CN117030990A - Application of 4-HNE scavenger in preparation of medicines for treating vascular calcification - Google Patents

Application of 4-HNE scavenger in preparation of medicines for treating vascular calcification Download PDF

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Publication number
CN117030990A
CN117030990A CN202310314550.XA CN202310314550A CN117030990A CN 117030990 A CN117030990 A CN 117030990A CN 202310314550 A CN202310314550 A CN 202310314550A CN 117030990 A CN117030990 A CN 117030990A
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China
Prior art keywords
hne
vascular calcification
scavenger
calcification
medicament
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CN202310314550.XA
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Chinese (zh)
Inventor
曹盛川
翟小轩
魏述建
袁秋环
边圆
李传保
陈玉国
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Qilu Hospital of Shandong University
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Qilu Hospital of Shandong University
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Abstract

The invention belongs to the field of biological medicine, and in particular relates to application of a 4-HNE scavenger in screening or preparing a medicament for preventing, relieving and/or treating vascular calcification. The invention provides a pharmaceutical application of a 4-HNE scavenger and a medicament for preventing, relieving and/or treating vascular calcification, wherein the active ingredients of the medicament comprise the 4-HNE scavenger; in the present invention we examined the level of 4-HNE during vascular calcification in human specimens and in mouse models and studied the effect of 4-HNE on VSMC osteochondral differentiation in vitro. We have found that 4-HNE promotes vascular calcification, promotes osteochondral differentiation of VSMC, and has potential vascular calcification treatment activity on the scavenging/metabolizing species of 4-HNE.

Description

Application of 4-HNE scavenger in preparation of medicines for treating vascular calcification
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to an application of a 4-HNE scavenger in preparing a medicament for treating vascular calcification.
Background
Vascular calcification refers to the pathological process of hydroxyapatite mineral deposition in the vascular system, commonly found in aging, atherosclerosis, diabetes and chronic kidney disease.
Vascular calcification is an active, cell-regulated osteoid process in which Vascular Smooth Muscle Cells (VSMCs) play a critical role. Long-term exposure of VSMCs to high levels of mineral ions can result in bone/cartilage-like cell differentiation, i.e., reduction of the contraction markers α smooth muscle actin and smooth muscle 22 α and increased expression of the osteogenic markers rut-related transcription factor 2, sarcomere homolog 2, osteopontin, etc., which are central links to the occurrence of vascular calcification.
At present, no medicine is available for inhibiting the osteogenic differentiation of VSMCs and delaying vascular calcification, so that a need exists for further intensive research on vascular calcification generation mechanisms and effective targets in the progress process.
Disclosure of Invention
The invention provides a pharmaceutical application of 4-hydroxynonenal (4-HNE) scavenger in preparation of a medicament for treating vascular calcification, in the invention, the level of 4-HNE in the vascular calcification process of a human specimen and a mouse model is detected, and the influence of 4-HNE on VSMC osteochondral differentiation is studied in vitro. We have found that 4-HNE promotes vascular calcification, promotes osteochondral differentiation of VSMC, and has potential vascular calcification treatment activity on scavenging agents of 4-HNE.
Specifically, the technical scheme of the invention is as follows:
use of a 4-HNE scavenger for screening or preparing a medicament for preventing, alleviating and/or treating vascular calcification.
Further, the 4-HNE scavenger includes agents that react with 4-HNE, including physical and chemical reactions, including, but not limited to, decomposition/enzymatic hydrolysis of 4-HNE, promotion of 4-HNE metabolism, binding to 4-HNE to reduce its activity, any pharmaceutical method of shielding the effect of 4-HNE.
Further, the 4-HNE scavengers include, but are not limited to, acetaldehyde dehydrogenase 2.
The 4-HNE scavenger is one or more selected from protein, polypeptide, enzyme, natural compound, synthetic compound, organic matter and inorganic matter for scavenging 4-HNE. Gene tools that overexpress 4-HNE scavengers by gene editing to exert 4-HNE scavenging effects are also within the 4-HNE scavenger selections of the present invention.
Further, vascular calcification as used herein refers to the common pathological manifestations of atherosclerosis, hypertension, diabetes, vascular lesions, chronic kidney disease and aging. The treatment diseases of the medicament for treating vascular calcification include, but are not limited to vascular calcification related diseases such as vascular calcification induced by Vit D3, renal insufficiency, arterial vascular calcification (cerebral vessels, cardiovascular vessels and the like), venous vascular calcification and the like.
The invention also provides a medicament for preventing, alleviating and/or treating vascular calcification, comprising a pharmaceutically acceptable carrier and an effective amount of an active ingredient, said active ingredient comprising a 4-HNE scavenger.
As used herein, a "pharmaceutically acceptable carrier" includes any and all physiologically acceptable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic or absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol or ethanol, and the like, and combinations thereof. In many cases, it is desirable to include an isotonic agent, for example, one or more of a sugar, a polyalcohol such as mannitol, sorbitol, or sodium chloride, and the like in the composition. The pharmaceutically acceptable carrier may also contain minor amounts of auxiliary substances, such as one or more of wetting or emulsifying agents, preserving or buffering agents, and the like, which enhance the present invention for the preparation of a medicament for the treatment of vascular calcification.
The invention also provides a method for screening medicaments for treating vascular calcification by detecting the content of 4-HNE in a subject before and after administration, wherein the reduction of the content of 4-HNE after administration is indicated as a candidate medicament.
The medicaments of the invention may be administered to other animals, human or non-human.
The invention has the beneficial effects that:
the invention discovers for the first time that 4-HNE can promote the transformation of vascular smooth muscle cells into an osteogenic phenotype, 4-HNE is a potential choice for treating vascular calcification, and the medicament prepared from the 4-HNE scavenger has good therapeutic activity on vascular calcification; the invention provides a new molecular mechanism for vascular calcification research and provides a potential new target for clinical prevention and treatment of vascular calcification.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a graph showing that 4-HNE promotes the phenotypic conversion of primary vascular smooth muscle cells in mice. (a-G) 4-HNE time gradient SM22- α, α -SMA, BMP2, MSX2, OPN and RUNX2 protein expression levels and statistical analysis (n=5) after stimulation of mouse primary vascular smooth muscle cells. (H-N) 4-HNE concentration gradient SM22- α, α -SMA, BMP2, MSX2, OPN and RUNX2 protein expression levels and statistical analysis (n=5) after stimulation of mouse primary vascular smooth muscle cells. (O) control group or beta-GP joint CaCl 2 Induction of primary vascular smooth muscle cells in mice Alizan red and Von kossa staining following 4-HNE stimulation. (P-V) 4-HNE stimulated mice primary vascular smooth muscle cells or SM22- α, α -SMA, BMP2, MSX2, OPN and RUNX2 protein expression levels following Alda-1 treatment and statistical analysis (n=5). Data are expressed in Mean ± standard error (Mean ± SEM). * P (P)<0.05，**P<0.01，***P<0.001，****P<0.0001。
FIG. 2 is a graph showing that 4-HNE promotes the phenotypic conversion of human primary vascular smooth muscle cells. (a-G) 4-HNE time gradient SM22- α, α -SMA, BMP2, MSX2, OPN and RUNX2 protein expression levels after stimulation of human primary vascular smooth muscle cells and statistical analysis (n=5). (H-N) 4-HNE concentration gradient SM22- α, α -SM a, BMP2, MSX2, OPN and RUNX2 protein expression levels and statistical analysis (n=5) after stimulation of human primary vascular smooth muscle cells. (O) control group or beta-GP joint CaCl 2 Induction of human primary vascular smooth muscle cells Alizan red and Von kossa staining following 4-HNE stimulation. (P-V)4-HNE stimulated human primary vascular smooth muscle cells or SM22- α, α -SMA, BMP2, MSX2, OPN and RUNX2 protein expression levels following Alda-1 treatment and statistical analysis (n=5). Data are expressed in Mean ± standard error (Mean ± SEM). * P (P)<0.05，**P<0.01，***P<0.001，****P<0.0001。
FIG. 3 shows immunohistochemical staining and statistical analysis of (D-E) WT and ALDH2-KO mice and aortic tissue (n=10) 4-HNE induced by 5/6 kidney-section combined with high-phosphorus diet, scale=50. Mu.m. Data are expressed in Mean ± standard error (Mean ± SEM). * P <0.05, P <0.0001.
FIG. 4 shows immunohistochemical staining and statistical analysis of (D-E) WT and ALDH2-KO mice and Vit D3 induced aortic tissue (n=10) 4-HNE, scale=50. Mu.m. Data are expressed in Mean ± standard error (Mean ± SEM). * P <0.05, P <0.0001.
Detailed Description
The invention is described below by means of specific embodiments. The technical means used in the present invention are methods well known to those skilled in the art unless specifically stated. Further, the embodiments should be construed as illustrative, and not limiting the scope of the invention, which is defined solely by the claims. Various changes or modifications to the materials ingredients and amounts used in these embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
The invention discovers that 4-HNE promotes the osteogenic transformation of VSMCs, thereby promoting vascular calcification; the 4-HNE scavenger can be used for improving vascular calcification by metabolizing/scavenging 4-HNE. The deep research on the molecular mechanism of vascular calcification provides a potential new target for clinical prevention and treatment of vascular calcification.
Example 1
This example demonstrates that 4-HNE promotes osteogenic differentiation of VSMCs.
Research method
1. Culture and experiment of vascular smooth muscle cells
1.1 extraction of primary mouse vascular smooth muscle cells (mVSMCs):
mice were dislocation killed, and soaked in 75% alcohol for 5min; the mice were removed and the limbs were fixed. Skin and subcutaneous tissue were cut from the lower abdomen to the heart, the right auricle was cut, and a 5mL hollow needle (containing 5mL PBS) was inserted into the left ventricle to flush the intravascular blood. The chest is cut off continuously to the vicinity of the collarbone, the lung is removed, the two ribs are fixed by the needle head, the visual field is as wide as possible, and the aortic separation is not affected. Thoracic aortic dissection: shearing off the thoracic aorta along the shape-moving direction of the thoracic aorta by using an ophthalmic scissors; the sheared thoracic aorta was placed under a microscope, and after the connective tissue around the thoracic aorta was cleaned with a microtome, it was placed in a 1.5ml EP tube and sheared with a microtome. The tissue suspension was removed to 25cm 2 The culture flask is evenly coated at the bottom of the culture flask, placed in an incubator, placed vertically for 30min, inverted for 1h, and then added with culture medium for culturing in a slowly and vertically placed manner. And (3) after the VSMCs climb out from the tissue fragments and proliferate to a proper density for passaging, after pancreatin digestion and serum neutralization, filtering out the tissue fragments by using a filter screen with a pore diameter of 100uM, centrifuging at 800rpm for 5min, collecting cell sediment, and carrying out cell passaging after resuspension.
1.2 calcification induction of vascular smooth muscle cells:
preparing a calcification medium: the DMEM medium contains 10% fetal bovine serum, 1% penicillin, 10mM beta-glycerophosphate, 1.5mM CaCl 2 The method comprises the steps of carrying out a first treatment on the surface of the VSMCs were cultured with calcified medium, and the medium was changed once every other day, and the culture was continued for 14 days to obtain a model.
2. Alizarin red and Von kossa staining
Incubating dewaxed aortic tissue sections or vascular smooth muscle cells fixed in 4% formaldehyde at room temperature in 2% alizarin red for 10min, flushing with double distilled water, and making positive cells red/purple; or incubating in Von Kossa dye solution (silver nitrate solution), and irradiating under ultraviolet for 30min, washing with double distilled water, and staining calcified nodule to brown to black.
Western blot experiment
The tissue or cell lysed by sonication or milling is placed in RIPA lysate for 30min, BCA protein quantification is performed, and SDS-PAGE gel electrophoresis is performed. After membrane transfer and sealing, adding a corresponding primary antibody, incubating overnight at 4 ℃, washing a membrane by TBST, adding a fluorescent-labeled secondary antibody, incubating for 2 hours at room temperature, and quantitatively analyzing a Western blot result by using an Image J.
4. Immunohistological staining
(1) Fluorescent staining of immune tissue: lung tissue sections were repaired by dewaxed hydration antigen, primary antibody incubated overnight at 4 ℃, fluorescence-labeled secondary antibody incubated, DAPI stained nuclei, blocked with blocking agent, observed under a fluorescence microscope and photographed, and data analyzed using Image-Pro Plus software.
(2) Immunohistochemical staining: lung tissue sections were repaired by dewaxed hydrated antigen, incubated at 4 ℃ overnight, incubated with biotin-labeled IgG, incubated with SABC, DAB developed and hematoxylin counterstained under a microscope, and then blocked, and the data were analyzed using Image-Pro Plus software.
5. Co-immunoprecipitation
The presence or absence of binding between proteins was detected by co-immunoprecipitation. After extracting the protein, the protein is incubated with the primary antibody and the magnetic beads in sequence. After the incubation is finished, centrifuging, discarding the supernatant, adding diluted protein loading buffer solution, and performing SDS-PAGE gel electrophoresis after protein boiling.
Results of the study
Sequencing results suggested that 4-HNE was able to promote vascular smooth muscle cell phenotype transformation, to further verify whether 4-HNE promoted vascular smooth muscle cell osteogenic differentiation, mVSMC 4-HNE was given time (0, 1, 3, 6, 12 h) and concentration (0, 1, 5, 10 μm) gradient stimulation. Western Blot analysis showed that SM22- α and α -SMA protein expression was significantly reduced in mVSMC, while BMP2, MSX2, OPN, and RUNX2 protein expression was significantly increased with increasing 4-HNE stimulation time, with the most significant change in 4-HNE stimulation for 12h (FIGS. 1A-G); with increasing 4-HNE stimulation concentration, SM22- α and α -SMA protein expression was significantly reduced in mvscs, while BMP2, MSX2, OPN, and RUNX2 protein expression was significantly increased, with the 4-HNE concentration being the most significant 10 μm change (fig. 1H-N). Alizan red and Von kossa staining results show that beta-GP is combined with CaCl 2 Can cause significant increase of mVSMC calcification, while 4-HNE stimulation can further aggravate beta-GP combined CaCl 2 Induced vascular smooth muscle cell calcification (fig. 1O). Alda-1 is administered to activate ALDH2 and then 4-HNE is used for puncturingResults of the excitation mVSMC and Western Blot analysis showed that Alda-1 was able to alleviate the decrease in SM22- α and α -SMA protein expression and the increase in BMP2, MSX2, OPN and RUNX2 protein expression in mVSMC caused by 4-HNE stimulation (FIG. 1P-V).
Example 2
This example demonstrates that 4-HNE promotes vascular smooth muscle cell osteogenic transformation in a time and concentration gradient dependent manner to promote vascular smooth muscle cell calcification.
The results of this experiment were as follows, following the study procedure of example 1:
hVSMC 4-HNE was given time (0, 1, 3, 6, 12 h) and concentration (0, 1, 5, 10. Mu.M) gradient stimulation. Western Blot analysis showed that SM22- α and α -SMA protein expression was significantly reduced in hVSMC, while BMP2, MSX2, OPN, and RUNX2 protein expression was significantly increased with increasing 4-HNE stimulation time, with the most significant change in 4-HNE stimulation for 12h (FIGS. 2A-G); with increasing 4-HNE stimulation concentration, SM22- α and α -SMA protein expression was significantly reduced in hVSMC, while BMP2, MSX2, OPN and RUNX2 protein expression was significantly increased, with the 4-HNE concentration being the most significant 10 μm change (fig. 2H-N). Alizan red and Von kossa staining results show that beta-GP is combined with CaCl 2 Can cause significant increase of hVSMC calcification, and 4-HNE stimulation can further aggravate beta-GP combined CaCl 2 Induced vascular smooth muscle cell calcification (fig. 2O).
The above results demonstrate that 4-HNE promotes vascular smooth muscle cell osteogenic transformation in a time and concentration gradient dependent manner to promote vascular smooth muscle cell calcification.
Example 3
This example demonstrates the therapeutic effect of clearing 4-HNE on renal insufficiency vascular calcification.
Acetaldehyde dehydrogenase 2 (ALDH 2) is an aldehyde substance metabolizing enzyme, is a key enzyme for alcohol metabolism, and can metabolize 4-HNE, and an ALDH2 knockout (ALDH 2-KO) mouse is constructed in this example.
A model of chronic renal insufficiency vascular calcification mice was constructed by combining 5/6 nephrotomy with a high-phosphorus diet using ALDH2-KO mice. Male ALDH2-KO mice of 6-7 weeks of age were divided into four groups: WT group, KO group, 5/6 kidney cut + high phosphorus diet (NR) group and KO + NR group. Wherein the operation group is fasted 24 hours before operation and normally drinks water. The left kidney superior and inferior poles were excised after inhalation of sevoflurane for anesthesia. After one week, the right kidney was completely resected. Sham mice received the same procedure at the same time as 5/6 nephrectomy mice, but only after kidney exposure, the kidney capsule was stripped off and the abdomen was closed. To accelerate the process of aortic calcification, animals were fed a high phosphate diet (0.9% Pi) one week after completion of the kidney 5/6 excision procedure during the study, and the control group was fed a normal diet. Drawing materials after 12 weeks. The aortic tissue of the mice was subjected to 4-HNE immunohistochemical staining.
Immunohistochemistry showed an increase in the 4-HNE immunohistochemical staining positive area of the calcified nodule portion of the NR group compared to the WT group; the ko+nr group 4-HNE immunohistochemical staining positive areas were significantly increased compared to the NR group, whereas no 4-HNE staining positive areas were evident in the aortic tissues of WT and KO groups mice (P <0.05, fig. 3D-E).
This suggests that ALDH2 acts as a 4-HNE scavenger, which reduces toxicity after 4-HNE metabolism and alleviates vascular calcification after 4-HNE removal.
Example 4
This example demonstrates the therapeutic effect of clearing 4-HNE on Vit D3-induced vascular calcification.
Research method
1. Constructing an ALDH2-Tg (over-expressed ALDH 2) mouse;
2. construction of vitamin (Vit) D3-induced vascular calcified mice:
male mice of about 6 weeks old are selected, and the calcified model group is subcutaneously injected with the Vit D3 injection (50 ten thousand units/Kg.day) for 3 days, and the control group is subcutaneously injected with the same amount of control solvent for 3 days. All mice were harvested 6 days after subcutaneous intervention.
Male mice of 6 weeks of age were divided into four groups: WT group, ALDH2-Tg (Tg) group, vit D3 (VD) group, and tg+vd group. The aortic tissue of the mice was subjected to 4-HNE immunohistochemical staining.
Results of the study
Immunohistochemistry showed that the VD group calcified nodule portion 4-HNE immunohistochemical staining positive area was increased compared to WT group; the tg+vd group 4-HNE immunohistochemical staining positive areas were significantly reduced compared to the VD group, whereas no 4-HNE staining positive areas were evident in the WT and Tg group mouse aortic tissues (P <0.05, fig. 4D-E).

Claims (5)

  1. Use of a 4-HNE scavenger for screening or preparing a medicament for preventing, alleviating and/or treating vascular calcification.
  2. 2. A medicament for preventing, alleviating and/or treating vascular calcification comprising a pharmaceutically acceptable carrier and an effective amount of an active ingredient, said active ingredient comprising a 4-HNE scavenger.
  3. 3. The use according to claim 1, wherein the 4-HNE scavenger comprises an agent that reacts with 4-HNE or promotes metabolism/breakdown of 4-HNE or that binds 4-HNE to deactivate it.
  4. 4. A method of screening for a drug for treating vascular calcification, wherein a decrease in 4-HNE content after administration is indicated as a candidate drug by detecting the 4-HNE content of the subject before and after administration.
  5. 5. The use of claim 3, wherein the 4-HNE scavenger comprises a gene tool that effects 4-HNE clearance by over-expression of the 4-HNE scavenger by gene editing.
CN202310314550.XA 2023-03-28 2023-03-28 Application of 4-HNE scavenger in preparation of medicines for treating vascular calcification Pending CN117030990A (en)

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