CN112915194B - Application of Tff1 in vascular diseases - Google Patents
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- CN112915194B CN112915194B CN202110174037.6A CN202110174037A CN112915194B CN 112915194 B CN112915194 B CN 112915194B CN 202110174037 A CN202110174037 A CN 202110174037A CN 112915194 B CN112915194 B CN 112915194B
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Abstract
The invention belongs to the technical field of Tff1 research, and particularly discloses application of Tff1 in vascular diseases. Tff1 is applied to the preparation of drugs for preventing and treating vascular related diseases. The medicine for preventing and treating relevant vascular diseases comprises an effective component Tff 1. Use of Tff1 as an inhibitor of vascular smooth muscle cell apoptosis. An inhibitor of vascular smooth muscle apoptosis, comprising an effective ingredient of Tff 1. A vascular spandex degradation inhibitor comprises an effective component Tff 1. The invention enables the trefoil factor 1 to have a new application approach; provides a new medicine for preventing and treating vascular diseases; trefoil factor 1 plays a key role in inhibiting vascular smooth muscle cell apoptosis and inhibiting vascular elastic fiber degradation.
Description
Technical Field
The invention belongs to the technical field of Tff1 research, and particularly relates to application of Tff1 in vascular diseases.
Background
Trefoil factor 1(Tff1) is a small secreted protein belonging to the trefoil factor protein family, mainly found in the gastrointestinal tract, with highest levels in the upper gastric mucosal cells. Expression was strong in breast cancer, but low in normal breast tissue. It is regulated by estrogen in MCF-7 cells. Strong expression was found in the normal gastric mucosa and regenerated tissue around the foci of gastrointestinal ulcers, but lower expression was found in gastric cancer (protein level).
Hemangioma is a relatively common vascular disease, is mostly congenital, and is usually present at birth. The reason is complex, no accurate statement exists at present, and the incidence rate of the infantile hemangioma is higher and higher in recent years, so that the infant hemangioma has attracted wide attention of numerous scholars and society.
At present, the trefoil factor 1 has reports about enhancing the treatment effect of certain types of intestinal diseases in the prior art, but the trefoil factor 1 has no literature report in the treatment of vascular-related diseases.
Disclosure of Invention
In order to solve the problems, the invention provides a new application way of Tff1, and also provides a new therapeutic drug for vascular diseases.
In order to solve the problems, the invention adopts the following technical scheme:
tff1 is applied to the preparation of drugs for preventing and treating vascular related diseases.
In some cases, the vascular-related disease is hemangioma.
In some cases, the vascular-related disease is an aortic aneurysm.
In some cases, the vascular-related disease is an abdominal aortic aneurysm.
In some cases, the use of said Tff1 as an inhibitor of vascular smooth muscle cell apoptosis and/or an inhibitor of vascular spandex degradation in the manufacture of a medicament for the treatment of a vascular-related disease.
The medicine for preventing and treating relevant vascular diseases comprises an effective component Tff 1.
In some cases, the Tff1 is an inhibitor of vascular smooth muscle apoptosis.
Use of Tff1 as an inhibitor of vascular smooth muscle cell apoptosis.
An inhibitor of vascular smooth muscle apoptosis, comprising an effective ingredient of Tff 1.
A vascular spandex degradation inhibitor comprises an effective component Tff 1.
The beneficial effects of the invention are:
the trefoil factor 1 has a new application approach; provides a new medicine for preventing and treating vascular diseases; trefoil factor 1 plays a key role in inhibiting vascular smooth muscle cell apoptosis and inhibiting vascular elastic fiber degradation.
Drawings
FIG. 1 is a summary of the results of example 1;
FIG. 2 is a summary of the results of example 2;
FIG. 3 is an overview of the results of example 3;
FIG. 4 is a summary of the results of example 4.
Detailed description of the preferred embodiments
The invention is further illustrated by the following examples:
tff1 is applied to the preparation of drugs for preventing and treating vascular related diseases.
The vascular-related disease is hemangioma.
The vascular-related disease is aortic aneurysm.
The vascular-related disease is abdominal aortic aneurysm.
The Tff1 is applied to preparing a medicament for treating vascular related diseases as an inhibitor of vascular smooth muscle cell apoptosis and/or an inhibitor of vascular elastic fiber degradation.
The medicine for preventing and treating relevant vascular diseases comprises an effective component Tff 1.
The Tff1 is an inhibitor of vascular smooth muscle cell apoptosis.
Use of Tff1 as an inhibitor of vascular smooth muscle cell apoptosis.
An inhibitor of vascular smooth muscle apoptosis, comprising an effective ingredient of Tff 1.
A vascular spandex degradation inhibitor comprises an effective component Tff 1.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and the disclosures and references cited herein and the materials to which they refer are incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein.
Example 1
1. Establishing an abdominal aortic aneurysm model induced by elastase
Male C57BL/6 or DERG mice 8-12 weeks old, anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50mg/kg), mounted dorsad down on mouse plates, and started to model under a stereomicroscope: cutting skin and subcutaneous fascia from the middle of the abdominal albany with ophthalmologic scissors to form a longitudinal incision of about 1.5cm, exposing abdominal viscera, pushing intestinal canal to both sides with a small cotton swab to fully expose abdominal aorta and inferior vena cava, carefully separating abdominal aorta with micro forceps and suture needle, uniformly covering the abdominal aorta wall with cotton cloth soaked with porcine trypsin for 40min, discarding the cotton cloth, flushing abdominal cavity with normal saline for 2 times, and finally suturing the incision to close the abdominal cavity.
2. Experiment grouping
(1) WT + DT group: c57BL/6 mice, establishing an AAA model induced by elastase, giving 1 mu g DT intervention on-2/-1/7/8 days, and taking materials after 14 days;
(2) DEREG + DT + control virus group: DeREG mice, establishing elastase-induced AAA model, administering 1 μ g DT intervention on-2/-1/7/8 days, performing intravenous injection of 200 μ l transfection solution containing control virus on the day of surgery, and taking materials 14 days later;
(3) DEREG + DT + Tff1 virus group: DeREG mice, a elastase-induced AAA model was established, given 1. mu.g of DT intervention on day-2/-1/7/8, and were harvested 14 days after intravenous injection of 200. mu.l of Tff 1-containing transfection fluid on the day of surgery.
3. Detection platform for establishing elastase-induced abdominal aortic aneurysm model
Maximum vessel diameter: after anesthesia (intraperitoneal injection of 1% sodium pentobarbital) and blood collection of orbital veins, mice are killed quickly by cervical dislocation, the pleuroperitoneal cavity is exposed, the whole aorta from the aortic arch to the iliac bifurcation is separated under a stereoscopic microscope, redundant fat and connective tissues on the aorta are removed by careful trimming with a microscope, a orderly vascular photograph is taken by a single lens reflex/mobile phone, and the maximum transverse diameter of the abdominal aorta (the part below the renal artery and above the iliac bifurcation) is repeatedly measured by IPP software, namely the maximum external diameter of the abdominal aortic aneurysm. The diameter of the abdominal aortic aneurysm exceeds 50% of the normal blood vessel diameter, i.e. it can be considered as tumorous.
And (3) degrading the elastic fiber: after separating mouse aorta, cutting blood vessel of lower abdominal aortic aneurysm part with a section knife, soaking in 4% paraformaldehyde fixing solution for 5h, dehydrating, transparentizing, soaking in wax, and finally embedding tissues with paraffin. When slicing, the thickness of the blood vessel slice is fixed to be 4 μm, and 4 tissue specimens of different layers are obtained from each tissue through discontinuous slicing, wherein the interval between the tissues of each layer is 150 μm. Each blood vessel specimen was stained and counted for vascular elastic fiber with 4 tissue sections.
Apoptosis of smooth muscle cells: the apoptosis of vascular smooth muscle cells was detected by immunofluorescence with smooth muscle cells in red (α -SMA +), apoptotic cells in green (TUNEL +), nuclei in blue (DAPI +), and each vascular specimen was stained with 4 tissue sections and counted.
4. Results of the experiment
Establishment of an abdominal aortic aneurysm model induced by elastase: each group of mice has good growth and development, smooth fur, flexible activity and normal water intake and ingestion. The week 2 vessel diameter results show a significant increase in the artery diameter in the elastase group compared to the normal vessel diameter, indicating successful model establishment (a in fig. 1).
Effect of over-expression of Tff1 on abdominal aortic aneurysm vessel diameter: under Treg knockout conditions, overexpression of Tff1 significantly reduced the abdominal aorta diameter (B in fig. 1).
Effect of over-expression of Tff1 on the degradation of vascular elastic fibers of abdominal aortic aneurysm: under Treg knockout conditions, overexpression of Tff1 significantly reduced aneurysm vascular spandex degradation (C in fig. 1).
Effect of over-expression of Tff1 on apoptosis of vascular smooth muscle cells of abdominal aortic aneurysm: under the condition of knocking out tregs, over-expression of Tff1 can significantly reduce the apoptosis of vascular smooth muscle cells of abdominal aortic aneurysm (D in fig. 1).
Example 2
1. Establishing an abdominal aortic aneurysm model induced by elastase
Male Foxp3cre/creTff1wt/wt or Foxp3 creTff1fl/fl mice of 8-12 weeks of age were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50mg/kg), fixed on mouse plates with their backs facing downwards, and the modeling was started under a stereomicroscope: cutting skin and subcutaneous fascia from the middle of the abdominal albany with ophthalmologic scissors to form a longitudinal incision of about 1.5cm, exposing abdominal viscera, pushing intestinal canal to both sides with a small cotton swab to fully expose abdominal aorta and inferior vena cava, carefully separating abdominal aorta with micro forceps and suture needle, uniformly covering the abdominal aorta wall with cotton cloth soaked with porcine trypsin for 40min, discarding the cotton cloth, flushing abdominal cavity with normal saline for 2 times, and finally suturing the incision to close the abdominal cavity.
2. Experiment grouping
(1) Control group: establishing an AAA model induced by elastase for 14 days by using a Foxp3cre/creTff1wt/wt mouse;
(2) tff1 conditional knockout group: foxp3cre/creTff1fl/fl mice, a elastase-induced AAA model was established, and the material was obtained 14 days later.
3. Detection platform for establishing elastase-induced abdominal aortic aneurysm model
Maximum vessel diameter: after anesthesia (intraperitoneal injection of 1% sodium pentobarbital) and blood collection of orbital veins, mice are killed quickly by cervical dislocation, the pleuroperitoneal cavity is exposed, the whole aorta from the aortic arch to the iliac bifurcation is separated under a stereoscopic microscope, redundant fat and connective tissues on the aorta are removed by careful trimming with a microscope, a orderly vascular photograph is taken by a single lens reflex/mobile phone, and the maximum transverse diameter of the abdominal aorta (the part below the renal artery and above the iliac bifurcation) is repeatedly measured by IPP software, namely the maximum external diameter of the abdominal aortic aneurysm. The diameter of the abdominal aortic aneurysm exceeds 50% of the normal blood vessel diameter, i.e. it can be considered as tumorous.
And (3) degrading the elastic fiber: after separating mouse aorta, cutting blood vessel of lower abdominal aortic aneurysm part with a section knife, soaking in 4% paraformaldehyde fixing solution for 5h, dehydrating, transparentizing, soaking in wax, and finally embedding tissues with paraffin. When slicing, the thickness of the blood vessel slice is fixed to be 4 μm, and 4 tissue specimens of different layers are obtained from each tissue through discontinuous slicing, wherein the interval between the tissues of each layer is 150 μm. Each blood vessel specimen was stained and counted for vascular elastic fiber with 4 tissue sections.
Apoptosis of smooth muscle cells: the apoptosis of vascular smooth muscle cells was detected by immunofluorescence with smooth muscle cells in red (α -SMA +), apoptotic cells in green (TUNEL +), nuclei in blue (DAPI +), and each vascular specimen was stained with 4 tissue sections and counted.
4. Results of the experiment
Establishment of an elastase-induced abdominal aortic aneurysm model: each group of mice has good growth and development, smooth fur, flexible activity and normal water intake and ingestion. The week 2 vessel diameter results show a significant increase in the artery diameter in the elastase group compared to the normal vessel diameter, indicating successful model establishment (a in fig. 2).
Conditioned knockout of the effect of Tff1 on abdominal aortic aneurysm vessel diameter: under the condition of specific knockout of Tff1 on Tregs, removal of Tff1 can significantly increase the abdominal aorta diameter (B in fig. 2).
Conditioned knockout of the effect of Tff1 on the degradation of vascular elastic fibers in abdominal aortic aneurysms: under the condition of specific knockout of Tff1 on Tregs, removal of Tff1 can significantly increase aneurysm vascular elastic fiber degradation (C in fig. 2).
Effect of conditional knockdown of Tff1 on apoptosis of vascular smooth muscle cells of abdominal aortic aneurysm: under the condition of specific knockout of Tff1 on Tregs, removal of Tff1 can significantly increase apoptosis of vascular smooth muscle cells of abdominal aortic aneurysm (D in fig. 2).
Example 3
1. Establishing an abdominal aortic aneurysm model induced by elastase
Male C57BL/6 mice, 8-12 weeks old, were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50mg/kg), mounted on mouse plates with their backs facing down, and the model was started under a stereomicroscope: cutting skin and subcutaneous fascia from the middle of the abdominal albany with ophthalmologic scissors to form a longitudinal incision of about 1.5cm, exposing abdominal viscera, pushing intestinal canal to both sides with a small cotton swab to fully expose abdominal aorta and inferior vena cava, carefully separating abdominal aorta with micro forceps and suture needle, uniformly covering the abdominal aorta wall with cotton cloth soaked with porcine trypsin for 40min, discarding the cotton cloth, flushing abdominal cavity with normal saline for 2 times, and finally suturing the incision to close the abdominal cavity.
2. Experiment grouping
(1) Control virus group: c57BL/6 mouse, establishing AAA model induced by elastase, injecting 200 μ l transfection solution containing control virus intravenously on the day of operation, and taking materials 14 days later;
(2) tff1 virome: c57BL/6 mice, establishing an AAA model induced by elastase, injecting 200 mu l of transfection solution containing Tff1 virus into the vein on the day of operation, and taking materials after 14 days.
3. Detection platform for establishing elastase-induced abdominal aortic aneurysm model
Maximum vessel diameter: after anesthesia (intraperitoneal injection of 1% sodium pentobarbital) and blood collection of orbital veins, mice are killed quickly by cervical dislocation, the pleuroperitoneal cavity is exposed, the whole aorta from the aortic arch to the iliac bifurcation is separated under a stereoscopic microscope, redundant fat and connective tissues on the aorta are removed by careful trimming with a microscope, a orderly vascular photograph is taken by a single lens reflex/mobile phone, and the maximum transverse diameter of the abdominal aorta (the part below the renal artery and above the iliac bifurcation) is repeatedly measured by IPP software, namely the maximum external diameter of the abdominal aortic aneurysm. The diameter of the abdominal aortic aneurysm exceeds 50% of the normal blood vessel diameter, i.e. it can be considered as tumorous.
And (3) degrading the elastic fiber: after separating mouse aorta, cutting blood vessel of lower abdominal aortic aneurysm part with a section knife, soaking in 4% paraformaldehyde fixing solution for 5h, dehydrating, transparentizing, soaking in wax, and finally embedding tissues with paraffin. When slicing, the thickness of the blood vessel slice is fixed to be 4 μm, and 4 tissue specimens of different layers are obtained from each tissue through intermittent slicing, wherein the interval of each layer tissue is 150 μm. Each blood vessel specimen was stained and counted for vascular elastic fiber with 4 tissue sections.
Apoptosis of smooth muscle cells: the apoptosis of vascular smooth muscle cells was detected by immunofluorescence with smooth muscle cells in red (α -SMA +), apoptotic cells in green (TUNEL +), nuclei in blue (DAPI +), and each vascular specimen was stained with 4 tissue sections and counted.
4. Results of the experiment
Establishment of an abdominal aortic aneurysm model induced by elastase: each group of mice has good growth and development, smooth fur, flexible activity and normal water intake and ingestion. The week 2 vessel diameter results show a significant increase in the artery diameter in the elastase group compared to the normal vessel diameter, indicating successful model establishment (a in fig. 3).
Effect of overexpression of Tff1 on the vessel diameter of abdominal aortic aneurysm: overexpression of Tff1 significantly reduced the abdominal aorta diameter in the background of normal wild mice (B in fig. 3).
Effect of over-expression of Tff1 on the degradation of vascular elastic fibers of abdominal aortic aneurysm: overexpression of Tff1 significantly reduced aneurysm vascular spandex degradation in the background of normal wild mice (C in fig. 3).
Effect of over-expression of Tff1 on apoptosis of vascular smooth muscle cells of abdominal aortic aneurysm: overexpression of Tff1 significantly reduced the apoptosis of vascular smooth muscle cells of abdominal aortic aneurysms in the background of normal wild-type mice (D in fig. 3).
In conclusion, Tff1 (whether derived from tregs or not) can protect the abdominal aortic aneurysm induced by elastase, indicating that Tff1 can be used as a new drug target for treating the abdominal aortic aneurysm.
Example 4
1. Establishing mouse aortic smooth muscle cell line culture system
Mouse aortic smooth muscle cell line MOVAS purchased from ATCC was subcultured in sterile incubator and plated after cell density reached a certain level.
2. Experiment grouping
(1) Control group: MOVAS + complete medium culture for 24 h;
(2) recombinant Tff1 experimental group: MOVAS + complete medium +500ng/ml TFF1 for 24 h.
3. Establishing mouse aorta smooth muscle cell line apoptosis detection platform
Flow detection of smooth muscle apoptosis: the cultured cells were collected, the supernatant was carefully aspirated with a pipette, transferred into a 10ml EP tube, the cells in the plate were cultured, digested with pancreatin, about 30s later 1ml of complete medium was added, and gently whipped until all was blown off. Then mixing the cells with the cells in the previous culture medium, and washing twice with PBS; flow cytometry labeling: add 100. mu.l of annexin V Binding Buffer to resuspend the cells; mu.l of the cell suspension was transferred to a 5ml tube, and 5. mu.l of FITC-Annexin V antibody and 10. mu.l of 7-AAD antibody were added. Incubating at 4 deg.C in dark for 15 min; add 400 μ l of annexin V binding buffer to each tube; and (5) performing flow-type on-machine detection as soon as possible.
4. Results of the experiment
Search for appropriate recombinant Tff1 action concentrations and times: when a mouse aortic smooth muscle cell line is cultured in vitro, the recombinant Tff1 with the concentration of 500ng/ml can inhibit the apoptosis of smooth muscle cells after being stimulated for 24h/48h (A in figure 4); when mouse aorta smooth muscle cell line is cultured in vitro, the recombinant Tff1 with the concentration of 200ng/ml, 500ng/ml and 1000ng/ml can inhibit the apoptosis of smooth muscle cells after being stimulated for 24h (B in figure 4).
Effect of recombinant Tff1 on smooth muscle cell apoptosis: the recombinant Tff1 was given a prognosis that significantly inhibited apoptosis of smooth muscle cells (C in fig. 4).
It will be apparent to those skilled in the art that various modifications may be made to the above embodiments without departing from the general spirit and concept of the invention. All falling within the scope of protection of the present invention. The protection scheme of the invention is subject to the appended claims.
Claims (3)
- Application of Tff1 in preparing a medicament for preventing and treating aortic aneurysm.
- 2. Use according to claim 1, characterized in that: the aortic aneurysm is an abdominal aortic aneurysm.
- 3. Use according to claim 1, characterized in that: the Tff1 is applied to preparing drugs for treating aortic aneurysm as vascular smooth muscle cell apoptosis inhibitors and/or vascular elastic fiber degradation inhibitors.
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