CN108159399A - A kind of applications of blood coagulating protein enzyme aPC in diabetic cardiomyopathy drug is prevented - Google Patents
A kind of applications of blood coagulating protein enzyme aPC in diabetic cardiomyopathy drug is prevented Download PDFInfo
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Abstract
The invention discloses the applications in a kind of blood coagulating protein enzyme aPC diabetic cardiomyopathy drugs caused by prevention streptozotocin induces；Blood coagulating protein enzyme aPC can stablize the expression of YB1, so as to mitigate cardiac myocyte hypertrophy and fibrosis by the ubiquitination of cardiac muscle cell YB1 under the high sugared state of inhibition in the present invention.Therapeutic studies are the results show that blood coagulating protein enzyme aPC has the effect of significantly mitigating cardiac myocyte hypertrophy and fibrosis, improvement myocardium shrinkage function, raising ejection fraction.
Description
Technical field
The invention belongs to technical field of new application of medicine, specifically, being related to a kind of blood coagulating protein enzyme aPC in prevention glycosuria
Application in sick cardiac muscle medicine.
Background technology
Diabetic cardiomyopathy (diabetic cardiomyopathy, DCM) is a kind of cardiac structure as caused by diabetes
And dysfunction, independently of hypertension, coronary atherosclerotic heart disease, valvulopathy and other are known cardiopathic
Disease.Progressive Hypertensive disease and diastole and/or contractile dysfunction are usually expressed as, pathological characteristic is cardiac muscle cell's fertilizer
Greatly, apoptosis, microangiopathies and interstitial fibrosis etc..Rubler in 1972 etc. is put forward for the first time diabetic cardiomyopathy this concept,
Over nearly more than 40 year, domestic and foreign scholars have carried out a large amount of basis and clinical research in this area, it was demonstrated that DCM is diabetic
The main reason for high Incidence of Heart Failure and high mortality.DCM affirmed at present as the complication of diabetes independence, and
Gradually paid attention to by clinician and epidemic disease expert.The pathogenesis of DCM is extremely complex, is related to metabolic disorder, oxidation is answered
Sharp, inflammatory reaction, autonomic nervous dysfunction, insulin resistance etc., specific mechanism is still indefinite.It there is no and control at present
Treat the drug of diabetic cardiomyopathy.
PROTEIN C (PC) system is to maintain the important natural anti-freezing system of body homeostasis, and the performance of activity is main
Based on activated protein C (aPC).Under the effect of soluble thrombomodulin (Thrombin-TM) compound, enzyme occurs for PC
Solution reaction, exposure serine hydrolase activity center, becomes aPC.APC and endothelial cell protein C receptors (EPCR) are combined and are led to
Cross hydrolysis g protein coupled receptor-proteinase activated receptors (protease activated receptor, PAR) extracellular peptide chain
So as to exposure, its own ligand is combined extracellular signal with autoreceptor by the G-protein of coupling and other signaling molecules
It is transferred to intracellular and plays biological function.A large amount of animals and clinical research confirmation in recent years, aPC and its activation exception and purulence
The occurrence and development of a variety of diseases such as toxication, disseminated intravascular coagulation (DIC), Deep vain thrombosis, purpura fulminans are close
It is related.APC not only regulates and controls blood coagulation and the Balance of Fibrinolysis System of body, but also by anti-inflammatory, anti-apoptotic mechanism, and protection endothelial cell changes
Kind microcirculation slows down organ dysfunction, participates in the pathophysiological process of a variety of diseases.Much research shows that aPC can pass through
Anti-apoptotic, anti-inflammatory, adjusting energetic supersession and autophagy body function shield to heart ischemia reperfusion damage.It is in addition, outer
Property aPC in source has diabetic nephropathy very strong protective effect.
Cold shock protein YB-1 (Ybox binding protein-1) is highly conserved nucleic acid binding protein, cold shock
A member of domain (Cold Shock Domain) superfamily protein, it is present in mammalian cell matter and nucleus, has more
Kind cell efficiency participates in the cell of genetic transcription, translational control, DNA damage induction reparation, anticarcinogen drug resistance and environmental stimulus
Reaction etc..YB-1 is by being rich in the N- ends of alanine/proline, the cold shock domain that intermediate mediated dna and RNA are combined and a band
By by positive or negative charge amino acid, alternately the C- ends zipper that forms forms, its effect in gene expression is very multiple
Miscellaneous, it can be combined with DNA directly adjusts gene expression or changes DNA conformations so as to influence the knot of other transcription factors indirectly
It closes.In addition, YB-1 can also with RNA with reference to adjust gene translation and with other protein bindings and influence its function.YB-1
It can induce or the expression of suppressor, including cell factor and chemotactic factor (CF) and its receptor, these funtion parts are existed by YB-1
The indexing from endochylema to core is adjusted into the cell.It is worth noting that, YB-1 can be unconventionally by monocyte or glomerulus system
Theca cell is secreted, and the secretion of YB-1 is related to 301/304 lysine residue of its C-terminal, and secretory protein is similar with chemotactic factor (CF)
Effect is combined (such as NOTCH-3) with some receptors so as to play a role as ligand.Research shows that YB-1 is participated in and is regulated and controled
Heart disease, such as David JJ to patient's cardiac tissue biopsies after heart transplant by having found that YB-1 can regulate and control cardiac muscle cell
Embryonic gene is expressed and the researchs such as and Kamalov G related to patient's long term prognosis find that YB-1 can be by adjusting mouse core
The proliferation of myofibroblast and migration influence the prognosis of myocardial infarction in being organized after dirty infarct.However there is not research yet at present
Report the relationship between YB-1 and DCM generations and development.
Invention content
For the deficiencies in the prior art, the purpose of the present invention is to provide a kind of blood coagulating protein enzyme aPC to prepare
It treats or prevents in diabetic cardiomyopathy as the new application with heart function protection drug, is particularly induced in streptozotocin
Diabetic cardiomyopathy in have apparent therapeutic effect.
To achieve these goals, this invention takes following technical solutions：
A kind of blood coagulating protein enzyme aPC diabetic cardiomyopathy drugs caused by preparing treatment or prevention streptozotocin and inducing
In application.
A kind of applications of blood coagulating protein enzyme aPC in following products are prepared, including：1) it treats and/or prevents the diabetes heart
The drug of myopathy；2) inhibit the ubiquitination of cardiac muscle cell YB1 under high sugared state, so as to stablize the drug (product) of YB1 expression；3)
Mitigate cardiac myocyte hypertrophy and fibrosis, the drug (product) for improving myocardium shrinkage function.
In the present invention, the blood coagulating protein enzyme aPC and other anti-diabetic cardiomyopathys it is medication combined as activity into
Divide the application in the drug for treating or preventing diabetes cardiomyopathy is prepared.
In the present invention, diabetic cardiomyopathy caused by the diabetic cardiomyopathy is induced for streptozotocin.
In the present invention, the dosage form of the drug is oral preparation or injection.
In addition, a kind of drug prevented and/or treat diabetic cardiomyopathy, the active constituent is also claimed in the present invention
Including blood coagulating protein enzyme aPC.
Compared with prior art, the present invention there is following following and effect：
Blood coagulating protein enzyme aPC can be stablized by the ubiquitination of cardiac muscle cell YB1 under the high sugared state of inhibition in the present invention
The expression of YB1, so as to mitigate cardiac myocyte hypertrophy and fibrosis.Therapeutic studies are the results show that blood coagulating protein enzyme aPC has
Significantly mitigate cardiac myocyte hypertrophy and fibrosis, improve myocardium shrinkage function, improve the effect of ejection fraction.
Description of the drawings
Fig. 1 is zoopery flow chart in the embodiment of the present invention 1；
Fig. 2A is dyed for 1 heart tissue HE of the embodiment of the present invention and cell area measurement result figure；
Fig. 2 B are dyed for 1 heart tissue WGA of the embodiment of the present invention and cell area statistical results chart；
Fig. 2 C are 1 mouse heart tissue Masson coloration result figures of the embodiment of the present invention；
Expression and the block diagram that Fig. 3 A are 1 myocardial hypertrophy marker β-MHC of the embodiment of the present invention；
Fig. 3 B are expression and the block diagram of 1 myocardial fibrosis marker TGF-β of the embodiment of the present invention；
Fig. 4 A are from left to right followed successively by 1 control group of the embodiment of the present invention, model group, blood coagulating protein enzyme aPC administration group mouse
Exemplary ultrasonic cardiogram；
Fig. 4 B are 1 blood coagulating protein enzyme aPC of the embodiment of the present invention to STZ induced diabetes cardiomyopathy mouse heart ejection fraction
(EF) and the influence statistical chart of shortening fraction (FS) and rear wall (LVPW) thickness；
Fig. 5 detects mechanocardiography for 1 cardiac catheter of the embodiment of the present invention；
Fig. 6 A are 1 control group of the embodiment of the present invention, model group, blood coagulating protein enzyme aPC administration group mouse heart tissue YB1 tables
Up to typical Western group figure；
Fig. 6 B detect control group, model group, blood coagulating protein enzyme aPC administrations for 1Westernbloting of the embodiment of the present invention
The expression of group mouse heart tissue YB1 albumen and block diagram statistics；
Fig. 7 is the influence figure that 2 blood coagulating protein enzyme aPC of the embodiment of the present invention expresses cardiac muscle cell YB1；
Fig. 8 is 3 co-immunoprecipitation method validation blood coagulating protein enzyme aPC of the embodiment of the present invention to YB1 albumen in cardiac muscle cell
Ubiquitination influence figure.
Specific embodiment：
Technical scheme of the present invention is described in further detail below in conjunction with specific embodiments.It should be understood that institute
Purpose for embodiment is the content that the present invention is further explained, and cannot be construed to protect the present invention in any sense
The limitation of range.
Embodiment 1
Therapeutic effects of the blood coagulating protein enzyme aPC to diabetic cardiomyopathy mouse cardiac insufficiency
Male C57BL6/J mouse (8 week old) are randomly divided into 3 groups：Control group, diabetes group and aPC treatment groups.Using
Multiple low dose streptozotocin (STZ is dissolved in the citrate buffer solution of 0.05M pH4.5,60mg/kg) dose regimen is to diabetes
Continuous 5 days intraperitoneal injection STZ solution of group and aPC treatment groups mouse, control group intraperitoneal injection citrate buffer solution (Fig. 1).It is noting
With left ventricular ejection fraction (leftventricular after Color Sonography detection mouse formation diabetes after penetrating STZ22 weeks
Ejection fraction, LVEF), fractional shortening of the ventricular minor semi axis (left ventricularfractional
Shortening, LVFS), left ventricular diastolic or systole phase chamber interval thickness (leftventricular internal
Dimension at diastole and systole, LVIDd and LVIDs), left ventricular posterior wall thickness (posterior wall
Thickness at diastole and systole, LVPWd and LVPWs) ultrasonic cardiography parameter.Invasive haemodynamics inspection
Survey left ventricular end diastolic presssure (LV end-diastolicpressure, PED), end pressure (LV end-systolic are shunk in left room
Pressure, PES), left ventricular pressure maximum falling speed (maximal rates ofdecline
ofventricularpressure,dp/dtmin) and left ventricular pressure maximum climbing speed (maximal rates ofrise
ofventricular pressure,dP/dtmax) etc. haemodynamics data.Then it harvests mice plasma and adopts as required
Distinct methods is taken to preserve each organ sample and record weight and organ weight.And carry out heart disease reason slice HE, WGA,
The dyeing such as Masson, YB-1 immunohistochemistry.The fingers such as β-MHC, TGF-β, YB-1 in WesternBlot detection mouse heart samples
Mark.
The results show that HE and WGA dyeing show blood coagulating protein enzyme aPC can improve STZ caused by diabetic cardiomyopathy it is small
Rat cardiomyocyte hypertrophy (Fig. 2A and Fig. 2 B).Meanwhile Masson dyeing detections show that blood coagulating protein enzyme aPC can inhibit STZ to lead
The diabetic cardiomyopathy mouse cardiac muscle fibrosis (Fig. 2 C) of cause.Western Blot detections show that blood coagulating protein enzyme aPC can
Inhibit the expression (Fig. 3 A and Fig. 3 B) of myocardial hypertrophy marker β-MHC and Fibrosis Markers TGF-β.Western Blot and exempt from
The detection of epidemic disease groupization shows that blood coagulating protein enzyme aPC can increase the diabetic cardiomyopathy mouse heart tissue cold shock protein of STZ inductions
The decline (Fig. 6 A and Fig. 6 B) of the expression of YB1.And cardiac ultrasonic the result shows that the ejection fraction of diabetic cardiomyopathy mouse and
Shortening fraction declines, and blood coagulating protein enzyme aPC can play apparent improvement result (Fig. 4 A and Fig. 4 B), cardiac catheter detection
As a result (Fig. 5) consistent with this shows that blood coagulating protein enzyme aPC significantly improves diabetic cardiomyopathy mouse heart function damage.
Experiment conclusion confirms that blood coagulating protein enzyme aPC according to the present invention has treatment diabetic cardiomyopathy heart function not
Full effect.
Embodiment 2
Blood coagulating protein enzyme aPC inhibits the degradation of cardiac muscle cell's YB1 albumen
H9C2 cells are randomly divided into group：PBS control group, proteasome inhibitor MG132 processing groups, blood coagulating protein enzyme aPC
Intervention group.According to above grouping, after giving protein synthesis inhibitor CHX (10mg/ml) interventions respectively 1 hour, intervened
PBS, MG132, blood coagulating protein enzyme aPC is after 0,1,3,6,12 hour, collects cell protein, after BCA standard measures, takes 20ug/ holes
Western Blot detect the expression of YB-1 and internal reference Protein G APDH.
As a result it shows, Western Blot are the result shows that blood coagulating protein enzyme aPC can significantly inhibit cardiac muscle cell's YB1 albumen
Degradation (Fig. 7).
Experiment conclusion confirms that blood coagulating protein enzyme aPC according to the present invention can stablize the table of cardiac muscle cell's YB1 albumen
It reaches.
Embodiment 3
Blood coagulating protein enzyme aPC inhibits the ubiquitination level of cardiac muscle cell's YB1 albumen
After H9C2 cells are handled 0,1,3,6,12,24 hour with high sugar, cell protein, co-immunoprecipitation experiment detection are collected
The ubiquitination level of YB1 albumen.
H9C2 cells are divided into 3 groups：Control group, high sugar processing group, high sugar plus blood coagulating protein enzyme aPC processing groups.More than
After grouping, high sugar plus blood coagulating protein enzyme aPC processing groups give blood coagulating protein enzyme aPC interventions 1 hour, high sugar processing group and high sugar add
Blood coagulating protein enzyme aPC processing group intervened high sugar after 3 hours respectively, collected cell protein, and it is each to carry out co-immunoprecipitation experiment detection
The ubiquitination level of group YB1 albumen.
All cell experiments for adding in high sugar stimulation increase isosmoticity mannitol group, exclude oozing caused by high sugar
Saturating influence of the buckling to experimental result.
The results show that co-immunoprecipitation experiment the result shows that the H9C2 cell YB1 ubiquitination levels of high sugar induced at 3 hours
Reach highest, blood coagulating protein enzyme aPC can inhibit the ubiquitination (Fig. 8) of cardiac muscle cell's YB1 albumen of high sugar induced.
Experiment conclusion confirms that blood coagulating protein enzyme aPC according to the present invention can inhibit the general of cardiac muscle cell's YB1 albumen
Elementization, so as to stablize the expression of YB1.
It should be pointed out that specific embodiment described above can make those skilled in the art that this hair be more fully understood
It is bright, but do not limit the invention in any way.Therefore, it will be appreciated by those skilled in the art that still can be carried out to the present invention
Modification or equivalent replacement；And technical solution and its improvement of all spirit and technical spirit that do not depart from the present invention, it should all
Cover in the protection domain of patent of the present invention.
Claims (6)
1. in a kind of blood coagulating protein enzyme aPC diabetic cardiomyopathy drugs caused by preparing treatment or prevention streptozotocin and inducing
Application.
2. a kind of applications of blood coagulating protein enzyme aPC in following products are prepared, which is characterized in that including：1) it treats and/or prevents
The drug of diabetic cardiomyopathy；2) inhibit the ubiquitination of cardiac muscle cell YB1 under high sugared state, so as to stablize the drug of YB1 expression；
3) mitigate cardiac myocyte hypertrophy and fibrosis, the drug for improving myocardium shrinkage function.
3. application according to claim 2, which is characterized in that the blood coagulating protein enzyme aPC and other anti-diabetic hearts
The medication combined application as active constituent in the drug for treating or preventing diabetes cardiomyopathy is prepared of myopathy.
4. according to claim 2-3 any one of them applications, which is characterized in that the diabetic cardiomyopathy helps bacterium for chain urea
Diabetic cardiomyopathy caused by element induces.
5. according to claim 2-4 any one of them applications, which is characterized in that the dosage form of the drug is oral preparation or note
Penetrate agent.
6. a kind of drug prevented and/or treat diabetic cardiomyopathy, which is characterized in that the active constituent includes blood coagulating protein
Enzyme aPC.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711484916.9A CN108159399B (en) | 2017-12-29 | 2017-12-29 | Application of thrombin aPC in medicine for preventing and treating diabetic cardiomyopathy |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711484916.9A CN108159399B (en) | 2017-12-29 | 2017-12-29 | Application of thrombin aPC in medicine for preventing and treating diabetic cardiomyopathy |
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| CN108159399B CN108159399B (en) | 2020-07-24 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111729083A (en) * | 2020-04-03 | 2020-10-02 | 广州医科大学附属第二医院 | Novel use of endothelin C receptor |
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| CN1252726A (en) * | 1997-03-24 | 2000-05-10 | 伊莱利利公司 | Methods for treating vascular disorders |
| CN1254284A (en) * | 1997-04-28 | 2000-05-24 | 伊莱利利公司 | Activated protein C formulations |
| CN1265598A (en) * | 1997-06-05 | 2000-09-06 | 伊莱利利公司 | Method for treating thrombotic disorders |
| CN1303428A (en) * | 1998-06-01 | 2001-07-11 | 伊莱利利公司 | Human protein c polypeptide |
| CN1535313A (en) * | 2000-10-18 | 2004-10-06 | 马克西根公司 | Protein C or activated protein C-like molecules |
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2017
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1252726A (en) * | 1997-03-24 | 2000-05-10 | 伊莱利利公司 | Methods for treating vascular disorders |
| CN1254284A (en) * | 1997-04-28 | 2000-05-24 | 伊莱利利公司 | Activated protein C formulations |
| CN1265598A (en) * | 1997-06-05 | 2000-09-06 | 伊莱利利公司 | Method for treating thrombotic disorders |
| CN1303428A (en) * | 1998-06-01 | 2001-07-11 | 伊莱利利公司 | Human protein c polypeptide |
| CN1535313A (en) * | 2000-10-18 | 2004-10-06 | 马克西根公司 | Protein C or activated protein C-like molecules |
Non-Patent Citations (3)
| Title |
|---|
| BRENDA GRIFFIN等: "A Friend in Need: Activated Protein C Stabilizes YB-1 during Renal Ischemia Reperfusion Injury", 《J AM SOC NEPHROL》 * |
| DAE-HWAN NAM等: "Activated protein C prevents methylglyoxal-induced endoplasmic reticulum stress and cardiomyocyte apoptosis via regulation of the AMP-activated protein kinase signaling pathway", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| WEI DONG等: "Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination", 《J AM SOC NEPHROL》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111729083A (en) * | 2020-04-03 | 2020-10-02 | 广州医科大学附属第二医院 | Novel use of endothelin C receptor |
| CN111729083B (en) * | 2020-04-03 | 2022-08-23 | 广州医科大学附属第二医院 | Novel use of endothelin C receptor |
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