CN109395057A - Medical composition and its use containing Apelin-12 - Google Patents
Medical composition and its use containing Apelin-12 Download PDFInfo
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- CN109395057A CN109395057A CN201810749165.7A CN201810749165A CN109395057A CN 109395057 A CN109395057 A CN 109395057A CN 201810749165 A CN201810749165 A CN 201810749165A CN 109395057 A CN109395057 A CN 109395057A
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- QZNKGTRFBWGADN-SLUWFFAESA-N apelin-12 Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CCSC)C(=O)N3CCC[C@H]3C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N QZNKGTRFBWGADN-SLUWFFAESA-N 0.000 title claims abstract description 51
- 108010006026 apelin-12 peptide Proteins 0.000 title claims abstract description 51
- 239000000203 mixture Substances 0.000 title description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 46
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 31
- 230000000694 effects Effects 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 11
- 102000008186 Collagen Human genes 0.000 claims abstract description 10
- 108010035532 Collagen Proteins 0.000 claims abstract description 10
- 229920001436 collagen Polymers 0.000 claims abstract description 10
- 208000031169 hemorrhagic disease Diseases 0.000 claims abstract description 10
- 210000004369 blood Anatomy 0.000 claims description 10
- 239000008280 blood Substances 0.000 claims description 10
- 230000002776 aggregation Effects 0.000 claims description 9
- 238000004220 aggregation Methods 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000003146 anticoagulant agent Substances 0.000 claims description 7
- 230000006698 induction Effects 0.000 claims description 7
- 230000002785 anti-thrombosis Effects 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 2
- 238000006731 degradation reaction Methods 0.000 claims description 2
- 239000003446 ligand Substances 0.000 abstract description 11
- 230000003331 prothrombotic effect Effects 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 2
- 210000001772 blood platelet Anatomy 0.000 description 23
- 238000012360 testing method Methods 0.000 description 19
- 108010052412 Apelin Proteins 0.000 description 11
- 241000283977 Oryctolagus Species 0.000 description 11
- 102000018746 Apelin Human genes 0.000 description 10
- BWVPHIKGXQBZPV-QKFDDRBGSA-N apelin Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCSC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 BWVPHIKGXQBZPV-QKFDDRBGSA-N 0.000 description 10
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- 102400000252 Apelin-13 Human genes 0.000 description 2
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- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- XXCCRHIAIBQDPX-PEWBXTNBSA-N apelin-13 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(N)=O)C1=CN=CN1 XXCCRHIAIBQDPX-PEWBXTNBSA-N 0.000 description 2
- 108010040480 apelin-13 peptide Proteins 0.000 description 2
- SVWSKJCJNAIKNH-MJZUAXFLSA-N apelin-17 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](N)CCCCN)C1=CN=CN1 SVWSKJCJNAIKNH-MJZUAXFLSA-N 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- 230000010118 platelet activation Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- 101800001808 Apelin-36 Proteins 0.000 description 1
- 102400000251 Apelin-36 Human genes 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101000621371 Homo sapiens WD and tetratricopeptide repeats protein 1 Proteins 0.000 description 1
- 101000892274 Human adenovirus C serotype 2 Adenovirus death protein Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 101000820656 Rattus norvegicus Seminal vesicle secretory protein 4 Proteins 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- BVTLGARMSLXAHI-VDEROMQGSA-N apelin-36 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C1=CN=CN1 BVTLGARMSLXAHI-VDEROMQGSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical group C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 210000001501 megacaryocyte Anatomy 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
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- 230000004218 vascular function Effects 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of endogenic ligand Apelin-12, which promotees platelet aggregation and pro-thrombotic effect by effect apj receptor, and ADP and collagen-induced rush platelet aggregation and pro-thrombotic can be cooperateed with to act on.Apelin-12 hemorrhagic disease basic research using the drug as a kind of novel rush platelet aggregation and thrombosis.
Description
Technical field
The present invention relates to the medical composition and its uses containing Apelin-12.Apelin-12 itself can by APJ by
Body promotees platelet aggregation, and also has the function of cooperateing with ADP and collagen-induced rush platelet aggregation and outer thrombosis.
Background technique
Apj receptor is a kind of g protein coupled receptor for having high homology with Angiotension type I receptor, and Apelin is it
Endogenic ligand.Mankind's Apelin gene is located at q25-26 sections of X chromosome, and coded product is the precursor containing 77 amino acid
Peptide is then cracked into the segment of different aminoacids length, comprising: Apelin-12, Apelin-13, Apelin-17 and
Apelin-36 etc..Apelin/APJ system is extensive in Tissue distribution, and physiology, pathological effect are abundant, cardiovascular function is regulated and controled,
Energetic supersession isohydria, angiogenesis etc. play an important role.
Blood platelet is a kind of cell fragment to get off from the megacaryocyte cytoplasm crack releasing of marrow maturation, and volume is small,
Cell-free core.Non-activated blood platelet is discoid in biconvex, activates vulnerable to mechanical, chemical stimulation.The blood platelet of the state of activation
Podocytic process can be stretched out, and secretes corresponding attachment proteins, makes to adhere to each other and assemble between blood platelet.Platelet aggregation is thrombus
And the important link that thrombotic diseases are formed.When damage or inflammation occur for body blood vessel endothelium, blood platelet is activation
Aggregation, and then start coagulation process.The formation of most thrombus all with blood platelet overactivity, occurs irreversible aggtegation and draws
It rises.Therefore, the endogenous factors for causing blood platelet to be assembled are studied, the receptor or logical for inducing that platelet aggregation is activated is explored
Road will inhibit platelet aggregation drugs for exploitation and find corresponding action target spot to provide new theory.
Apelin/APJ system play corresponding function during, it may evidence influential on platelet aggregation also by
Gradually display.Scholar in 2005 reports that [29,30] Apelin has enhancing myocardial contractive power, expands the effect of blood vessel, and the heart
The increase of myotility and its generation of vasorelaxation action are related with Na+/H+ and Na+/Ca2+ permutoid.Modgil in 2013
A etc. reports that [32] Apelin inhibits the channel dependence K+ Ca2+ to promote cerebral artery smooth muscle cell contraction by PI3K approach.
The mark of platelet activation and initiating agent first is that in Platelets Ca2+ concentration raising.Ca2+ concentration increases in blood platelet
ATP enzyme can be activated by adding, and cause the release of ATP, provide energy for blood platelet, and promote the activation of blood platelet.Ca2+ participates in the overall process
Into platelet activation, adherency, aggregation and thrombosis.
In addition, present inventor has found, Apelin promotes rat aorta smooth by 14-3-3-ERK1/2 signal path
Muscle cell multiplication.When blood platelet activates, 14-3-3 is secreted into outside film as other secretion of platelet albumen, participates in blood
The formation of bolt.Tissue factor (tissue factor, TF) solidifies grade when the integrality of vascular wall is by destroying, through activation
Connection reaction plays anastalsis.Cirillo in 2015 etc. [37] is reported in during the inside Epithelial Cell Adhesion of monocyte,
Apelin is capable of the expression of procoagulant Factor TF.These reports imply that Apelin has the adjustment effect of thrombus and vascular function.
And Kuba in 2007 etc. [38] report Apelin knock-out mice will lead to the heart failure of Pressure Overload-induced induction, and have tail portion
Bleeding time shortens and the risk of pro-thrombotic.However, Adam etc. [39] reports that Apelin-13 inhibits collagen and coagulates in the recent period again
The platelet aggregation of hemase induction, extends the time of mouse tail bleeding.This shows that Apelin is an inhibition platelet aggregation again
The factor of collection.
Myocardial contraction, myocardial preservation and hemodynamics are concentrated mainly on about APJ ligand isoform Apelin-12 research at present
Learn etc., and there has been no any reports in terms of Apelin-12 and platelet function and thrombosis.This patent is mainly inquired into
The functional study of Apelin-12 and platelet aggregation and thrombosis.It was found that Apelin-12 can by activation apj receptor come
Promote platelet aggregation and ex vivo thrombosis.Apj receptor blocking agent F13A inhibits the platelet aggregation of Apelin-12 induction
And ex vivo thrombosis.
Summary of the invention
The present invention provides a kind of pharmaceutical composition for treating hemorrhagic disease, it includes endogenic ligand Apelin-12.
The present invention also provides the purposes that above-mentioned endogenic ligand Apelin-12 is used to prepare drug, and wherein the drug is used for
Treat the hemorrhagic disease as caused by platelet aggregation disorder；Or the chemoprophylaxis platelet aggregation or antithrombotic.
Present invention finds the physiologic function of above-mentioned endogenic ligand Apelin-12, can by effect apj receptor come
Treat the hemorrhagic disease as caused by platelet aggregation disorder；Or it is used to prevent platelet aggregation or antithrombotic.
Present invention finds the physiologic function of above-mentioned endogenic ligand Apelin-12, ADP and collagen-induced can be cooperateed with
Rush platelet aggregation and thrombosis act on to treat the hemorrhagic disease as caused by platelet aggregation disorder；Or this its
For preventing platelet aggregation or antithrombotic.
Present invention finds the physiologic function of above-mentioned endogenic ligand Apelin-12, can by degradation Apelin-17 or
Its target spot APJ is blocked to inhibit aggregation and the antithrombus formation of blood platelet.
In vitro in test, the gradient of concentration is 0.001mol/L, 0.01mol/L, 0.1mol/L, 1.0 μm of ol/L, preferably
For 1.0 μm of ol/L.
Advantageous effects of the invention
1, endogenic ligand Apelin-12 of the invention has the function of preferably promoting platelet aggregation, therefore, can be used for
Prepare drug.
2, endogenic ligand Apelin-12 of the invention has synergistic effect to ADP and collagen-induced rush platelet aggregation,
Therefore it can be used for treating the hemorrhagic disease as caused by platelet aggregation disorder；Or it is used to prevent platelet aggregation or prevention
Thrombosis.
Detailed description of the invention:
Fig. 1 is that Apelin-12 promotes platelet aggregation；
Fig. 2 is the rush the Platelet Aggregation in Rabbit that F13A blocks Apelin-12；
Fig. 3 is that Apelin-12 has synergistic effect to the rush rabbit platelet aggregation that ADP is induced；
Fig. 4 is that Apelin-12 has synergistic effect effect to collagen-induced rush rabbit platelet aggregation；
Fig. 5 is that Apelin-12 promotes thrombosis；
Fig. 6 is the new zealand rabbit ex vivo thrombosis effect that F13A blocks apelin-12 induction.
Specific embodiment
Preparation example 1
Its function is detected, shown in following examples.Implement below for illustrating the present invention, but should not be used to the limitation present invention
Range.
Embodiment 1 measures influence of the Apelin-12 to new zealand rabbit platelet aggregation
It is small with platelet aggregation coagulation factor analyzer (LG-PABER-I type, Beijing Steellex Scientific Instrument Company) measurement blood
Plate aggregation rate.This instrument tests platelet aggregation using photoelectric turbidimetry: using platelet poor plasma (platelet poor
Plasma, PPP) it is used as substrate, it is measured using Platelet-rich plasm (platelet richplasma, PRP).In magnetic
Under the stirring of power pearl, inducer is added in PRP, blood platelet is assembled, and the light transmittance of PRP increases or turbidity reduction.By light
The variation of turbidity is converted to the variation of electric signal, to calculate the aggregation rate of blood platelet.
Aggregation rate=(measurement voltage value-PPP photoelectricity voltage value)/(PRP photoelectricity voltage value-PPP photoelectricity voltage value) *
100%
1. measuring the shadow of the Apelin-12 to new zealand rabbit platelet aggregation of various concentration (1*10-7-1*100 μm of ol/L)
It rings
Arterial blood drawing in new zealand rabbit ear, it is anticoagulant with sodium citrate, it is then centrifuged for, is first centrifuged 10min with 800r/min, takes
Supernatant obtains PRP, then is centrifuged 10min with 3000r/min, and supernatant is taken to obtain PPP.Accurately it is added 300 μ l's in test cup
PPP is put into TCH test channel, presses after PPP key carries out substrate measurement and takes out.In another test cup, the accurate PRP that 300 μ l are added,
At 37 DEG C after pre-temperature 1min, using adding pearl device that 1 test pearl is added in the test cup, after starting test, divide in three seconds
Not Jia Ru the Apelin-12 of various concentration (0.001,0.01,0.1,1 μm of ol/L) test 5min, the maximum for recording blood platelet is poly-
Collection rate (referring to Fig. 1).
2. measuring effect of the apj receptor blocking agent F13A to Apelin-12 induction new zealand rabbit platelet aggregation
PPP is acquired, PRP is same as above, and F13A is added in PRP and is incubated for 5min, is placed into the test section for having mixed up baseline,
Test pearl is added, after starting test, Apelin-12 is added in three seconds and tests 5min, records the maximum aggregation rate of blood platelet, sees
It examines test result detection F13A and new zealand rabbit platelet aggregation is promoted to Apelin-12.Judge that apj receptor mediates with this
The rush platelet aggregation (referring to fig. 2) of Apelin-12.
3. measuring various concentration Apelin-12 to the synergistic effect of ADP and collagen-induced new zealand rabbit platelet aggregation
PPP is acquired, PRP is same as above, and Apelin-12 is added in PRP and is incubated for 5min, places into the test for having mixed up baseline
Test pearl is added in Qu Zhong, after starting test, ADP is added in three seconds and collagen tests 5min, record the maximum aggregation of blood platelet
Rate, synergistic effect (ginseng of the observation test result detection Apelin-12 to ADP and collagen-induced new zealand rabbit platelet aggregation
See Fig. 3 and Fig. 4).
Embodiment 2 measures influence of the Apelin-12 to ex vivo thrombosis
Thrombosis model is established with thrombometer (LMK-12 type, Zhengzhou Ming Ju scientific & technical corporation), this instrument is used
Chandler method: blood is injected in external rotating ring, and blood flow state is in analogue body to form thrombus.
1. measuring influence of the Apelin-12 of various concentration (1*10-7-1*100 μm of ol/L) to ex vivo thrombosis
Arterial blood drawing (is not added any anti-coagulants, using straight extracting vein blood 1ml, and pays attention to inject in new zealand rabbit ear
Bubble removal in device, after being handled with various concentration Apelin-12 (0.001,0.01,0.1,1 μm of ol/L), blood sample dress fills annulus,
Slowly by 1m1 blood sample along the tube wall injection pipe of plastic hoop one end, connect into annulus at any time, be satisfied in corresponding turntable.It is put into
Middle revolving speed is 20 ± 2rpm, and at 37 DEG C, after recycling 10min, removal of thromboses measures and records the weight in wet base and length of thrombus.
The above-mentioned thrombus for having claimed weight in wet base is put into drying and processing in 60 DEG C ± 1 DEG C of baking oven, after 30min, again by the thrombus of drying
Weighing records thrombus dry weight (referring to Fig. 5).
2. measuring effect of the apj receptor blocking agent F13A to the Apelin-12 new zealand rabbit ex vivo thrombosis induced
Equally thrombosis model is constructed with chandler method.Apelin-12 is added to the New Zealand of 1ml together with F13A
According to the test method in 1 in rabbit blood, removal of thromboses disease records experimental result.And observe F13A (apj receptor blocking agent) resistance
Disconnected Apelin-12 induction new zealand rabbit thrombosis effect.Judge that apj receptor mediates the pro-thrombotic of Apelin-12 with this
It acts on (referring to Fig. 6).
In conclusion endogenous Apelin-12 ligand of the invention has ideal rush platelet aggregation and thrombosis
The effect of, it can be used in preparing relevant drug.
Claims (5)
1. a kind of pharmaceutical composition for treating hemorrhagic disease, it is characterised in that: the pharmaceutical composition includes Apelin-12.
2.Apelin-12 is used to prepare the purposes of drug, and wherein the drug is for treating as caused by platelet aggregation disorder
Hemorrhagic disease；Or the chemoprophylaxis platelet aggregation or antithrombotic.
3. Apelin-12 according to claim 2 is used to prepare the purposes of drug, Apelin-12 can by effect APJ by
Body treats the hemorrhagic disease as caused by platelet aggregation disorder；Or it is used to prevent platelet aggregation or pre- preventing thrombosis shape
At.
4. Apelin-12 according to claim 2 is used to prepare the purposes of drug, Apelin-12 can cooperate with ADP and collagen
The rush platelet aggregation and thrombosis of induction act on to treat the hemorrhagic disease as caused by platelet aggregation disorder；Or
This its be used to prevent platelet aggregation or antithrombotic.
5.Apelin-12 is used to prepare the purposes of drug, by degradation Apelin-12 or can block its target spot APJ and inhibits blood
The aggregation of platelet and antithrombus formation.
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| CN114099642A (en) * | 2021-11-12 | 2022-03-01 | 南通大学 | Application of gene Apln in preparation of drugs for treating diseases related to cell angiogenesis |
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| CN101735307A (en) * | 2008-11-18 | 2010-06-16 | 北京航空航天大学 | Platelet envelope glycoprotein oligopeptide or trim/derivate thereof and application thereof |
| CN102617680A (en) * | 2011-02-01 | 2012-08-01 | 复旦大学 | Bi-functional antiplatelet aggregation medicine and application thereof |
| CN104958288A (en) * | 2015-06-26 | 2015-10-07 | 苏州大学 | Platelet inhibitor and application of platelet inhibitor for preparing medicine for resisting platelet diseases |
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| CN101735307A (en) * | 2008-11-18 | 2010-06-16 | 北京航空航天大学 | Platelet envelope glycoprotein oligopeptide or trim/derivate thereof and application thereof |
| CN102617680A (en) * | 2011-02-01 | 2012-08-01 | 复旦大学 | Bi-functional antiplatelet aggregation medicine and application thereof |
| CN104958288A (en) * | 2015-06-26 | 2015-10-07 | 苏州大学 | Platelet inhibitor and application of platelet inhibitor for preparing medicine for resisting platelet diseases |
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| CN114099642A (en) * | 2021-11-12 | 2022-03-01 | 南通大学 | Application of gene Apln in preparation of drugs for treating diseases related to cell angiogenesis |
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