CN116617368A - Application of Elabela in vascular endothelial cell aging resistance - Google Patents
Application of Elabela in vascular endothelial cell aging resistance Download PDFInfo
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- CN116617368A CN116617368A CN202310624656.XA CN202310624656A CN116617368A CN 116617368 A CN116617368 A CN 116617368A CN 202310624656 A CN202310624656 A CN 202310624656A CN 116617368 A CN116617368 A CN 116617368A
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- 210000003556 vascular endothelial cell Anatomy 0.000 title claims abstract description 22
- 230000032677 cell aging Effects 0.000 title claims abstract description 21
- 230000002792 vascular Effects 0.000 claims abstract description 21
- 230000009758 senescence Effects 0.000 claims abstract description 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 17
- 210000002889 endothelial cell Anatomy 0.000 claims abstract description 16
- 230000002137 anti-vascular effect Effects 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000001934 delay Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000032683 aging Effects 0.000 abstract description 13
- 210000004027 cell Anatomy 0.000 abstract description 7
- 241001465754 Metazoa Species 0.000 abstract description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 210000003606 umbilical vein Anatomy 0.000 abstract description 4
- 150000003384 small molecules Chemical class 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 21
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 210000002403 aortic endothelial cell Anatomy 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011870 unpaired t-test Methods 0.000 description 4
- 101000697844 Arabidopsis thaliana Thiosulfate sulfurtransferase 16, chloroplastic Proteins 0.000 description 3
- 235000009200 high fat diet Nutrition 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 108091008803 APLNR Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101000733249 Homo sapiens Tumor suppressor ARF Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000004618 arterial endothelial cell Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
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Abstract
The invention discloses an application of Elabela in vascular endothelial cell aging resistance. The invention discloses the effect of Elabela (19-32) on resisting vascular endothelial cell senescence and further delaying vascular senescence, and provides a potential applicable small molecule for treating vascular senescence. The invention takes the vascular aging of a type 2 diabetes mouse as a model, takes the vascular aging of human umbilical vein endothelial cells induced by high sugar as a model on cells, and discovers the effect of the Elabela (19-32) small peptide on vascular endothelial cell aging on animal level and cell level.
Description
Technical Field
The invention belongs to the technical field of life science, relates to application of a peptide fragment of hormone peptide in resisting vascular endothelial cell aging, and in particular relates to application of Elabela in resisting vascular endothelial cell aging.
Background
The vascular system is the main channel for maintaining the energy metabolism balance of organs, and vascular aging is currently considered to be one of the early manifestations of body aging and important pathophysiological basis. Endothelial cell aging is considered as an important driver of vascular aging, and long-term hyperglycemic conditions lead to vascular endothelial cell aging in diabetics, which in turn leads to premature vascular aging and the occurrence of various cardiovascular diseases. Therefore, the search for effective drugs for treating vascular aging is of great importance in reducing the occurrence of cardiovascular events in patients with vascular aging.
Elabela is a hormone peptide, which was first found in embryonic stem cells and plays an important role in the development of embryos. The Elabela-APJ signaling axis, which is currently considered to be one of the endogenous ligands of APJ receptors, has been demonstrated to have important regulatory roles in cardiovascular diseases such as heart failure, hypertension, atherosclerosis, angiogenesis, etc. However, it is not clear whether Elabela can regulate vascular endothelial cell aging.
Disclosure of Invention
A first object of the present invention is to provide the use of Elabela (19-32) small peptides for anti-vascular endothelial cell aging, which addresses the deficiencies of the prior art.
Preferably, the Elabela (19-32) small peptide delays vascular endothelial cell aging and reduces vascular endothelial cell inflammation level.
Preferably, the Elabela (19-32) small peptide improves vascular stiffness.
The second object of the invention is to provide the application of the Elabela (19-32) small peptide in preparing the anti-vascular endothelial cell aging medicine.
A third object of the present invention is to provide an anti-vascular endothelial cell aging agent comprising a safe and effective amount of an Elabela (19-32) small peptide.
Preferably, the medicament further comprises a pharmaceutically acceptable excipient or carrier.
Based on clinical problems and the early vascular aging of diabetics, the invention constructs a model mouse of type 2 diabetes, and the vascular endothelial cells of the model mouse of type 2 diabetes are proved to be aged by analyzing the aorta of the mouse, so that the model mouse has consistency with the early vascular aging of diabetics. Further, the administration of Elabela (19-32) by intraperitoneal injection (2 mg/kg) twice daily was found to significantly improve vascular endothelial cell senescence in type 2 diabetic mice. On cells, elabela (19-32) was found to be able to improve high sugar-induced human umbilical vein endothelial cell senescence in a dose-dependent manner.
The invention has the beneficial effects that:
the invention discloses the effect of Elabela (19-32) on vascular endothelial cell senescence for the first time, and provides a potential applicable small molecule for vascular senescence treatment. The invention discloses an application of an Elabela (19-32) small peptide in resisting vascular endothelial cell aging for the first time, wherein the animal is modeled by vascular aging of a type 2 diabetes mouse, the cell is modeled by vascular endothelial cell aging induced by high sugar, and the effect of the Elabela (19-32) small peptide on resisting vascular endothelial cell aging is found at animal level and cell level.
Drawings
FIG. 1 is a western blot of aortic endothelial cells of type 2 diabetic mice showing an senescent phenotype, wherein A is the aortic endothelial cells of diabetic mice (T2D) and healthy control mice (WT), and the expression of vasculoinflammation-associated protein vcam1 and senescence-associated protein P16 is examined; b is a statistical graph of the graph A, and the inspection method comprises the following steps: unpaired t-test.
FIG. 2 shows the improvement of arteriosclerosis in type 2 diabetic mice by Elabela (19-32), and the detection of arteriosclerosis in type 2 diabetic mice (T2D-ELA) and type 2 diabetic mice (T2D) by intraperitoneal injection of PBS, respectively, wherein A is the left carotid Pulse Wave Velocity (PWV) of the two mice, B is the left carotid vascular compliance of the two mice, C is the aortic Pulse Wave Velocity (PWV) of the two mice, D is the aortic vascular compliance of the two mice, and the detection method is: unpaired t-test.
FIG. 3 shows the results of Elabela (19-32) reduction in arterial endothelial cell senescence in type 2 diabetic mice, detection of aortic endothelial cell senescence in Abela (19-32) intraperitoneally injected diabetic mice (T2D-ELA) and in PBS intraperitoneally injected diabetic control (T2D), wherein A is the result of Western immunoblotting of endothelial cells in two groups of mice, detection of expression of vasculoinflammation-associated protein vcam1 and senescence-associated protein P16, B is the statistical result of P16in A, and C is the statistical result of vcam1 in A, and the test method is: unpaired t-test.
FIG. 4 shows the reduction of high glucose-induced endothelial cell senescence in human umbilical vein by Elabela (19-32), the experimental group was that different doses of Elabela (19-32) were administered after high glucose-induced endothelial cell senescence, wherein A is a representative graph of SA- β -gal staining of cells, B is a statistical graph of A, C is a western blotting result, and the expression of endothelial cell inflammation-associated protein vcam1 and senescence-associated protein P16 was detected by the following test method: unpaired t-test.
Fig. 5 is a flow chart of the mechanism of the present invention.
Detailed Description
The invention is further described below, without limiting the invention, in connection with the examples and the figures.
The invention uses mice which are all C57BL/6J strains and are raised in Special Pathogen Free (SPF) class animal houses of Hangzhou university laboratory animal centers. All mice used in the experiments were male mice of 12 weeks old, and all mice were tested in compliance with the "use of laboratory animals" by the ethical committee of the university of Hangzhou, china. The arterial stiffness of the experimental mice was evaluated using a Vevo3100 mouse ultrasound imaging system. Streptozotocin (STZ) was purchased from Sigma-Aldrich company; SA-beta-gal staining kit was purchased from Shanghai Biyun biotechnology Co., ltd; 60% high fat diet (D12492) was purchased from research diets; anti-CDKN2A/p16INK4a antibody (ab 211542) used in immunoblots was purchased from abcam corporation and Anti-VCAM1Recombinant RabbitMonoclonal antibody (ET 1601-18) was purchased from Hua' an organism; the AlphaTubulin Monoclone antibody (66031-1-Ig) was purchased from Wohan Sanying Biotechnology Co. All experimental results included 3 and more independent experimental replicates with data presented as mean ± SEM.
The amino acid sequence of the Elabela (19-32) small peptide used in the invention is as follows:
QRRCMPLHSRVPFP。
example 1: anti-vascular endothelial cell aging effect of Elabela (19-32) small peptides
Based on the phenomenon of premature vascular aging of diabetics, a model mouse of type 2 diabetes is constructed by using a high-fat diet combined with STZ induction mode (60% of high-fat diet is injected intraperitoneally after 100mg/kg of STZ is injected for 7 weeks) and the model mouse is discovered to have a vascular endothelial cell aging phenotype by extracting active endothelial cells of the mouse and performing western blotting (figure 1).
In order to explore the role of Elabela in vascular aging, the main active fragment of Elabela, elabela (19-32) small peptide, was synthesized in vitro. On animals, mice were given twice daily doses of 2mg/kg of the Elabela (19-32) small peptide by intraperitoneal injection while a model of type 2 diabetes was being constructed. Elabela (19-32) significantly improved arterial hardness in type 2 diabetic mice compared to control PBS (FIG. 2); further isolation of mouse aortic endothelial cells for immunoblotting to detect expression of senescence-associated markers demonstrated that Elabela (19-32) significantly reduced the senescence and inflammation levels of aortic endothelial cells (fig. 3). On cells, administration of human umbilical vein endothelial cells with high sugar induced senescence while different doses of Elabela (19-32) were administered, we found that Elabela (19-32) dose-dependently reduced endothelial cell senescence by SA- β -gal staining and western blotting experiments (FIG. 4).
The results indicated that Elabela (19-32) was able to combat vascular endothelial cell senescence and thus delay vascular senescence (FIG. 5).
The above embodiments are not intended to limit the present invention, and the present invention is not limited to the above embodiments, and falls within the scope of the present invention as long as the present invention meets the requirements.
Claims (6)
- The application of Elabela (19-32) small peptide in resisting vascular endothelial cell aging.
- 2. The use according to claim 1, wherein the small peptide of Elabela (19-32) delays vascular endothelial cell senescence and reduces vascular endothelial cell inflammation levels.
- 3. The use according to claim 1, wherein the Elabela (19-32) small peptide improves vascular stiffness.
- Application of Elabela (19-32) small peptide in preparing anti-vascular endothelial cell aging medicine.
- 5. An anti-vascular endothelial cell aging agent comprising a safe and effective amount of an Elabela (19-32) small peptide.
- 6. The medicament of claim 5, further comprising a pharmaceutically acceptable excipient or carrier.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310624656.XA CN116617368A (en) | 2023-05-30 | 2023-05-30 | Application of Elabela in vascular endothelial cell aging resistance |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310624656.XA CN116617368A (en) | 2023-05-30 | 2023-05-30 | Application of Elabela in vascular endothelial cell aging resistance |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150153365A1 (en) * | 2013-12-03 | 2015-06-04 | Agency For Science, Technology And Research (A*Star) | Polypeptides, nucleic acids and uses thereof |
| CN106831945A (en) * | 2017-04-07 | 2017-06-13 | 华中科技大学 | Polypeptide and its application in acute injury of kidney is treated |
| CN109922823A (en) * | 2016-07-15 | 2019-06-21 | 新加坡科技研究局 | The diagnostic and therapeutic method of pre-eclampsia |
| CN110960671A (en) * | 2019-12-25 | 2020-04-07 | 广州中医药大学(广州中医药研究院) | New application of Elabela polypeptide and medicine thereof |
| CN112007144A (en) * | 2020-08-24 | 2020-12-01 | 广州中医药大学(广州中医药研究院) | Application of Elabela polypeptide in preparation of antioxidant product |
-
2023
- 2023-05-30 CN CN202310624656.XA patent/CN116617368A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150153365A1 (en) * | 2013-12-03 | 2015-06-04 | Agency For Science, Technology And Research (A*Star) | Polypeptides, nucleic acids and uses thereof |
| WO2015084264A1 (en) * | 2013-12-03 | 2015-06-11 | Agency For Science, Technology And Research | Polypeptides, nucleic acids and uses thereof |
| CN109922823A (en) * | 2016-07-15 | 2019-06-21 | 新加坡科技研究局 | The diagnostic and therapeutic method of pre-eclampsia |
| CN106831945A (en) * | 2017-04-07 | 2017-06-13 | 华中科技大学 | Polypeptide and its application in acute injury of kidney is treated |
| CN110960671A (en) * | 2019-12-25 | 2020-04-07 | 广州中医药大学(广州中医药研究院) | New application of Elabela polypeptide and medicine thereof |
| CN112007144A (en) * | 2020-08-24 | 2020-12-01 | 广州中医药大学(广州中医药研究院) | Application of Elabela polypeptide in preparation of antioxidant product |
Non-Patent Citations (3)
| Title |
|---|
| ALEXANDRE MURZA等: "Discovery and Structure−Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 59, 17 March 2016 (2016-03-17), pages 2962 - 2972, XP055363511, DOI: 10.1021/acs.jmedchem.5b01549 * |
| CHAO YE等: "Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects", 《ACTA PHARMACOLOGICA SINICA》, vol. 43, 8 March 2022 (2022-03-08), pages 2573 - 2584 * |
| ZHENG MA等: "Declined ELABELA plasma levels in hypertension patients with atrial fibrillation: a case control study", 《BMC CARDIOVASC DISORD.》, vol. 21, 12 August 2021 (2021-08-12), pages 390 * |
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