CN114259565A - Application of Wnt4 in preparing medicament for treating fibrosis - Google Patents

Application of Wnt4 in preparing medicament for treating fibrosis Download PDF

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Publication number
CN114259565A
CN114259565A CN202111627210.XA CN202111627210A CN114259565A CN 114259565 A CN114259565 A CN 114259565A CN 202111627210 A CN202111627210 A CN 202111627210A CN 114259565 A CN114259565 A CN 114259565A
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Prior art keywords
wnt4
fibrosis
substance
protein
fibroblasts
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CN202111627210.XA
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Inventor
段金柱
董文艳
赵悦
温达强
蔡文倩
林应炯
曾锤
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Guangzhou Women and Childrens Medical Center
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Guangzhou Women and Childrens Medical Center
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Abstract

The invention discloses an application of Wnt4 in preparing a medicament for treating fibrosis. The invention provides an application of a substance for promoting Wnt4 gene expression or improving Wnt4 content and/or activity in preparing a product; the product has the functions of treating myocardial fibrosis, promoting angiogenesis and the like. Experiments prove that the Wnt4 gene overexpression can induce the transformation of fibroblasts to endothelial cells, so that the fibroblasts have the capacity of forming blood vessels, the cardiac function is increased, the blood vessel density is improved, and the like. Wnt4 protein is expected to become one of effective treatment methods for targeting cardiac fibroblasts, inhibiting myocardial fibrosis and promoting angiogenesis. Can generate conversion action on fibrosis formed by different mechanisms, and has considerable development prospect.

Description

Application of Wnt4 in preparing medicament for treating fibrosis
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to an application of Wnt4 in preparation of a medicine for treating fibrosis.
Background
When tissue damage occurs to human organs such as heart, lung, skin and kidney, rapid activation of fibroblasts is accompanied to replace dead tissue or functional cells, finally forming fibrosis or scars, affecting the function of the organ and repairing the organ. Therefore, how to improve or remove fibrosis is one of the problems that need to be solved in the treatment of various organ diseases.
Cardiovascular disease is one of the major diseases with high morbidity and mortality worldwide. Myocardial cell death is induced by a number of pathological factors that arise during the development of cardiovascular disease, such as oxidative stress, pressure and/or volume overload, certain cytokines, ischemia hypoxia, and neuro-endocrine dysregulation. The adult heart has no ability to regenerate, and the dead heart muscle is replaced by activated fibroblasts, which become fibrotic, leading to decreased cardiac function and ultimately to progression of the malignant cycle to heart failure.
Myocardial fibrosis refers to excessive accumulation of collagen fibers in the normal tissue structure of the myocardium, a significant increase in collagen concentration in heart tissue, or a change in collagen composition. This pathological change is present in a variety of cardiovascular diseases and is believed to be closely related to cardiac arrhythmias, cardiac dysfunction and even sudden cardiac death. Vascular weakening is a pathophysiological mechanism that accompanies the development of myocardial fibrosis. The weakening of the blood vessels promotes the reduction of blood supply to heart tissues, and further induces the death of myocardial cells.
In recent years, myocardial fibrosis and cardiovascular angiogenesis are increasingly emphasized by cardiovascular experts at home and abroad, but the research on the clinical and experimental aspects is relatively less. Angiotensin Converting Enzyme Inhibitor (ACEI) drugs are widely used in clinic at present, but no obvious evidence shows that the myocardial fibrosis can be improved at present. Recent studies have found that the histamine antagonist tranilast (tranilast) H1 also has anti-fibrotic, hair growth stimulating and collagen synthesis inhibiting effects. Although it has been used for the treatment of scars, whether the drug can improve myocardial fibrosis has yet to be further confirmed.
In summary, no effective drug for inhibiting myocardial fibrosis and promoting angiogenesis exists in clinic, so that the development of a novel myocardial fibrosis inhibitor/inhibitor has great significance not only for treating cardiovascular diseases, but also for treating fibrosis after other organ injury.
Myocardial fibrosis is often secondary to various cardiovascular diseases. It can cause structural disorder of cardiac muscle and increase of tissue heterogeneity, and is the structural basis for arrhythmia, and also the potential risk cause of sudden death and chronic cardiac insufficiency. At present, the common medicines for clinically treating cardiovascular diseases mainly comprise beta receptor blockers, angiotensin converting enzyme inhibitors, diuretics and the like aiming at increasing myocardial contractility and reducing myocardial oxygen consumption. Myocardial fibrosis is a complex pathological process involving multiple autoregulatory systems and is associated with the formation of myocardial fibrosis in different heart diseases and even in different types of the same disease. However, no effective drug for inhibiting fibrosis exists in the current clinical treatment.
Disclosure of Invention
The invention aims to provide application of Wnt4 in preparing a medicament for treating fibrosis.
The technical scheme adopted by the invention is as follows:
in the first aspect of the present invention, there is provided an application of a Wnt4 protein or a substance that regulates the expression of a Wnt4 gene in the preparation of a functional product having any one of the functions (I) to (VI):
(I) treating fibrosis;
(II) treatment of cardiovascular disease;
(III) promoting angiogenesis;
(IV) enhancing cardiac function;
(V) increasing vascular density;
(VI) promoting the transformation of fibroblasts into endothelial cells.
In a second aspect of the present invention, there is provided a use of a substance that modulates the activity of Wnt4 protein according to the first aspect of the present invention in the preparation of a functional product having any one of the functions (I) to (VI):
(I) treating fibrosis;
(II) treatment of cardiovascular disease;
(III) promoting angiogenesis;
(IV) enhancing cardiac function;
(V) increasing vascular density;
(VI) promoting the transformation of fibroblasts into endothelial cells.
In a third aspect of the present invention, there is provided an application of a substance for regulating Wnt4 protein content in the first aspect of the present invention in preparing a functional product having any one of (I) to (VI):
(I) treating fibrosis;
(II) treatment of cardiovascular disease;
(III) promoting angiogenesis;
(IV) enhancing cardiac function;
(V) increasing vascular density;
(VI) promoting the transformation of fibroblasts into endothelial cells.
In some embodiments of the invention, the agent that modulates Wnt4 gene expression is an agent that increases or enhances the Wnt4 gene expression; the substance for regulating the activity of the Wnt4 protein of the first aspect of the invention is a substance for improving or enhancing the activity of the Wnt4 protein, and the substance for regulating the content of the Wnt4 protein of the first aspect of the invention is a substance for improving or enhancing the content of the Wnt4 protein.
In some embodiments of the present invention, the agent that increases or enhances expression of the Wnt4 gene, the agent that increases or enhances activity of the Wnt4 protein, or the agent that increases or enhances content of the Wnt4 protein is a biological material related to Wnt4 protein, and the biological material is any one of the following B1) to B4):
B1) a nucleic acid molecule encoding said Wnt 4;
B2) an expression cassette comprising the nucleic acid molecule of B1);
B3) a recombinant vector containing the nucleic acid molecule of B1) or a recombinant vector containing the expression cassette of B1);
B4) a recombinant microorganism containing the nucleic acid molecule according to B1), or a recombinant microorganism containing the expression cassette according to B2), or a recombinant microorganism containing the nucleic acid molecule according to B1
B3) A recombinant microorganism of said recombinant vector.
In the fourth aspect of the present invention, a product is provided, the active ingredient of which is a substance that increases or enhances the expression of the Wnt4 gene and/or a substance that increases or enhances the activity of the Wnt4 protein and/or a substance that increases or enhances the content of the Wnt4 protein; the application of the product is shown in any one of the following (I) to (VI):
(I) treating fibrosis;
(II) treatment of cardiovascular disease;
(III) promoting angiogenesis;
(IV) enhancing cardiac function;
(V) increasing vascular density;
(VI) promoting the transformation of fibroblasts into endothelial cells.
In some embodiments of the present invention, the agent that increases or enhances expression of the Wnt4 gene, the agent that increases or enhances activity of the Wnt4 protein, or the agent that increases or enhances content of the Wnt4 protein is a biological material related to Wnt4 protein, and the biological material is any one of the following B1) to B4):
B1) a nucleic acid molecule encoding said Wnt 4;
B2) an expression cassette comprising the nucleic acid molecule of B1);
B3) a recombinant vector containing the nucleic acid molecule of B1) or a recombinant vector containing the expression cassette of B1);
B4) a recombinant microorganism containing the nucleic acid molecule according to B1), or a recombinant microorganism containing the expression cassette according to B2), or a recombinant microorganism containing the nucleic acid molecule according to B1
B3) A recombinant microorganism of said recombinant vector.
In some embodiments of the invention, the fibrosis is myocardial fibrosis, skin fibrosis (scar), renal fibrosis, pulmonary fibrosis, liver fibrosis, glial scar formed by stellate cells in brain injury, gastrointestinal fibrosis, muscle fibrosis, and the like. Because the fibrosis principle of different organs is consistent, and fibroblasts are activated and proliferated after the organs are damaged, it can be concluded that adding Wnt4 into skin scar treatment products increases the scar treatment effect or related fibrosis diseases such as renal fibrosis, pulmonary fibrosis, hepatic fibrosis, glial scar formed by stellate cells in brain injury, fibrosis of intestines and stomach, muscle fibrosis and the like.
In some embodiments of the invention, the fiber cell is a cardiac fiber cell.
In the fifth aspect of the present invention, a method for promoting the conversion of myocardial fibroblasts into endothelial cells is provided, wherein the expression of the Wnt4 gene is increased or enhanced, the activity of the Wnt4 protein is increased or enhanced, and/or the content of the Wnt4 protein is increased or enhanced.
In some embodiments of the invention, Wnt4 gene expression may be increased or enhanced by viral vectors containing Wnt4 gene, activators that regulate the upstream gene of Wnt4 expression and its molecular signaling pathway, activators that potentially promote Wn4 protein expression, and the like; the content of the Wnt4 protein is improved or enhanced by directly administering exogenous Wnt4 protein, functional mimics of Wnt4 and the like.
The invention has the beneficial effects that:
the research of the invention finds that a part of fibroblasts after the heart injury can be transformed into endothelial cells through mesenchyme, and the new phenomenon is called mesenchyme-endothelium transformation (MEndoT). Meanwhile, the transformation of the fiber to endothelial cells is increased, and the edge area of the heart injury generates new blood vessels, thereby reducing the heart injury. Wnt4 is a secreted glycoprotein. The invention discovers that Wnt4 can inhibit myocardial fibrosis, promote angiogenesis, reduce fibrosis and protect cardiac function by regulating the transformation of fibroblasts to endothelial cells; plays a key role in cardiac repair. Wnt4 protein is expected to become one of effective treatment methods for targeting cardiac fibroblasts, inhibiting myocardial fibrosis and promoting angiogenesis. Can generate transformation action on fibrosis formed by different mechanisms and fibrosis formed in different diseases, and has considerable development prospect.
Drawings
FIG. 1 is a flow chart.
FIG. 2 shows that increased expression of Wnt4 was accompanied by increased expression of the endothelial cell-associated marker gene in isolated mouse cardiac fibroblasts.
FIG. 3 shows that Wnt4 expression level in fibroblasts of the fluorescence-labeled damaged cardiac region increased with time after the mouse cardiac injury.
Figure 4 shows that Wnt4 was significantly highly expressed in myofibroblast-transformed endothelial cells in cardiac tissue.
FIG. 5 shows that the overexpression of Wnt4 in mouse fibroblasts significantly increases the expression level of the endothelial cell-associated marker gene. Wherein FIG. 5A shows the expression level of Wnt 4; FIG. 5B shows the expression levels of endothelial cell-associated marker genes VECAD, vWF and eNOS.
Figure 6 is a tube forming experiment demonstrating the ability of over-expressing Wnt4 to render fibroblasts neovascular. Wherein FIG. 6A is a form diagram; FIG. 6B is a tube length statistic.
FIG. 7 is a Low Density Lipoprotein (LDL) uptake assay showing that overexpression of Wnt4 confers fibroblast function as an endothelial cell; white arrows indicate cells that have taken up LDL. FIG. 7A is a schematic view; FIG. 7B is a statistical chart of LDL uptake rates.
Figure 8 is an animal in which overexpression of Wnt4 increased cardiac function following injury. The left ventricular ejection fraction and the left ventricular contraction rate are both indexes reflecting ventricular functions; pre, I/R7 d, I/R14 d represent Pre-cardiac injury, post-cardiac injury 7d and 14d, respectively. FIG. 8A is a schematic view; FIG. 8B is a left ventricular ejection fraction histogram; fig. 8C is a left ventricular contraction rate histogram.
Figure 9 is that overexpression of Wnt4 in mouse cardiac fibroblasts reduced fibrosis following cardiac injury. FIG. 9A is a schematic view; FIG. 9B is a statistical chart of the area of fibrosis.
Figure 10 is that overexpression of Wnt4 in mouse cardiac fibroblasts increased neovascularization after cardiac injury; the grey-white color in the figure represents the blood vessel. FIG. 10A is a schematic view; fig. 10B is a blood vessel density histogram.
Figure 11 shows that overexpression of Wnt4 transformed cardiac fibroblasts into endothelial cells by activating the phosphorylated JNK signaling pathway. Wherein VECAD and Occludin are endothelial cell markers.
FIG. 12 is a statistical view of the expression level detection results of FIG. 11.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
The method for targeting the fibroblast cells to treat heart diseases by over-expressing Wnt4 to induce MEndoT is shown in figure 1.
Example 1 cell experiments
1. C57 wild type mice were euthanized, hearts were removed and digested with pancreatin and collagenase to obtain cardiac fibroblasts.
2. Wnt4 is over-expressed in isolated cardiac fibroblasts by lentivirus, RNA of the cells is extracted 48 hours later, and the expression levels of Wnt4 and endothelial cell related marker genes are detected. As shown in fig. 2 to 5: after virus transfection, the expression level of Wnt4 is obviously increased, and the expression of endothelial cell related marker genes VECAD, vWF and eNOS is also obviously increased, which indicates that the over-expression of Wnt4 in normal myocardial fibroblasts cultured in vitro can induce the transformation of the fibroblasts into endothelial cells.
3. In a culture chamber previously plated with matrigel at 6X 104/cm2Cardiomyocytes overexpressing Wnt4 at density and containing 5% CO at 37 ℃2The cell culture box is used for culturing for 12 hours. As shown in figure 6, cardiac fibroblasts over-expressing Wnt4 formed tubules, indicating that over-expressing Wnt4 confers vascular-forming ability to fibroblasts.
4. In 24-well plates previously plated with gelatin at 6X 104/cm2Cardiomyocytes overexpressing Wnt4 at density and containing 5% CO at 37 ℃2The cell culture box of (2) for 4 hours. As shown in fig. 7, it was observed that after Wnt4 was overexpressed in cardiac fibroblasts, the number of cells that could take up LDL, which is one of the main functions of endothelial cells, was increased.
The results show that the Wnt4 is over-expressed in vitro, so that the transformation of the myocardial fibroblasts into endothelial cells can be induced, and the endothelial cells have the functions of endothelial cells and further promote angiogenesis.
Example 2 animal experiments
1. The Cre-dependent expression of adeno-associated virus was expressed at 1X 1011U/mouse, jugular intravenous injection into Col1a2-Cre mice, followed by 10 consecutive days of tamoxifen, resulted in specific overexpression of Wnt4 in cardiac fibroblasts.
2. Mice specifically overexpressing Wnt4 in cardiac fibroblasts and control mice were respectively subjected to suction anesthesia to open their breasts, ligate the left anterior descending branch of the coronary artery 1mm below the left atrium, and after 45 minutes, the ligation was released to confirm vascular recanalization, and then close their breasts. The electrocardiogram was connected during the operation to confirm the success of modeling myocardial ischemia reperfusion injury. Sterilizing after operation, relieving pain, feeding liquid and keeping warm.
3. Mice cardiac function was monitored by echocardiography 7 days, 14 days post-operative heart injury, respectively. Overexpression of Wnt4 in cardiac fibroblasts significantly improved cardiac function in mice after I/R surgery.
The left ventricular ejection fraction refers to the proportion of the volume of the left ventricle in the whole volume of the left ventricle which is pumped out by each contraction of the left ventricle, and the ejection function of the ventricle is reflected from the perspective of the volume. The left ventricular contraction rate is the rate of change of the heart inner diameter at each contraction of the left ventricle, and is the ejection function of the ventricle reflected in the length of the inner diameter. As shown in fig. 8, after Wnt4 was overexpressed in cardiac fibroblasts, the mouse ejection fraction increased, the heart pumping capacity increased, and an increase in cardiac function was observed.
4. Mouse hearts were harvested 14 days after heart injury surgery, Masson stained, and area of fibrosis calculated. The detection results are shown in fig. 9, and it can be seen from fig. 9 that Wnt4 is overexpressed in cardiac fibroblasts to significantly reduce post-operative cardiac fibrosis in mice.
5. The mouse hearts were harvested 14 days after the heart injury surgery, and the vascular endothelium was labeled by fluorescent staining (green fluorescence) and the vascular area was calculated. The results are shown in fig. 10, and it can be seen from fig. 10 that Wnt4 was overexpressed in cardiac fibroblasts to significantly increase vascular density.
Example 3 molecular mechanism of Wnt4 to promote the transformation of fibroblasts into endothelial cells
1. C57 wild type mice were euthanized, hearts were removed and digested with pancreatin and collagenase to obtain cardiac fibroblasts.
2. Wnt4 downstream signal pathway JNK and beta-catenin inhibitors are respectively added into the separated cardiac fibroblasts, after the downstream signal pathways are inhibited, cell proteins are extracted, and the expression levels of Wnt4 and endothelial cell related markers are detected. As shown in fig. 11-12: overexpression of Wnt4 transformed cardiac fibroblasts into endothelial cells by activating the phosphorylated JNK signaling pathway.
The present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.

Claims (10)

  1. The application of Wnt4 protein or substance for regulating Wnt4 gene expression in preparing functional products of any one of (I) to (VI):
    (I) treating fibrosis;
    (II) treatment of cardiovascular disease;
    (III) promoting angiogenesis;
    (IV) enhancing cardiac function;
    (V) increasing vascular density;
    (VI) promoting the transformation of fibroblasts into endothelial cells.
  2. 2. Use of a substance that modulates the activity of Wnt4 protein according to claim 1 in the preparation of a functional product having any one of the functions (I) to (VI):
    (I) treating fibrosis;
    (II) treatment of cardiovascular disease;
    (III) promoting angiogenesis;
    (IV) enhancing cardiac function;
    (V) increasing vascular density;
    (VI) promoting the transformation of fibroblasts into endothelial cells.
  3. 3. Use of a substance capable of regulating the content of Wnt4 protein according to claim 1 in the preparation of a functional product having any one of the functional components (I) to (VI):
    (I) treating fibrosis;
    (II) treatment of cardiovascular disease;
    (III) promoting angiogenesis;
    (IV) enhancing cardiac function;
    (V) increasing vascular density;
    (VI) promoting the transformation of fibroblasts into endothelial cells.
  4. 4. The use according to any one of claims 1 to 3, wherein the substance that regulates the expression of Wnt4 gene is a substance that increases or enhances the expression of Wnt4 gene; the substance for regulating the activity of the Wnt4 protein in claim 1 is a substance for increasing or enhancing the activity of the Wnt4 protein, and the substance for regulating the content of the Wnt4 protein in claim 1 is a substance for increasing or enhancing the content of the Wnt4 protein.
  5. 5. The use according to claim 4, wherein the substance that increases or enhances the expression of Wnt4 gene, the substance that increases or enhances the activity of Wnt4 protein, or the substance that increases or enhances the content of Wnt4 protein is a biological material related to Wnt4 protein, the biological material is any one of the following B1) to B4):
    B1) a nucleic acid molecule encoding said Wnt 4;
    B2) an expression cassette comprising the nucleic acid molecule of B1);
    B3) a recombinant vector containing the nucleic acid molecule of B1) or a recombinant vector containing the expression cassette of B1);
    B4) a recombinant microorganism containing the nucleic acid molecule according to B1), or a recombinant microorganism containing the expression cassette according to B2), or a recombinant microorganism containing the nucleic acid molecule according to B1
    B3) A recombinant microorganism of said recombinant vector.
  6. 6. A product, the active ingredients of which are substances for improving or enhancing the expression of the Wnt4 gene and/or substances for improving or enhancing the activity of the Wnt4 protein and/or substances for improving or enhancing the content of the Wnt4 protein; the application of the product is shown in any one of the following (I) to (VI):
    (I) treating fibrosis;
    (II) treatment of cardiovascular disease;
    (III) promoting angiogenesis;
    (IV) enhancing cardiac function;
    (V) increasing vascular density;
    (VI) promoting the transformation of fibroblasts into endothelial cells.
  7. 7. The product according to claim 6, wherein the substance that increases or enhances the expression of the Wnt4 gene, the substance that increases or enhances the activity of the Wnt4 protein, or the substance that increases or enhances the content of the Wnt4 protein is a biological material related to the Wnt4 protein, and the biological material is any one of the following B1) to B4):
    B1) a nucleic acid molecule encoding said Wnt 4;
    B2) an expression cassette comprising the nucleic acid molecule of B1);
    B3) a recombinant vector containing the nucleic acid molecule of B1) or a recombinant vector containing the expression cassette of B1);
    B4) a recombinant microorganism containing the nucleic acid molecule according to B1), or a recombinant microorganism containing the expression cassette according to B2), or a recombinant microorganism containing the nucleic acid molecule according to B1
    B3) A recombinant microorganism of said recombinant vector.
  8. The application of Wnt4 gene or Wnt4 protein as target spot in screening or developing the functional product of any one of (I) to (VI):
    (I) treating fibrosis;
    (II) treatment of cardiovascular disease;
    (III) promoting angiogenesis;
    (IV) enhancing cardiac function;
    (V) increasing vascular density;
    (VI) promoting the transformation of fibroblasts into endothelial cells.
  9. 9. Use according to any one of claims 1 to 5 or a product according to any one of claims 6 to 7 or a use according to claim 8, wherein the fibrosis is myocardial fibrosis, skin fibrosis, kidney fibrosis, lung fibrosis, liver fibrosis, glial scar formed by stellate cells in brain injury, gastrointestinal fibrosis, muscle fibrosis.
  10. 10. A method for promoting the transformation of fibroblasts into endothelial cells, which is characterized in that the expression of the Wnt4 gene is increased or enhanced, the activity of the Wnt4 protein is increased or enhanced, and the content of the Wnt4 protein is increased or enhanced.
CN202111627210.XA 2021-12-28 2021-12-28 Application of Wnt4 in preparing medicament for treating fibrosis Pending CN114259565A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104202984A (en) * 2012-04-04 2014-12-10 萨穆梅德有限公司 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
CN107015001A (en) * 2016-11-22 2017-08-04 哈尔滨医科大学 Purposes of the Wnt4 as the early stage biological markers of acute injury of kidney in detection early stage acute injury of kidney
CN113694187A (en) * 2021-07-20 2021-11-26 上海市东方医院（同济大学附属东方医院） Pharmaceutical composition for inhibiting myocardial fibrosis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104202984A (en) * 2012-04-04 2014-12-10 萨穆梅德有限公司 Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
CN107015001A (en) * 2016-11-22 2017-08-04 哈尔滨医科大学 Purposes of the Wnt4 as the early stage biological markers of acute injury of kidney in detection early stage acute injury of kidney
CN113694187A (en) * 2021-07-20 2021-11-26 上海市东方医院（同济大学附属东方医院） Pharmaceutical composition for inhibiting myocardial fibrosis

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