes plumpness, fibrosis and cardiac function to each group of mice of sham operated rats and operation group, research RECS1 gene overexpression is on the impact of the myocardial hypertrophy that aorta arch constriction is induced.Result shows that process LAN RECS1 gene significantly suppresses myocardial hypertrophy and fibrosis, cardiac function protecting (Fig. 4, Fig. 5, Fig. 6, Fig. 8).
Significantly promote myocardial hypertrophy, fibrosis by the known RECS1 genetic flaw of above result, worsen cardiac function, RECS1 gene overexpression significantly suppress myocardial hypertrophy, fibrosis, cardiac function protecting.Therefore the effect that the myocardial hypertrophy relevant disease that RECS1 gene has cardiac function protecting and suppresses myocardial hypertrophy and Fibrotic effect, particularly RECS1 gene that aorta arch constriction can be suppressed to cause occurs.
The function of RECS1 in myocardial hypertrophy, is mainly reflected in the effect of the myocardial hypertrophy generation that RECS1 gene has cardiac function protecting and suppresses the effect, particularly RECS1 gene of myocardial hypertrophy that aorta arch constriction can be suppressed to cause.
For the above-mentioned functions of RECS1; the application of a kind of RECS1 is provided; application, particularly RECS1 that major embodiment is RECS1 in cardioprotection and the treatment myocardial hypertrophy application in the medicine preparing cardioprotection function and/or prevention, alleviation and/or treatment myocardial hypertrophy.
A medicine for cardioprotection function, comprises RECS1.
Prevention, alleviation and/treatment myocardial hypertrophy a medicine, comprise RECS1.
The present invention has following advantage and effect relative to prior art:
(1) the present invention finds the New function of RECS1 gene, and namely have can cardioprotection function and suppress the effect of myocardial hypertrophy for RECS1 gene.
(2) based on RECS1 in cardioprotection function with suppress in myocardial hypertrophy disease effect, it may be used for preparing the medicine of cardioprotection function and/or prevention, alleviation and/or treatment myocardial hypertrophy.
Accompanying drawing explanation
Fig. 1 is the statistics block diagram of WT and RECS1-KO mice AB model HW/BW, LW/BW and HW/TL after 4 weeks, result display RECS1 knocks out and significantly promotes HW/BW, LW/BW and HW/TL(*:p < 0.05vsWTSham group, #:p < 0.05vsWTAB group).
Fig. 2 is the rear heart tissue HE dyeing in 4 weeks of WT and RECS1-KO mice AB model and cardiomyocytes cross-sectional area statistics block diagram, result display RECS1 knocks out and significantly promotes cardiac myocyte hypertrophy (*: p < 0.05vsWTSham group, #:p < 0.05vsWTAB group).
Fig. 3 is WT and RECS1-KO mice AB model 4 weeks rear heart tissue sirius red stains figure, and result display RECS1 knocks out the fibrosis significantly promoting heart.
Fig. 4 is the statistics block diagram of NTG and TG mice AB model HW/BW, LW/BW and HW/TL after 4 weeks, result display RECS1 process LAN can suppress HW/BW, LW/BW and HW/TL(*:p < 0.05vsNTGSham group, #:p < 0.05vsNTGAB group).
Fig. 5 is the rear heart tissue HE dyeing in 4 weeks of NTG and TG mice AB model and cardiomyocytes cross-sectional area statistics block diagram, result display RECS1 process LAN can suppress cardiac myocyte hypertrophy (*: p < 0.05vsNTGSham group, #:p < 0.05vsNTGAB group).
Fig. 6 is the fibrosis that NTG and TG mice AB model 4 weeks rear heart tissue sirius red stains figure, result display RECS1 process LAN can suppress heart.
Fig. 7 is WT and RECS1-KO mice AB model 4 weeks rear ultrasound detection cardiac function result statistics block diagrams, and result display RECS1 knocks out and significantly worsens cardiac function; Wherein, LVEDD is LVED (Left Ventricular End Systolic Dimension), LVESD is left room end systolic diameter, EF is ejection fraction, FS is shortening fraction (*: p < 0.05vsWTSham group, #:p < 0.05vsWTAB group).
Fig. 8 is NTG and TG mice AB model 4 weeks rear ultrasound detection cardiac function result statistics block diagrams, the remarkable cardiac function protecting of result display RECS1 process LAN; Wherein, LVEDD is LVED (Left Ventricular End Systolic Dimension), LVESD is left room end systolic diameter, EF is ejection fraction, FS is shortening fraction (*: p < 0.05vsNTGSham group, #:p < 0.05vsNTGAB group).
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Animal for research and raising
Laboratory animal: select 8-10 age in week, body weight is at 23.5-27.5g, male, heartspecific Cre mice (α-MHC-Cre(names WT), background is C57BL/6, purchased from JacksonLaboratory, article No. 005650), RECS1 knock out mice (RECS1-KO, purchased from Japanese RIKEN company, article No.: RIKEN01772), heartspecific RECS1 transgenic mice (TG, heartspecific RECS1 transgenic mice is taught laboratory by Wuhan University angiocardiopathy institute Li Hongliang and is built) and nontransgenic mice (NTG, littermate control nontransgenic mice of the same age) be experimental subject.
The structure of heartspecific RECS1 transgenic mice:
With primer (forward primer: GTTGTCGACGCCACCATGTCCAATCCCAGTGCCCC; Downstream primer: GCCAAGCTTAGTCTCTACTTCCTACGAGC) increase mice RECS1 full-length gene (NCBI, GeneID:69660, NM_027154), the RECS1 full-length gene of amplification is connected to myocardial myosin heavy chain (α-MHC) promoter downstream, the sequence of structure is configured to fertilized embryo (C57BL/6J background) by microinjection, obtains heartspecific RECS1 transgenic mouse.(above-mentioned transgenic mice is prepared with reference to following document: JiangDS; BianZY; ZhangY; ZhangSM; LiuY, ZhangRetal.Roleofinterferonregulatoryfactor4intheregulat ionofpathologicalcardiachypertrophy.Hypertension2013; 61:1193-1202.)
Feeding environment: all experiment mices are all raised in angiocardiopathy institute of Wuhan University SPF level Experimental Animal Center.The large mouse feed of SRF level is purchased from Fukang bio tech ltd of China, Beijing.Rearing conditions: room temperature is between 22-24 DEG C, and humidity is between 40-70%, and it is 12h that light and shade replaces lighting hours, freely drinks water and ingests.
Embodiment 1 myocardial hypertrophy (AB) model obtains
1. laboratory animal grouping: male background C57BL/6 wild-type mice (WT), RECS1 knock out mice (RECS1-KO) and heartspecific RECS1 transgenic mice (TG) and nontransgenic mice (NTG), sets up myocardial hypertrophy model by coarctation of aorta art.Be divided into 8 groups at random, be grouped as follows: C57BL/6 background wild-type mice sham operated rats (WTSham) and AB art group (WTAB), RECS1 knock out mice sham operated rats (RECS1-KOSham) and AB art group (RECS1-KOAB), nontransgenic mice sham operated rats (NTGSham) and AB art group (NTGAB), heartspecific RECS1 transgenic mice sham operated rats (TGSham) and AB art group (TGAB).
2. myocardial hypertrophy model adopts aorta arch constriction operation, model manipulation flow process:
2.1 Preoperative Method
(1) anaesthetize: first to mouse weights, calculate required anaesthetic (3% pentobarbital sodium) amount according to 90mg/kg body weight, by lumbar injection, and record some inject time.Folder tail, folder toe without significant reaction and mice in good condition be anesthesia Success criteria (after general injection, about 10min is without significant reaction, and respond with the little mousetrap toe of about 50min after anaesthetizing, after anesthesia, about 30min is best operating time).
(2) art district prepares: by the skin unhairing of left for mice chest, left side chest and left fore oxter.Shave Mao Houyong wet gauze wiping art district and remove Mus hair, be advisable not affect surgical field of view.
(3) tracheal intubation: upper for mice front tooth is fixed on V shaped slab inclined-plane with rubber band, and rapidly tracheal intubation is accurately inserted tracheal strips through glottis, right arm reclining is placed in (heating cushion need shift to an earlier date preheating) on heating cushion subsequently, then tracheal intubation is connected with respirator, fixing mice.If the thorax of mice rises and falls consistent with respirator frequency, tracheal intubation success is described.
2.2 aortic arch descending branch ligations
Get right arm reclining, mice left fore is placed in above right fore, and is fixed by two forelimbs with medical adhesive tape.Being encased inside cotton swab below right chest, raising thorax, is 75% ethanol to the sterilization of operation area skin by iodine tincture and volume fraction successively.Left hand is held ophthalmic tweezers and has been pinched by left skin of chest, the right hand is held eye scissors and is cut off skin and be about 1cm, separating muscle and soft tissue successively, in 2-3 rib horizontal opening thoracic cavity, slightly push left lung aside with cotton swab, free aortic arch descending branch, by 7-0 sutures through blood vessel, and above blood vessel parallel placement one section of 26G(25.0-27.5g mice) or 27G(23.5-25.0g) syringe needle, by blood vessel and syringe needle, ligation is good together, then extracts the Vasoconstriction that syringe needle can reach respective degrees out.Sew up successively after ligation, close thoracic cavity, extract 1cc gas out to recover negative pressure in thoracic cavity with syringe from sealing insertion thoracic cavity, rapid skin suture otch after extracting syringe.Sham operated rats (Sham) is a threading not ligation after the descending aorta that dissociates, the same myocardial hypertrophy of all the other steps (AB) model group.
2.3 postoperative care
After aortic arch descending branch ligation, treat that autonomous respiration appears in mice, kickback appears in folder toe, extract tracheal intubation, and mice is put into the rearging cage of bedding and padding, feedstuff and drinking water autoclaving being housed and crossing, continue breeding observing in receptacle.RECS1 knock out mice and postoperative 4 weeks of wild-type mice, nontransgenic mice and the postoperative detection carrying out indices for 4 weeks respectively of heartspecific RECS1 transgenic mice.
Embodiment 2 mouse cardiac muscle plumpness (AB) model myocardial hypertrophy and fibrosis detect
1. draw materials
(1) previous work: the urine cup preparing volume fraction 10% formaldehyde that 20mL is housed in advance, and post label (mouse number, group, type of surgery and draw materials the date).The culture dish filling mass fraction 10%KCl solution is placed in the place that draws materials.Open analytical balance, return to zero for subsequent use.Weigh again and put to death mice.
(2) draw materials: the vessel pedicle below auricle clamped by the curved tweezer of ophthalmology, cuts heart, be placed in rapidly mass fraction 10%KCl solution.Until cardiac arrest after relaxing period, be placed on sterile gauze, extrude heart intracavity liquid gently, after dipping in dry surface liquid, weigh and record, heart is put into corresponding urine cup, detect for pathology after fixing 48h.
(3) measurement of correlation and calculating: take out mice lungs, after pruning, filter paper blots, and weighs and record.Cut off mouse hind leg tibia place skin, measure and record tibia length.Calculate the heart and weigh the ratio (HW/BW) with body weight, lung weighs with the ratio (LW/BW) of body weight and the heart is heavy and the ratio (HW/TL) of tibia length.
2. pathology detect
2.1 prepare paraffin specimen section
Main operation sequence comprises pruning heart → embedding frame process → running water → dehydration → transparent → waxdip → embedding → section → stand sheet → dry or for subsequent use after toasting.
2.2 hematoxylin-eosins (HE) dye
Key step is: 55 DEG C of baking 30min → dimethylbenzene 5min, 3 times → 100% ethanol 1min → 95% ethanol 1min → 70% ethanol 1min → distilled water 1min → haematoxylin solution (Zhuhai shellfish rope, BA-4021) 5min → washing 1min → 1% hydrochloride alcohol (getting 3mL concentrated hydrochloric acid fully to mix homogeneously with 297mL70% ethanol) 1-3s → washing 1min → Scott liquid (sodium bicarbonate 0.35g, Magnesium sulfate heptahydrate 2g, both are dissolved in 100mL distilled water) 1min → washing 1min → Yihong solution (Zhuhai shellfish rope, BA-4024) 3-5min → distilled water washes away loose colour → 70% ethanol 1s → 95% ethanol 1s → 100% ethanol 30s, 3 times → dimethylbenzene 2min, 3 times → take advantage of in the not dry mounting → fume hood immediately of dimethylbenzene and dry up, microscope is taken pictures.
HE dyeing picture statistics: every pictures selects more than 3 clear border, and core is roughly positioned at the cell of central authorities, with Image-ProPlus6.0 software circle cell area.
2.3 Picro-Sirius reds (PSR) dye
Key step is: 55 DEG C of baking 30min → dimethylbenzene 2min, 3 times → 100% ethanol 1min → 95% ethanol 1min → 70% ethanol 1min → running water 10min → distilled water 1min → mass fraction 0.2% phosphomolybdic acid 2min → 0.1% sirius red picric acid solution drips in tissue, dye in wet box 90min → removal residual liquid → 0.01N hydrochloric acid 4s → 70% ethanol 1 time → 90% ethanol 1 time → 100% ethanol 30s, 3 times → dimethylbenzene 2min, 3 times → take advantage of dimethylbenzene not dry coverslip immediately mounting, microscope is taken pictures.
Cardiac muscular tissue is made up of myocardial cell and stroma, and heart is a whole end differentiation organ, and myocardial cell loses multiplication capacity, the myocardial cell reaction that various physiology or pathological stimuli cause, and can only be that the volume of individual cells increases and can not quantitatively breed.Therefore, in the pathophysiological process of myocardial hypertrophy, main manifestations is that myocardial cell volume increases, muscle segment increasing number, cell arrangement is disorderly, and cardiac mesenchymal changes the propagation and the conversion that comprise Cardiac Fibroblasts, collagen fiber density increases, and collagen secretion increases, collagen proportional balancing method imbalance etc.
Phenotypic results after WT and RECS1-KO mice AB model is shown in Fig. 1, Fig. 2, Fig. 3.Sham(sham-operation) the equal not statistically significant of the difference between HW/BW, LW/BW and HW/TL of WT mice and RECS1-KO mice in group; WT mice AB HW/BW, LW/BW, HW/TL of postoperative 4 weeks are higher than its Sham group; Postoperative 4 weeks of AB, HW/BW, LW/BW and HW/TL all comparatively WT mice rising (Fig. 1) of RECS1-KO mice.HE stained can be observed: Sham group heart no significant difference, and AB group all increases compared with the heart of Sham group, and the heart of RECS1-KO mice is obviously greater than WT group mice; Sham group myocardium myo fibril cell arrangement is neat, fine and close, and form is complete, karyon and nucleolar structure clear; AB group myofilament arrangement disorder, loose, myocardial cell volume obviously increases, form irregularity, karyon engrain, increase, deformity, and kernel is fuzzy, and RECS1-KO group is then obvious than WT group cellular mast, and difference has statistical significance (Fig. 2).After PSR dyeing, find the comparatively Sham group increase of AB group myocardium of ventricle interstitial collagen content, around arteries, collagen increase is more obvious, and collagen increases thick, and arrangement disorder becomes network-like; AB postoperative RECS1-KO mouse collagen content and perivascular collagen content are greater than WT group mice (Fig. 3).These results suggest that, after AB model, obvious myocardial hypertrophy occurs mice, the myocardial hypertrophy degree of RECS1-KO mice is greater than WT mice.
Fig. 4, Fig. 5, Fig. 6 are the phenotypic results after NTG and RECS1-TG mice AB model.Same NTG mice AB HW/BW, LW/BW and HW/TL of postoperative 4 weeks are higher than its Sham group; The degree that HW/BW, LW/BW and HW/TL of AB postoperative 4 weeks TG mices increase is significantly less than NTG mice (Fig. 4).Cardiac phenotype, AB group all increases compared with the heart of Sham group, and the degree that the postoperative TG mouse heart of AB increases is much smaller than NTG mice.HE stained can be observed: TG mice AB postoperative myocardial cell cross section is long-pending is greater than Sham group, is significantly less than NTG mice AB group (Fig. 5).PSR dyeing is visible, and TG mice AB postoperative myocardial interstitial collagen content and perivascular collagen content are all less than NTG mice AB group (Fig. 6).These results suggest that, after AB model, obvious myocardial hypertrophy occurs mice, the myocardial hypertrophy degree of RECS1-TG mice is less than NTG mice.
Embodiment 3 myocardial hypertrophy (AB) model mice ultrasound detection cardiac function
1 early-stage preparations
(1) anesthetic machine prepares: first connect the intake interface on oxygen cylinder and anesthetic machine, then turn on dosing mouth seal cover on anesthetic machine, tighten seal cover after adding rapidly isoflurane to safe scale.Turn on total valve on oxygen cylinder, the knob of adjustment flow control valve, outlet pressure maintains 0.2-0.3mPa.
(2) mice to be measured prepares: after mice to be detected is anaesthetized rapidly with isoflurane, hair is shaved in left anterior pectorial region, the mouse head handled well is stretched into anesthetis conduit pullover in, maintain the stable narcotism of mice with 1.5-2.0% isoflurane.
2 cardiac function detect
Mice gets left lateral position or dorsal position, and is shaving hair-fields uniform application ultrasonic coupling agent (Tianjin Cheng Xin company).Adopt high-frequency ultrasound in diagnosis instrument, frequency is 15MHz, selection standard papillary muscles of left ventricle short axis view, measures LVED (Left Ventricular End Systolic Dimension) (LVEDD), left room end systolic diameter (LVESD), ejection fraction (EF) and shortening fraction (FS).
The present embodiment uses M type echocardiography to evaluate myocardial hypertrophy and cardiac function.Fig. 7 is cardiac function testing result figure after WT and RECS1-KO mice AB model.Compared with WTSham group, WT mice AB shows decreased cardiac function and myocardial hypertrophy in postoperative 4 weeks, and main manifestations is index LVEDD, the LVESD increase all in various degree of myocardial hypertrophy, reflects the index EF of cardiac function, FS then declines.Postoperative 4 weeks of AB, the degree that the degree of the index increase of RECS1-KO mouse cardiac muscle plumpness and the index of reflection cardiac function decline is more obvious than WT mice.Illustrate that the cardiac function of RECS1-KO mice significantly worsens, myocardial hypertrophy degree is more serious, these results are all consistent with the more significant result of RECS1-KO mouse cardiac muscle plumpness.
Fig. 8 is the ultrasonic testing results after NTG and RECS1-TG mice AB model.Compared with NTGSham group, NTG mice AB shows decreased cardiac function and myocardial hypertrophy in postoperative 4 weeks.Main manifestations is that index LVEDD, the LVESD of myocardial hypertrophy increases, and reflects the index EF of cardiac function, FS then declines.Postoperative 4 weeks of AB, compared with NTG mice, the degree that the degree of the index increase of TG mouse cardiac muscle plumpness and the index of reflection cardiac function decline then is less than NTG group.These results are consistent with the plump repressed result of TG mouse cardiac muscle.
From above result, in the myocardial hypertrophy disease model that aorta arch constriction causes, RECS1 genetic flaw significantly promotes myocardial hypertrophy, fibrosis, and worsen cardiac function, RECS1 gene overexpression significantly suppress myocardial hypertrophy, fibrosis, cardiac function protecting.Therefore the effect that the myocardial hypertrophy relevant disease that RECS1 gene has cardiac function protecting and suppresses myocardial hypertrophy and Fibrotic effect, particularly RECS1 gene that aorta arch constriction can be suppressed to cause occurs.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
SEQUENCELISTING
<110> Wuhan University
<120> centrifugal force and shearing force response protein 1(RECS1) treating the function and application in myocardial hypertrophy
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gttgtcgacgccaccatgtccaatcccagtgcccc35
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Claims (1)
1.RECS1 in preparation prevention, alleviate and/or treat the application in the medicine of myocardial hypertrophy.
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