WO2022033152A1 - Utilisation de cilp2 dans la préparation d'un médicament destiné à amoindrir le vieillissement cardiaque et l'hypertrophie myocardique - Google Patents

Utilisation de cilp2 dans la préparation d'un médicament destiné à amoindrir le vieillissement cardiaque et l'hypertrophie myocardique Download PDF

Info

Publication number
WO2022033152A1
WO2022033152A1 PCT/CN2021/099281 CN2021099281W WO2022033152A1 WO 2022033152 A1 WO2022033152 A1 WO 2022033152A1 CN 2021099281 W CN2021099281 W CN 2021099281W WO 2022033152 A1 WO2022033152 A1 WO 2022033152A1
Authority
WO
WIPO (PCT)
Prior art keywords
cilp2
aging
cardiac
heart
mice
Prior art date
Application number
PCT/CN2021/099281
Other languages
English (en)
Chinese (zh)
Inventor
王志华
吕舰
李丽莉
胡依萌
汤立许
Original Assignee
武汉大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉大学 filed Critical 武汉大学
Publication of WO2022033152A1 publication Critical patent/WO2022033152A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to the application of CILP2 in the preparation of medicines for improving cardiac aging and cardiac hypertrophy.
  • Heart failure can occur after the aging of the heart causes changes in its structure. Unlike “systolic heart failure,” most age-related heart failure occurs when systolic function is normal and is called “diastolic heart failure.” For example, aging-induced left ventricular fibrosis, stiffness, and wall thickening can cause myocardial diastolic dysfunction, leading to heart failure.
  • the number of cardiomyocytes may decrease with age, but cardiac fibroblasts, which produce extracellular matrix and collagen, proliferate significantly.
  • cardiac fibroblasts proliferate excessively, the synthesis and degradation of collagen will be unbalanced, the proportion of collagen will be unbalanced, the arrangement of cells will be disordered, and the deposition of extracellular matrix will occur.
  • Collagen accumulation leads to interstitial fibrosis in the atria, stellate ganglia, and ventricles of the elderly, which in turn causes myocardial systolic and diastolic dysfunction.
  • the CILP2 gene is located in band 11 (19p13.11) of the short arm 13 region of chromosome 19, with a length of 8395 bp.
  • the protein encoded by the CILP2 gene is called cartilage intermediate layer protein 2 (cartilage intermediate layer protein 2).
  • CILP2 is highly homologous to CILP1. As a massively secreted glycoprotein present in extracellular fluid, CILP1 is thought to play a role in the scaffolding of cartilage, and its dysfunction may lead to cartilage diseases. Studies have shown that CILP1 is expressed in the heart and muscle of adult mice, suggesting that it may function outside the cartilage.
  • CILP2 also exists as a glycoprotein in human articular cartilage and ultrastructure, and may be involved in the formation of collagen VI in ultrastructure. Both CILP-1 and CILP-2 proteins can be cleaved into N-terminal fragments and C-terminal fragments at the furin endoprotease site. It is inferred from the protein structure and function: the N-terminal WxxW sequence is involved in the interaction of CILP with TGF- ⁇ play a key role ( Figure 1).
  • the C-terminus has a homology of more than 90.9% with nucleotide pyrophosphohydrolase (NTPPHase), which may be related to the activity of nucleotide pyrophosphodiesterase (NPP), but it lacks the NPP catalytic site or bivalent cationic binding site.
  • NPPPHase nucleotide pyrophosphohydrolase
  • the present invention provides the application of CILP2 in the preparation of medicines for improving cardiac aging and cardiac hypertrophy, aiming to solve some of the problems in the prior art or at least alleviate some of the problems in the prior art.
  • the invention provides an application of CILP2, which is mainly reflected in the application of CILP2 in the preparation of a medicine for preventing, relieving and/or treating cardiac hypertrophy caused by aging.
  • the present invention is specifically the application of CILP2 in the preparation of a medicine for improving and/or treating cardiac aging and/or cardiac hypertrophy.
  • CILP2 is a C-terminal fragment of CILP2 cleaved at the furin endoprotease site.
  • the drug includes a secretagogue or agonist of CILP2.
  • a drug for preventing, relieving and/or treating cardiac aging and/or cardiac hypertrophy comprising at least one of CILP2, a secretagogue or agonist of CILP2.
  • the CILP2 secretagogue or agonist includes at least one of an overexpression plasmid of the CILP2 gene and an agonist capable of promoting the expression of CILP2.
  • CILP2 secretagogue or agonist in the preparation of a medicament for improving and/or treating cardiac aging and/or cardiac hypertrophy.
  • CILP2 gene and/or the expression product of CILP2 gene as a drug target in the preparation of a drug for improving and/or treating cardiac aging and/or cardiac hypertrophy.
  • the present invention performs protein spectrum detection on the plasma of the aging population and the young population, and finds that the level of CILP2 in the blood circulation of the aging population decreases. Furthermore, in the results of protein spectrum detection in the plasma of the aging population and the young population, the peptide identification list shows that the 7 peptides marked in the mass spectrometry were compared with the full-length amino acid sequence of CILP2, and it was found that these peptides were all located in the C of the gene. end fragment.
  • the invention establishes a mouse aging model by naturally rearing 22-month-old wild-type mice, using 8-week-old young control wild-type C57BL/6 mice, 22-month-old aging control mice and 22-month-old aging CILP2 overexpression mice as experiments object.
  • the mouse cardiac ultrasound examination, cardiac weighing, myocardial fibrosis, cardiomyocyte size detection, cardiac hypertrophy markers and cardiac aging markers were performed.
  • the results showed that compared with the young mice, the aged control mice had significantly thicker ventricular wall thickness, aggravated myocardial fibrosis, increased cross-sectional area of cardiomyocytes, and significantly increased cardiac hypertrophy indexes, including aging markers P16, P21, and P53. increased expression.
  • the overexpression of CILP2 in the aging experimental group can reduce the thickness of the ventricular wall, reduce the weight of the heart, and the size of the cardiomyocytes is also significantly reduced.
  • the expression levels of , P21 and P53 decreased, and the expression levels of inflammatory factors IL-1 ⁇ , IL-6, and TNF- ⁇ in the myocardium also decreased, and the trend changed to a younger age.
  • the above results indicate that aging can promote the occurrence of aging cardiac hypertrophy, and overexpression of CILP2 can improve aging cardiac hypertrophy by improving the expression of aging marker genes, and provide new targets and strategies for the prevention, mitigation and/or treatment of aging-induced cardiac hypertrophy. Provided the theoretical basis and clinical basis.
  • the research of the present invention proves that in an aging model, overexpression of CILP2 can inhibit the aging of the heart, reduce myocardial hypertrophy and fibrosis, and especially improve the effect of aging myocardial hypertrophy.
  • CILP2 has the effect of improving cardiac aging and cardiac hypertrophy; based on the function of CILP2 in cardiac aging and cardiac hypertrophy, it provides a target for the development of drugs for the treatment of cardiac aging and cardiac hypertrophy;
  • the agonists of CILP2 can be used for the preparation of medicaments for preventing, alleviating and/or treating cardiac aging and cardiac hypertrophy.
  • Fig. 1 is the CILP2 gene structure diagram
  • FIG. 2 is a mouse processing flow
  • Figure 3 shows that the level of CILP2 transcription in myocardium is up-regulated after virus transfection. **: p ⁇ 0.01; ns: no statistical difference;
  • Figure 4 shows the changes of cardiac structure and function in mice detected by cardiac ultrasound, as well as the changes of cardiac weight in mice;
  • A typical M-mode diagram of cardiac ultrasound;
  • B analysis results of LVPWs, LVPWd and EF values detected by cardiac ultrasound;
  • C mouse Whole heart weight analysis, heart weight to body weight/tibia length ratio analysis, left and right ventricular weight analysis. ***: p ⁇ 0.001; **: p ⁇ 0.01; *: p ⁇ 0.05; ns: no statistical difference;
  • Figure 5 shows HE staining and wheat germ agglutinin (WGA) staining of myocardial tissue sections.
  • A HE staining of heart tissue sections, representative images under light microscope at 400 times;
  • B WGA staining of heart tissue sections, representative images at 200 times and 400 times of light microscope;
  • C RT-PCR detection of myocardial hypertrophy markers Myh6 and Myh7 changes at the mRNA level.
  • Figure 6 shows the changes in the levels of markers P16, P21 and P53 of myocardial aging detected by RT-PCR and the level of cardiac inflammation in mice.
  • A RT-PCR to detect the changes in the levels of markers P16, P21 and P53 of myocardial aging;
  • B RT-PCR to detect the level of cardiac inflammation in mice.
  • the normal temperature in the following embodiments of the present invention refers to the natural room temperature conditions in the four seasons without additional cooling or heating treatment. Generally, the normal temperature is controlled at 10-30°C, preferably 15-25°C.
  • the invention discloses the application of CILP2 in the preparation of medicines for improving cardiac aging and cardiac hypertrophy.
  • the species, gender, size and source of the experimental animals involved in the present invention C57BL/6, male mouse, 8-week-old young wild-type mouse, and 22-month-old aged wild-type mouse.
  • the experimental mice were purchased from Beijing Huafukang Biotechnology Co., Ltd.
  • the present invention takes C57BL/6 as the experimental object, uses AAV9 virus to overexpress the CILP2 gene at the transcription level, and establishes a model of cardiac senescence and cardiac hypertrophy by rearing for 22 months.
  • Expression of CILP2 can significantly reduce the levels of cardiac aging indicators P16, P21 and P53 in aging mice, reduce the levels of myocardial inflammatory factors IL-1 ⁇ , IL-6 and TNF- ⁇ , and the expression level of myocardial hypertrophy marker Myh7 in aging mice. And increase the expression level of Myh6, the thickness of the posterior wall of the heart is reduced, the degree of fibrosis is weakened, and the cardiomyocytes are reduced.
  • CILP2 can regulate the occurrence of cardiac aging and cardiac hypertrophy, and has a protective effect on cardiac aging and cardiac hypertrophy. clinical basis. Therefore, in view of the above functions of CILP2, CILP2 can be used as a drug target to screen drugs for the treatment of cardiac aging and cardiac hypertrophy.
  • the numbers of CILP2 (human) involved in the present invention in the NCBI database gene ID is 148113, nucleotide sequence number NM_153221.2, protein sequence NP_694953.2.
  • mice used in the research were raised in the barrier environment of the Animal Experiment Center of the People's Hospital of Wuhan University, with constant temperature (20-26°C), constant humidity (40-70%), low noise ( ⁇ 60 decibels), and ventilation frequency of 15 times in the barrier. 12/12 hours light/dark cycle, 4 animals per cage were housed, and mice were fed ad libitum. Natural rearing to 22 months of age to build an aging model.
  • the pHBAAV-CMV-MCS-3flag-T2A-ZsGreen plasmid vector was used to construct a true CILP2C fragment (sequence shown in SEQ ID NO.21).
  • the nuclear expression plasmid was packaged as adeno-associated virus AAV9-CILP2, while the empty pHBAAV-CMV-MCS-3flag-T2A-ZsGreen plasmid was packaged as adeno-associated virus AAV9-Neg as a control.
  • mice were injected with AAV9 virus via tail vein when they were 16 months old: adenovirus AAV9-Neg in control group and adenovirus AAV9-CILP2 in CILP2 overexpression group, the dose of virus per mouse injection was 5.5 ⁇ 10 11 particles, as shown in Figure 2 .
  • RT-PCR Real-time PCR
  • RNA extraction Add 1 ml of Trizol solution to the collected cardiomyocytes, pipet repeatedly on ice until the cardiomyocytes are fully lysed, let stand for 5 minutes, add 0.2 ml of chloroform, shake vigorously for 15-30 seconds, let stand for 2-3 minutes, Centrifuge at 12000rpm x 15min at 4°C. Pipette the aqueous layer into a new EP tube, add 0.5ml of isopropanol, mix the liquid in the tube gently, let stand for 10 minutes at room temperature, and centrifuge at 12000rpm x 10min at 4°C.
  • RNA Discard the supernatant, add 1 ml of pre-cooled 75% ethanol to the pellet, resuspend the pellet and wash thoroughly, and centrifuge at 12000rpm x 5min at 4°C. The supernatant was discarded, air-dried, and an appropriate amount of DEPC water was added to solubilize the RNA at 65°C. Take 2ul RNA for agarose gel electrophoresis to check whether the RNA is extracted successfully, and store the remaining RNA at -80°C when not in use.
  • RT-PCR Real-time fluorescence quantitative PCR
  • RNA was extracted from the heart tissue of mice in each group, and cDNA was obtained after reverse transcription. The 2 method was used to specifically detect the mRNA expression level of CILP2 to verify whether CILP2 can be specifically up-regulated by AAV9-CILP2 virus.
  • the results are shown in Figure 3.
  • the transfection virus was identified at the transcriptional level.
  • the CILP2 mRNA level in cardiomyocytes in the CILP2 overexpression group was about 10 times higher than that in the control group.
  • the experiment was divided into three groups: 8-week-old young control group (Young control), aging control group (Old-AAV9-Neg), and aging CILP2 overexpression group (Old-AAV9-CILP2).
  • Young control 8-week-old young control group
  • Old-AAV9-Neg aging control group
  • Old-AAV9-CILP2 aging CILP2 overexpression group
  • HE staining method paraffin section I xylene for 2-5 minutes, II xylene for 2-5 minutes, 100% ethanol for 1 min, 95% ethanol for 1 min, 80% ethanol for 1 min, 70% ethanol for 1 min, first wash with tap water and then distilled water for 0.5 min, Harris' hematoxylin liquid 5min. Hematoxylin is a basic dye that can stain cell nuclei.
  • 1% acidic alcohol a mixture of 1 mL of HCl and 99 mL of 70% alcohol
  • the carbolic acid was washed with I xylene for 1 min and made it more transparent. After passing through II xylene for 1 min, the sections were taken out from the xylene, and the xylene other than the sections was wiped off with dry gauze. Results: The nucleus was blue-purple and the cytoplasm was red.
  • Dewaxing the paraffin sections to water Place the sections in xylene I for 15 min, xylene II for 15 min, anhydrous ethanol I for 5 min, anhydrous ethanol II for 5 min, 85% alcohol for 5 min, 75% alcohol for 5 min, and distilled water for washing.
  • DAPI counterstained cell nuclei the slides were placed in PBS (PH7.4) and washed 3 times with shaking on a destaining shaker, 5 min each time. After the sections were slightly dried, DAPI staining solution was added dropwise to the circle, and incubated at room temperature for 10 min in the dark.
  • Cover slides The slides were placed in PBS (PH7.4) and washed three times with shaking on a destaining shaker, 5 min each time. After drying, the sections were mounted with anti-fluorescence quenching mounting medium.
  • Wheat germ agglutinin can specifically bind to the myocardial cell membrane.
  • the combination of the two can stain the myocardial cell membrane, and observe the stained cells in the myocardium through a microscope, so as to measure the diameter and area, and analyze whether the myocardial cells are hypertrophic.
  • FIG. 5B cardiomyocytes in aging mice were significantly enlarged, and overexpression of CILP2 could significantly reduce the size of cardiomyocytes.
  • the total RNA was extracted from the heart tissues of mice in each group, and the mRNA expression levels of Myh6 and Myh7, the indicators of cardiac hypertrophy, were detected by the method of 2.
  • mice were sacrificed by cervical dislocation, the hearts were taken out and washed with PBS. After the whole body was weighed, the left and right ventricles were separated and weighed separately. The weight of the mouse heart was detected, as shown in Figure 4C, after the intervention of the expression level of CILP2, the weight of the left and right ventricles of the heart was reduced.
  • Total RNA was extracted from the heart tissue of mice in each group, and the mRNA expression levels of aging-related factors P16, P21, and P53, and the mRNA expression levels of inflammatory factors IL-1 ⁇ , IL-6, and TNF- ⁇ were detected by two methods.
  • P16, P21 and P53 are indicators of cardiac aging, and the expression levels of these three genes in the myocardium increase with age, and the expression levels of P16, P21 and P53 in the myocardium are reversed after up-regulation of CILP2 expression.
  • chronic inflammation is a feature and pathogenic factor of aging
  • the expression levels of inflammatory factors IL-1 ⁇ , IL-6 and TNF- ⁇ in the myocardium of three groups of mice were also detected in this application, and it was found that inflammatory factors in aging mice were The level of inflammatory factors in the myocardium was down-regulated after up-regulation of CILP2 expression.
  • up-regulation of CILP2 expression may improve cardiac aging.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne l'utilisation de CILP2 dans la préparation d'un médicament destiné à amoindrir le vieillissement cardiaque et l'hypertrophie myocardique. Des souris sont utilisées en tant que sujets expérimentaux, un virus AAV9 est utilisé pour la surexpression du niveau de transcription du gène CILP2, et l'étude comparative est réalisée par l'établissement d'un modèle de vieillissement cardiaque et d'hypertrophie myocardique. Les résultats montrent que, par comparaison à un groupe témoin de type sauvage de vieillissement, la surexpression de CILP2 peut de toute évidence réduire le niveau d'indice de vieillissement cardiaque des souris vieillissantes, réduire le taux d'indice de facteurs de myocardite de souris vieillissantes, augmenter le niveau d'expression de marqueurs d'hypertrophie myocardique, réduire l'épaisseur de la paroi postérieure du cœur, réduire le degré de fibrose et réduire les cellules myocardiques. Les résultats prouvent que le niveau d'expression de CILP2 peut réguler et lutter contre l'apparition du vieillissement cardiaque et de l'hypertrophie myocardique, a un effet protecteur contre le vieillissement cardiaque et l'hypertrophie myocardique, et peut fournir une base théorique et une base clinique pour la recherche de nouvelles cibles et de nouvelles stratégies pour prévenir et traiter le vieillissement cardiaque et l'hypertrophie myocardique.
PCT/CN2021/099281 2020-08-14 2021-06-10 Utilisation de cilp2 dans la préparation d'un médicament destiné à amoindrir le vieillissement cardiaque et l'hypertrophie myocardique WO2022033152A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010819200.5A CN111840514B (zh) 2020-08-14 2020-08-14 Cilp2在制备改善心脏衰老和心肌肥厚的药物中的应用
CN202010819200.5 2020-08-14

Publications (1)

Publication Number Publication Date
WO2022033152A1 true WO2022033152A1 (fr) 2022-02-17

Family

ID=72970106

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/099281 WO2022033152A1 (fr) 2020-08-14 2021-06-10 Utilisation de cilp2 dans la préparation d'un médicament destiné à amoindrir le vieillissement cardiaque et l'hypertrophie myocardique

Country Status (2)

Country Link
CN (1) CN111840514B (fr)
WO (1) WO2022033152A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117054652A (zh) * 2023-08-04 2023-11-14 南京医科大学 一种用于辅助检测心肌肥厚的生物标志物及其应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111840514B (zh) * 2020-08-14 2021-07-30 武汉大学 Cilp2在制备改善心脏衰老和心肌肥厚的药物中的应用
CN113577285B (zh) * 2021-07-30 2022-09-06 中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院) Slc25a26在制备抑制心肌肥厚的药物中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070446A1 (fr) * 2004-01-15 2005-08-04 Scios Inc. Procede de remodelage cardiaque suite a une lesion myocardique
CN101680902A (zh) * 2007-03-27 2010-03-24 安娜玛医药有限公司 软骨中间层蛋白2c1及其区分骨关节炎与类风湿性关节炎及非疾病状态的用途
CN105209607A (zh) * 2013-04-05 2015-12-30 大学健康网络 产生软骨细胞谱系细胞和/或类软骨组织的方法和组合物
CN111840514A (zh) * 2020-08-14 2020-10-30 武汉大学 Cilp2在制备改善心脏衰老和心肌肥厚的药物中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108904782A (zh) * 2018-07-10 2018-11-30 中国人民解放军第四军医大学 Ctrp3用于制备预防治疗心肌肥厚药物的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070446A1 (fr) * 2004-01-15 2005-08-04 Scios Inc. Procede de remodelage cardiaque suite a une lesion myocardique
CN101680902A (zh) * 2007-03-27 2010-03-24 安娜玛医药有限公司 软骨中间层蛋白2c1及其区分骨关节炎与类风湿性关节炎及非疾病状态的用途
CN105209607A (zh) * 2013-04-05 2015-12-30 大学健康网络 产生软骨细胞谱系细胞和/或类软骨组织的方法和组合物
CN111840514A (zh) * 2020-08-14 2020-10-30 武汉大学 Cilp2在制备改善心脏衰老和心肌肥厚的药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HIROSE J., I MASUDA, L M RYAN: "EXPRESSION OF CARTILAGE INTERMEDIATE LAYER PROTEIN/NUCLEOTIDE PYROPHOSPHOHYDROLASE PARALLELS THE PRODUCTION OF EXTRACELLULAR INORGANIC PYROPHOSPHATE IN RESPONSE TO GROWTH FACTORS AND WITH AGING", ARTHRITIS & RHEUMATISM, vol. 43, no. 12, 31 December 2000 (2000-12-31), pages 2703 - 2711, XP055900343, DOI: 10.1002/1529-0131(200012)43:12<2703::AID-ANR10>3.0.CO;2-Y *
JEEMON PANNIYAMMAKAL, PETTIGREW KERRY, SAINSBURY CHRISTOPHER, PRABHAKARAN DORAIRAJ, PADMANABHAN SANDOSH, JEEMON P, PETTIGREW K, SA: "Implications of discoveries from genome-wide association studies in current cardiovascular practice", WORLD JOURNAL OF CARDIOLOGY, vol. 3, no. 7, 26 July 2011 (2011-07-26), pages 230, XP055900340, ISSN: 1949-8462, DOI: 10.4330/wjc.v3.i7.230 *
LIU DAWEI: "Changes of Plasma CILP2and the Correlations in the Coronary Heart Disease", CHINESE MASTER’S THESES FULL-TEXT DATABASE, MEDICINE & HEALTH SCIENCES, 15 March 2014 (2014-03-15), XP055900346 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117054652A (zh) * 2023-08-04 2023-11-14 南京医科大学 一种用于辅助检测心肌肥厚的生物标志物及其应用
CN117054652B (zh) * 2023-08-04 2024-05-17 南京医科大学 一种用于辅助检测心肌肥厚的生物标志物及其应用

Also Published As

Publication number Publication date
CN111840514A (zh) 2020-10-30
CN111840514B (zh) 2021-07-30

Similar Documents

Publication Publication Date Title
WO2022033152A1 (fr) Utilisation de cilp2 dans la préparation d&#39;un médicament destiné à amoindrir le vieillissement cardiaque et l&#39;hypertrophie myocardique
Ji et al. MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca2+–Dependent Antioxidant Response
Wang et al. Sirt3 modulate renal ischemia‐reperfusion injury through enhancing mitochondrial fusion and activating the ERK‐OPA1 signaling pathway
Gao et al. Hyaluronan oligosaccharides promote excisional wound healing through enhanced angiogenesis
Conlon et al. Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa
Xie et al. Suppression of microRNA-135b-5p protects against myocardial ischemia/reperfusion injury by activating JAK2/STAT3 signaling pathway in mice during sevoflurane anesthesia
Chen et al. Knockdown of circROBO2 attenuates acute myocardial infarction through regulating the miR-1184/TRADD axis
WO2016197592A1 (fr) Utilisation d&#39;un arn long non codant, hnf1a-as1, dans la préparation d&#39;un médicament destiné au traitement d&#39;une tumeur solide maligne humaine
Liu et al. Deletion of diacylglycerol-responsive TRPC genes attenuates diabetic nephropathy by inhibiting activation of the TGFβ1 signaling pathway
Tan et al. RETRACTED: Sevoflurane up-regulates microRNA-204 to ameliorate myocardial ischemia/reperfusion injury in mice by suppressing Cotl1
Zhou et al. Silencing of GAS5 alleviates glaucoma in rat models by reducing retinal ganglion cell apoptosis
Wang et al. Dysregulation of miR-342-3p in plasma exosomes derived from convalescent AMI patients and its consequences on cardiac repair
WO2021244010A1 (fr) Utilisation d&#39;une protéine de liaison à facteur de choc thermique 2 pour des atteintes hépatiques d&#39;ischémie-reperfusion et des atteintes hépatiques médicamenteuses
Tan et al. C3 transferase-expressing scAAV2 transduces ocular anterior segment tissues and lowers intraocular pressure in mouse and monkey
Leng et al. Long-term correction of copper metabolism in Wilson's disease mice with AAV8 vector delivering truncated ATP7B
CN112138159B (zh) 乳酸脱氢酶在组织炎症和纤维化治疗中的应用
Zhang et al. The effects of extracellular vesicles derived from Krüppel-Like Factor 2 overexpressing endothelial cells on the regulation of cardiac inflammation in the dilated cardiomyopathy
Li et al. Mechanism of N-acetylcysteine in alleviating diabetic myocardial ischemia reperfusion injury by regulating PTEN/Akt pathway through promoting DJ-1
Wu et al. A microfibril-associated glycoprotein 4 (MFAP4) from Nile tilapia (Oreochromis niloticus) possesses agglutination and opsonization ability to bacterial pathogens
CN104056282A (zh) Mindin基因在肝脏缺血再灌注损伤中的应用
Wang et al. Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway
Luo et al. Inhibition of miR-423-5p exerts neuroprotective effects in an experimental rat model of cerebral ischemia/reperfusion injury
JP6461810B2 (ja) Ｂｐｉｆｂ４タンパク質の変異体
Peng et al. Protective effects of neural crest-derived stem cell-conditioned media against ischemia-reperfusion-induced lung injury in rats
Huang et al. Optimization of strategy for modified mRNA inducing cardiac-specific expression in mice

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21855208

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21855208

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 03.08.2023)

122 Ep: pct application non-entry in european phase

Ref document number: 21855208

Country of ref document: EP

Kind code of ref document: A1