CN114578052A - Application of ADAM10 in occlusive cardiovascular and cerebrovascular diseases - Google Patents
Application of ADAM10 in occlusive cardiovascular and cerebrovascular diseases Download PDFInfo
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Abstract
The invention relates to the field of medicine, in particular to diagnosis and treatment of collateral circulation establishment of occlusive cardiovascular and cerebrovascular diseases. More specifically, the present invention relates to ADAM10 and its use as a biomarker and therapeutic target in the diagnosis of establishment of collateral circulation in a vaso-occlusive patient. The invention provides application of ADAM10 as a biological marker for collateral circulation establishment of patients with occlusive cardiovascular and cerebrovascular diseases, which can effectively predict collateral circulation establishment of patients with occlusive cardiovascular and cerebrovascular diseases and prevent development of adverse cardiovascular events into clinical cardiovascular events, has important value, can improve survival rate of patients with occlusive cardiovascular and cerebrovascular diseases and can improve long-term prognosis.
Description
Technical Field
The present invention relates to the field of medicine, and in particular to diagnosis and treatment of collateral circulation establishment. More specifically, the present invention relates to the use of ADAM10 as a biomarker and therapeutic target in the diagnosis of establishment of collateral circulation in patients with vascular occlusion.
Background
Coronary atherosclerotic heart disease (coronary heart disease) has become the leading disease threatening the health and development of humans, and rupture of unstable plaque, bleeding and subsequent thrombosis results in narrowing or even total occlusion of the coronary lumen. Coronary artery Chronic Total Occlusion (CTO) refers to a lesion in which the lumen is interrupted by discontinuous and antegrade blood flow and the occlusion time is greater than 3 months, with no forward contrast agent passing distally (TIMI 0 grade).
Occlusive cardiovascular and cerebrovascular diseases have a common pathological basis. When the main blood supply vessels of patients are occluded, irreversible damage can occur to nerve cells or cardiac muscle cells, so that the lethality rate and the disability rate are high. Many studies have proved that if good collateral circulation can be formed after occlusion, the infarct size can be effectively reduced, the myocardial and cerebral blood perfusion can be maintained, even the incidence of cardiovascular adverse events can be integrally reduced, the survival rate and the life quality of patients can be improved, and the survival time of the patients can be prolonged. Therefore, "therapeutic angiogenesis" has been developed as a therapeutic means based on the concept of collateral circulation. Therefore, it is important to find new therapeutic targets and biomarkers that can be administered with exogenous pro-angiogenic factors to promote the formation of new blood vessels or the maturation of pre-existing blood vessels to bypass occluded blood vessels and restore the blood supply to organs.
Disintegrin metalloprotease 10(a disintegrin and metalloprotease 10, ADAM10) is a member of the disintegrin metalloprotease family. It is an important alpha-secretase enzyme that triggers a continuous transmembrane proteolytic process, regulates the transmission of intracellular signals and regulates the activities of growth factors, adhesion molecules, receptors, and cytokines, which are expressed in endothelial cells, vascular smooth muscle cells, and leukocytes. Many substrates related to ADAM10, such as tumor necrosis factor alpha, chemokine CX3CLl, etc., are involved in the processes of angiogenic development, inflammation and regeneration of blood vessels. Currently, studies on ADAM10 have focused on neurological diseases such as alzheimer's disease and lacunar infarction, and malignant tumors, and have different roles in different diseases. For example, ADAM10 is highly expressed in oral squamous carcinoma tissues and is obviously related to tumor metastasis, and ADAM10 is supposed to increase angiogenesis and promote tumor metastasis by cutting vascular endothelial cadherin (VE-cadherin). In addition, in breast cancer, the expression of ADAM10 was found to be increased, the growth of cancer cells could be promoted by cleaving human epidermal growth factor receptor 2, and after applying ADAM10 inhibitor GI254023X, the proliferation of inhibitor group cells was found to be decreased, angiogenesis was decreased, apoptosis was increased, and invasion and migration ability was found to be decreased. Also, it has been shown that ADAM10 can ameliorate the symptoms of chronic obliterative vasculitis by reducing the release of inflammatory mediators by blocking the RAGE/NF κ B signaling pathway, thereby reducing endothelial cell damage. Also, researches show that after ADAM10 is silenced, VEGFR-2 protein expression in endothelial cells is reduced, and angiogenesis in pancreatic cancer is inhibited; upregulation of ADAM10 expression promotes increased angiogenesis after porcine arterial endothelial cells are stimulated with VEGF.
Disclosure of Invention
The invention provides application of ADAM10 protein as a biomarker for collateral circulation formation of occlusive cardiovascular and cerebrovascular diseases and a therapeutic target.
The technical scheme of the invention is as follows: the application of ADAM10 as a biomarker for promoting collateral circulation of patients with occlusive cardiovascular and cerebrovascular diseases, the significant up-regulation of ADAM10 protein of patients with good establishment of collateral circulation in patients with chronic total occlusion (chronic total occlusion), provides the application of ADAM10 protein as a biomarker for collateral circulation; and the ADAM10 protein expression quantity has correlation with the prognosis of patients with occlusive vascular diseases, and the prognosis of patients with high ADAM10 protein expression is found to be better than that of patients with low ADAM10 protein expression.
It is shown that ADAM10 can be used as a biomarker for predicting the establishment of collateral circulation in an early stage and can also be used as a biomarker for predicting the long-term prognosis of patients with occlusive vascular diseases.
The second technical scheme provided by the invention is as follows: the application of ADAM10 as a therapeutic target for promoting establishment of collateral circulation is that firstly, exogenous ADAM10 protein is found to be applied to mice with lower limb vascular occlusion, and the protein can promote collateral circulation and blood supply of lower limbs of the mice.
Meanwhile, the invention is based on the fact that the proliferation, migration and angiogenesis of endothelial cells can be remarkably promoted when the overexpression of the adeno-associated virus is studied in vitro, which can show that the increase of the expression of the ADAM10 protein can remarkably promote the angiogenesis.
The ADAM10 promotes the increase of the density of tiny blood vessels at a histological level (CD31-MDV), but the increase of the number of new blood vessels is not obvious, and the ADAM10 is supposed to increase the blood flow by increasing the shearing force so as to open collateral circulation, so that a new target point can be provided for a novel medicament for treating patients with vascular occlusion to promote the collateral circulation to open.
The beneficial technical effects of the invention are as follows: the invention provides application of ADAM10 as a biological marker for collateral circulation establishment of patients with occlusive vascular diseases, which can effectively predict collateral circulation establishment of patients with occlusive vascular diseases and prevent development of adverse cardiovascular events into clinical cardiovascular events, has important value, can improve survival rate of patients with occlusive vascular diseases and can improve long-term prognosis.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the description of the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 ADAM10 was shown to be a biomarker for predicting collateral circulation establishment and patient prognosis in patients with occlusive vascular disease, with higher ADAM10 expression in patients with good collateral circulation;
figure 2ADAM10 can be used as a biomarker for predicting collateral circulation establishment;
FIG. 3 prognosis is better in patients with high ADAM10 expression;
FIG. 4 shows that ADAM10 recombinant protein injection in a mouse lower limb femoral artery occlusion model promotes the formation of collateral circulation and perfusion of lower limb blood flow. (number of mice N ═ 8)
FIG. 5 tissue level, neovascularization increased, greater vascular density, and greater patency of collateral circulation following ADAM10 injection;
FIG. 6 promotion of endothelial cell proliferation after overexpression of ADAM10 by human umbilical vein endothelial cells;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
1. in the examples, patients who were clearly diagnosed as occlusive vascular diseases by coronary angiography were selected, and the intraoperative diagnoses were classified into a good collateral circulation group and a poor collateral circulation group. Serum samples are kept before opening, and the ADAM10 expression quantity is measured by a double-antibody sandwich ELISA method. As a result, it was found that the expression level of ADAM10 in the group with good collateral circulation was significantly higher than that in the group with poor collateral circulation (FIG. 1).
2. In addition, ADAM10 was found to be a good predictor of collateral circulation by the subject's working curve (FIG. 2), suggesting that the protein can enrich the study of the pathological mechanisms that occlude the generation of collateral circulation in patients and allow early diagnosis without intervention.
3. Finally, we found that after the follow-up of patients, the incidence of cardiovascular adverse events of the ADAM10 protein-elevated group was significantly lower than that of the ADAM10 protein-low group by at least 12 months of follow-up (FIG. 3). In conclusion, the ADAM10 protein can be used as a therapeutic target for promoting collateral circulation, and provides a theoretical basis for clinical treatment and drug development of patients with vascular occlusion.
Example 2
1. In the embodiment, male C57BL/6J mice with 8-12 weeks are adopted, 1.25% isoflurane is used for inducing anesthesia and then fixed on an operation table, depilatory is used for depilation in operation areas of lower limbs on two sides, the residual depilatory is cleaned by clear water, iodine is disinfected, alcohol is deiodinated, an aseptic operation sheet is laid, a longitudinal incision with the length of about 2-4 mm is made from the middle point of a inguinal ligament to the inner side of a knee, subcutaneous tissues are separated bluntly, femoral nerve vascular sheaths and branches of the femoral nerve vascular sheaths are exposed, external iliac arteries and femoral arteries are separated by using a glass needle under a dissecting microscope, external iliac arteries and femoral arteries are ligated by No. 6 silk threads, and the upper ends of the iliac arteries and the femoral arteries are ligated by No. 4 surgical suture threads. The right femoral artery was sham-operated, with only the femoral artery and vein isolated without ligation, and skin sutured with a surgical suture No. 4. And establishing a mouse lower limb unilateral limb ischemia model. The experimental group was age matched to the control group. . The mice were injected intraperitoneally with 0.5ml of antibiotic at a concentration of 5 mg/ml and then placed in an incubator at 37 ℃ until they were awake.
Performing laser Doppler blood flow perfusion measurement after operation, and judging the standard: the blood velocity is reduced to less than 10% before the operation after the operation, and the frequency spectrum of the blood flow is obviously changed, namely the model building is successful. After the model is successfully made, mice in the experimental group are injected with ADAM10 recombinant protein intervention model in the abdominal cavity: ADAM10 was 6ug/kg once daily for 14 days.
As a result, it was found that: from day 7, the blood perfusion of the affected limb of the mouse in the experimental group is obviously higher than that of the control group, and the blood perfusion is further increased in days 7, 14 and 21 and is still higher than that of the control group. (FIG. 4)
After 2.21 days, mice were sacrificed by cervical dislocation after deep anesthesia. Collateral circulation formation was assessed pathologically by taking adductor muscles, gastrocnemius muscles (gastrocnemius and intimal muscles are the major muscles of the lower limbs of mice, supplied mainly by the deep femoral artery, and ischemia occurred in both muscles after ligation of the femoral artery and its branches (fig. 5).
(1) HE dyeing;
(2) immunohistochemistry: CD31 calculation of microvascular density;
(3) immunofluorescence: calculating the density of the new blood vessels by double staining CD31/Ki 67;
as a result, it was found that: first, in HE staining, the experimental group had more vessels than the control group; in immunohistochemistry, the experimental group microvascular density (positive for CD 31) was found to be significantly higher than the control group. In double-stained immunofluorescence, the experimental group Ki67 was more positive than the control group.
Example 3
1. Firstly, an ADAM10 overexpression plasmid based on adeno-associated virus is constructed through genetic engineering, the vector is transfected into Human Umbilical Vein Endothelial Cells (HUVEC), and the overexpression of ADAM10 protein level is promoted, so that the mechanism of regulating and controlling the angiogenesis of endothelial cells in vitro by ADAM10 protein is researched.
2. After the cell model is successfully constructed, cell proliferation, migration and angiogenesis phenotypes are detected respectively;
as a result, it was found that: endothelial cell proliferation, migration and angiogenesis were promoted upon overexpression of ADAM10 compared to the control group (fig. 6).
In summary, the embodiments of the present invention are explained in detail and in multiple dimensions with reference to the drawings: the ADAM10 protein can promote the formation of collateral circulation, is a potential therapeutic target for angiogenesis, and provides a theoretical basis for clinical treatment and drug development of patients with vascular occlusion.
Finally, it should be noted that: although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that: modifications and equivalents may be made thereto without departing from the spirit and scope of the invention and it is intended to cover in the claims the invention any modifications and equivalents.
Claims (2)
- The application of ADAM10 recombinant protein as a biomarker for establishment of collateral circulation of patients with occlusive cardiovascular and cerebrovascular diseases.
- The application of ADAM10 recombinant protein as a target point for promoting collateral circulation treatment of patients with occlusive cardiovascular and cerebrovascular diseases.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004024089A2 (en) * | 2002-09-11 | 2004-03-25 | Sloan-Kettering Institute For Cancer Research | Inhibition or activation of adam9 and adam15 for treatment of vascularization-related disease and wound healing |
| CN112336729A (en) * | 2020-09-28 | 2021-02-09 | 陈国俊 | Application of canaprisone in preparation of drugs for preventing or treating amyloid cerebrovascular diseases |
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2022
- 2022-03-08 CN CN202210228444.5A patent/CN114578052A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004024089A2 (en) * | 2002-09-11 | 2004-03-25 | Sloan-Kettering Institute For Cancer Research | Inhibition or activation of adam9 and adam15 for treatment of vascularization-related disease and wound healing |
| CN112336729A (en) * | 2020-09-28 | 2021-02-09 | 陈国俊 | Application of canaprisone in preparation of drugs for preventing or treating amyloid cerebrovascular diseases |
Non-Patent Citations (2)
| Title |
|---|
| JENNIFER L LUCITTI等: "Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17", CIRC RES, vol. 111, no. 12, 7 December 2012 (2012-12-07), pages 1544 * |
| 卢志强;张艳军;崔广智;庄朋伟;张金保;: "心肌缺血模型的制作方法研究进展", 中国药理学通报, no. 08, 20 August 2012 (2012-08-20) * |
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