CN117982650A - Application of TXNDC5 in preparation of medicines for preventing, treating and relieving pulmonary arterial hypertension - Google Patents
Application of TXNDC5 in preparation of medicines for preventing, treating and relieving pulmonary arterial hypertension Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicine, and particularly provides application of TXNDC5 in preparation of a medicine for preventing, treating and relieving pulmonary arterial hypertension. The invention discovers that the expression of TXNDC5 in the PH rat lung tissue induced by HySu is increased through transcriptome sequencing and qPCR, and the TXNDC5 is positively related to ECM reconstruction, inflammation and metabolism related genes, including TGF beta R1, FN1, CTGF, POSTN, COL A1, COL3A1, OSM, INOS, IL-1 beta and PKM2. Immunofluorescent staining was used to find that TXNDC5 was localized mainly in the pulmonary endothelial and adventitial fibroblast layers in the lung tissue of Hyp and HySu-induced PH rats. TGF beta 1 was used to stimulate HPF and HUVECs, and TGF beta 1 was found to stimulate up-regulation of TXNDC 5. Over-expression of TXNDC5 in HUVECs was mediated by lentivirus, and TXNDC5 was found to promote EndMT of HUVECs. Therefore, the TXNDC5 can be used as a new drug target for treating pulmonary hypertension, and has important significance for developing pulmonary hypertension drugs.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of TXNDC 5in preparation of a medicine for preventing, treating and relieving pulmonary arterial hypertension.
Background
Pulmonary hypertension (Pulmonary Hypertension, PH) refers to a class of syndromes characterized by significant remodeling of pulmonary vessels and progressive increases in vascular load, with disease progression often accompanied by right ventricular remodeling and hypertrophy, ultimately leading to right heart failure and even death. The hemodynamics of PH is defined as the mean pulmonary artery pressure (MeanPulmonaryArterial Pressure, mPAP) of 20mmHg or more measured through the right heart catheter at sea level resting state. PH is often classified into 5 categories according to the etiology, hemodynamics, etc.: ① Pulmonary Arterial Hypertension (PAH); ② Pulmonary hypertension due to left heart disease; ③ Pulmonary hypertension due to pulmonary disease/hypoxia; ④ Pulmonary arterial hypertension due to obstructive lesions of the pulmonary artery; ⑤ Pulmonary hypertension due to multiple factors or unknown factors. Epidemiological investigation results show that about 1% of the population worldwide is affected by PH, with up to 10% of people over 65 years old, of which 80% come from developing countries. PH pathology mainly includes pulmonary vasomotor imbalance and pulmonary vascular remodeling. Currently, clinical drugs for treatment of PH passed by the U.S. Food and drug administration (Food and DrugAdministration, FDA) act primarily on vasoconstriction-related signaling pathways such as prostacyclin, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase agonists, although treatment with these vasoconstrictor-targeted drugs increases the 5-year survival of patients to 64.5%, long-term prognosis is still not ideal. Therefore, intensive research on the pathogenesis of PH is critical for developing drug targets, antibody drugs and new therapeutic approaches for treating PH.
TXNDC5 is a protein in the thioredoxin family. The protein is encoded by the TXNDC5 gene located on human chromosome 6. TXNDC5 is a multifunctional protein which is mainly expressed in the endoplasmic reticulum of cells and participates in the oxidative folding of newly synthesized proteins, and in various cellular processes. Abnormal expression of TXNDC5 is associated with a variety of diseases including fibrosis, cancer, neurodegenerative diseases, and metabolic diseases. TXNDC5 promotes fibrosis primarily by activating the transcriptional growth factor β (tgfβ) signaling pathway, tgfβ induces organ fibrosis primarily by activating the classical SMAD signaling pathway and the non-classical signaling pathways (e.g., JNK, ERK, p, PI3K, and JAKs). TXNDC5 knockdown is effective in inhibiting renal fibrosis, pulmonary fibrosis, liver fibrosis, and cardiac fibrosis progression. It was found that TXNDC5 was significantly upregulated in bleomycin-induced pulmonary fibrosis in mice lung tissue, and that TXNDC5 knockout mice significantly reduced bleomycin-induced pulmonary fibrosis, by mechanisms, TXNDC5 induced pulmonary fibrosis by direct binding to tgfβr1 and stabilizing its structure, enhancing tgfβ signaling in lung fibroblasts. Overexpression of TXNDC5 triggers activation and proliferation of human cardiac fibroblasts (Human Cardiac Fibroblasts, HCFs) and increases ECM protein production. TXNDC5 promotes correct folding of ECM proteins, resulting in ECM sedimentation, promotes fibrosis, while deletion of TXNDC5 results in misfolding and degradation of ECM proteins in HCFs, reducing fibrosis. Knocking out TXNDC5 in mice can reduce isoproterenol-induced myocardial fibrosis and significantly improve cardiac function. Currently, there is no study on TXNDC5 function in PH.
Disclosure of Invention
The invention aims to provide an application of TXNDC5 serving as a drug target in preparing a drug for preventing and treating pulmonary arterial hypertension.
Therefore, the invention provides application of TXNDC5 in preparing medicines for preventing, treating and relieving pulmonary arterial hypertension.
Specifically, the above-mentioned drugs are drugs that inhibit transcription of TXNDC5 gene or expression of protein.
Specifically, the drug is one or more of small molecules, chemical agents, antisense oligonucleotides, siRNA, miRNA, ribozymes, polypeptides or protein inhibitors.
Specifically, the protein inhibitor comprises a structure of formula I;
The protein inhibitors inhibit the expression of TXNDC 5.
The invention also provides a pharmaceutical composition for preventing and treating pulmonary arterial hypertension, which comprises a pharmaceutically acceptable carrier and an active ingredient, wherein the active ingredient comprises the protein inhibitor.
Specifically, the pharmaceutically acceptable carrier is injection, capsule, granule, tablet, pill or oral liquid.
The invention also provides a method for screening drugs for preventing, treating, alleviating or improving pulmonary hypertension, comprising the steps of:
(1) Feeding a pulmonary arterial hypertension animal model under conditions of administration of a candidate agent and non-administration of said candidate agent, respectively;
(2) Determining the amount of TXNDC5 expression in the pulmonary artery endothelial layer and adventitia fibroblast layer of a pulmonary artery high pressure animal model with and without administration of the candidate agent;
(3) When the amount of TXNDC5 expressed in the candidate agent is greater than in the absence of the candidate agent, the candidate agent is used as an indication of a medicament for preventing, treating, alleviating or ameliorating pulmonary arterial hypertension.
Compared with the prior art, the invention has the following advantages and beneficial effects:
The invention proves that the TXNDC5 participates in the occurrence and development of PH, has an important effect on improving PH, and provides that the TXNDC5 can be used as a PH drug target for preparing PH prevention and treatment drugs. Overexpression of TXNDC5 induces endothelial cells EndMT and inhibitors ZEX that inhibit expression of TXNDC5 inhibit tgfβ1-induced proliferation of RPAFs cells. ZEX can inhibit the RVSP and right cardiac hypertrophy index of bleomycin induced mouse PH. Therefore, the TXNDC5 can be used as a drug target for preparing a drug for preventing and treating PH, and has important significance for development, prevention and treatment of PH drugs.
The present invention will be described in further detail with reference to the accompanying drawings.
Drawings
FIG. 1 shows the results of RNA-seq and gene co-expression analysis; wherein A is HySu induced PH model mouse pulmonary artery up-regulating gene KEGG analysis result; b is an RNA-seq result, n=4; c is qRT-PCR result, n=7; mean ± s.e.m. student's t-test: * P <0.05, < P <0.01, < P <0.001; d is the positive correlation of TXNDC5 with ECM, inflammation-related genes, and tgfβ signaling pathway-related protein gene expression; nor: normal oxygen; hySu: hypoxia + Sugen5416.
FIG. 2 shows that TXNDC5 is expressed predominantly in PAFs and PAECs and responds to TGF-beta 1 stimulation; wherein A is immunofluorescence stained rat lung tissue section; b is TGF beta 1 to induce TXNDC5 and fibrosis related proteins to be up-regulated in HPFs/HUVECs; c is Westernblotting detection of lentivirus-mediated overexpression of TXNDC5 in HUVEC; d is qRT-PCR detected at EndMT, metabolic and ECM related gene expression, and the sample is a cell sample of lentivirus-mediated TXNDC5 over-expressed in HUVEC for 5 days.
FIG. 3 is a graph showing that TXNDC5 inhibitors inhibit bleomycin-induced PH; wherein a is the binding of recombinant protein TXNDC5 to CY 3-labeled inhibitor ZEX; b is ZEX to inhibit TGF beta 1 induced increase in HPF fibrotic protein; c is a mouse death curve; d is right heart systolic pressure of the mice; e is the right ventricular hypertrophy index of the mice; f is a mouse lung 2D structure; g is a mouse lung 3D structure; VE: normal control; ve+ ZEX: the trachea instills normal saline and simultaneously irrigates the stomach ZEX every day; BLM: bleomycin induction; blm+ ZEX: BLM induction with daily lavage ZEX; n=5-8, mean±s.e.m.one-wayANOVA: * P <0.05, < P <0.01, < P <0.001.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in the following examples, and it is obvious that the described examples are only some examples of the present invention, but not all examples. Although representative embodiments of the present invention have been described in detail, those skilled in the art to which the invention pertains will appreciate that various modifications and changes can be made without departing from the scope of the invention. Accordingly, the scope of the invention should not be limited to the embodiments, but should be defined by the appended claims and equivalents thereof.
The invention provides application of TXNDC5 serving as a drug target in preparation of a drug for preventing and treating pulmonary arterial hypertension. The related gene TXNDC5 protein Coding region (CDS) is characterized in that the full length of the sequence of the transcript of the murine TXNDC5 gene in NCBI database is 1254bp, and the sequence is shown as SEQ ID NO. 1.
SEQ ID NO.1
The drug inhibits the activity of TXNDC5 or inhibits TXNDC5 to promote the folding of TFG beta 1 or inhibits the gene expression of TXNDC 5.
Specifically, the drug is one or more of small molecules, chemical agents, antisense oligonucleotides, siRNA, miRNA, ribozymes, polypeptides or protein inhibitors. The medicine can be prepared into solid preparation or liquid preparation. Further, the medicine can be prepared into injection, oral liquid, granule, powder, tablet or capsule.
Preferably, the protein inhibitor comprises a structure of formula I;
the protein inhibitor, designated ZEX, was able to inhibit the expression of TXNDC 5.
Stimulation of isolated rat pulmonary artery smooth muscle cells with EGF stimulated phosphorylation of TXNDC5 ZEX was effective in inhibiting phosphorylation of TXNDC5, while ZEX was effective in activating pyruvate kinase activity of TXNDC 5.
ZEX can activate the pyruvate kinase activity of purified TXNDC5 protein and stabilize the tetrameric structure of TXNDC5 in vitro biochemical experiments.
The invention also provides a pharmaceutical composition for preventing and treating pulmonary arterial hypertension, which comprises a pharmaceutically acceptable carrier and an active ingredient, wherein the active ingredient comprises the protein inhibitor. The pharmaceutically acceptable carrier is injection, capsule, granule, tablet, pill or oral liquid.
The obtained pharmaceutical composition can slow down the mouse RVSP and cardiac hypertrophy index induced by bleomycin and inhibit the proliferation of rat pulmonary artery fibroblasts stimulated by TGF beta 1.
The invention also provides a method for screening drugs for preventing, treating, alleviating or improving pulmonary hypertension, comprising the steps of:
(1) Feeding a pulmonary arterial hypertension animal model under conditions of administration of a candidate agent and non-administration of said candidate agent, respectively;
(2) Determining the amount of TXNDC5 expression in the pulmonary artery endothelial layer and adventitia fibroblast layer of a pulmonary artery high pressure animal model with and without administration of the candidate agent;
(3) When the amount of expression of TXNDC5 under conditions of administration of the candidate agent is lower than the conditions of no administration of the candidate agent, the candidate agent is used as an indication of a medicament for preventing, treating, alleviating or ameliorating pulmonary arterial hypertension.
In a preferred embodiment, the invention provides a method for preparing a lentivirus with TXNDC5 over-expression, comprising the following steps:
(1) Obtaining target gene fragments: the full-length cDNA of the rat is used as a template, a primer is amplified through a PCR reaction, a specific primer for amplifying TXNDC5 is utilized, a model gene fragment is obtained through a polymerase chain reaction, and a target gene fragment is a DNA double-stranded fragment of TXNDC 5.
Fragment of interest and vector ligation: and (3) carrying out enzyme digestion on the vector plasmid by using EcoRI and BamHI to obtain a linearized vector fragment, and carrying out agarose gel electrophoresis after enzyme digestion is finished to recover the target fragment. And (3) further cloning a connection system, and connecting the DNA double-stranded bottoming fragment of the TXNDC5 in the step (1) into the pCDH-GFP+Puro-3xFlag vector after enzyme digestion to obtain the TXNDC5 over-expressed lentiviral vector.
Lentivirus packaging: and simultaneously transfecting 293T cells with the constructed viral vector and Pmd2.G and psPAX2 lentivirus packaging auxiliary plasmids, packaging the viruses in the cells, collecting the cells, performing cell lysis, centrifuging to obtain supernatant, performing ultracentrifugation to obtain virus particles, and measuring the virus titer.
The correlation between TXNDC5 and pulmonary arterial hypertension is described in detail below by way of specific examples. .
Example 1:
This example shows that TXNDC5 is associated with ECM, inflammation and metabolism in PH by RNA-seq and gene co-expression analysis
1. Experimental animal
To investigate the effect of TXNDC5 on hypoxia-induced PH, SD rats were randomly divided into normoxic (Nor), hypoxic (Hyp-PH) and hypoxic+sugen (HySu-PH) groups of 8 normoxic (Nor) groups placed at normoxic; hypoxia groups were placed in a 10% hypoxia incubator for 4 weeks at 8 weeks of age in rats; the hypoxia + Sugen group was injected by neck injection of Sugen5416 at 8 weeks of age in rats, then placed in a 10% hypoxia incubator for 3 weeks and then placed under normoxic conditions for 2 weeks. Each PH related index detection is carried out on the 3 groups of model mice, and the specific method is as follows:
① Determination of right ventricular systolic pressure and mean pulmonary artery pressure: groups of mice were anesthetized by intraperitoneal injection and Right Ventricular Systolic Pressure (RVSP) was determined by catheterization. After the pressure measurement is finished, the heart and the lung are completely taken out immediately, the Right Ventricle (RV) and the left ventricle adding chamber interval (LV+S) are separated, the filter paper is used for absorbing the water, the water is respectively weighed, and the ratio RV/(LV+S) of the two is calculated to be used as the right heart hypertrophy index to reflect the right ventricular hypertrophy change.
② Preparation of lung tissue specimens: taking the left lung of a rat, fixing formaldehyde, slicing paraffin, and staining with HE; part of the kit is directly frozen in liquid nitrogen, and immunohistochemical detection is carried out through frozen sections.
③ Pulmonary vascular morphology analysis: after the lung tissue section HE is stained, the pulmonary arterioles with the diameter of 0-100 mu m are observed under a microscope, images are acquired by using professional software, the outer diameter, the wall thickness, the total area of blood vessels and the wall area of the pulmonary arterioles are analyzed, and the percentage of the wall thickness to the outer diameter and the percentage of the wall area to the total area are calculated.
④ Immunofluorescence detection: smooth muscle cell marker protein alpha-SMA, TXNDC5
⑤ QRT-PCR detects the expression level of ECM, inflammation, proliferation, migration and fibrosis related proteins, such as TGF beta R1, FN1, CTGF, POSTN, COL A1, COL3A1, OSM, INOS, IL-1 beta and PKM2.
2. Statistical analysis
The comparison between the two groups was performed using the unpaired t-test and the comparison between the groups was performed using one-way analysis of variance (one-wayANOVA, tukey's multiple comparison test) expressed as mean.+ -. Standard deviation (mean.+ -. SD) using prism9.0 software. Assume that the test level is determined at α=0.05. P is less than or equal to 0.05, and the difference is statistically significant. Correlation analysis the Spearman correlation analysis was used. Assume that the test level is determined at α=0.05. P <0.05 indicates that the difference is statistically significant.
3. Experimental results
To identify new target proteins associated with pulmonary artery remodeling, normoxic and HySu-induced rat pulmonary arteries were RNA-seq and analyzed to find that a large number of genes were up-regulated in HySu-induced rat pulmonary arteries, and these genes were clustered and KEGG enriched to find that a cluster of genes was all enriched in ECM-related signaling pathways (fig. 1A). Consistent with the results of the functional assays, the expression level of ECM-and tgfβr1-related genes was significantly up-regulated (fig. 1B). Meanwhile, qRT-PCR results showed that extracellular matrix (ECM) proteins, fibrosis-related proteins, and inflammation-related protein genes were significantly up-regulated in HySu-induced PH model rat pulmonary arteries (fig. 1C). Association analysis showed that protein TXNDC5 associated with tgfβ signaling pathway is positively correlated with ECM remodeling, inflammation and metabolism related genes including tgfβr1, FN1, CTGF, POSTN, COL A1, COL3A1, OSM, INOS, IL-1 β, PKM2 (fig. 1D).
By validating from mRNA levels, increased expression of TXNDC5 in HySu-PH rat lung tissue suggests that TXNDC5 is involved in the development of PH.
Example 2:
this example was studied on the basis of example 1 and found that TXNDC5 is expressed predominantly in PAFs and PAECs and responds to tgfβ1 stimulation.
1. Immunofluorescent staining
5 ΜM sections of paraffin-embedded lung tissue samples were dried at 65℃for 30 min, and the sections were sequentially placed in xylene for 10 min, absolute ethanol (I) for 5min, absolute ethanol (II) for 5min, 90% ethanol for 5min, 80% ethanol for 5min, 70% ethanol for 5min, deionized water for 5min; subsequently, the slice is placed in the repairing liquid for 10 minutes at high temperature; then, the sections are sequentially placed in a blocking solution (PBST solution of 5% BSA) for incubation for 1 hour at normal temperature; incubating overnight at 4deg.C in a blocking solution containing TXNDC5 and a-SMA primary antibody; PBST is washed 3 times; incubating for 45 minutes at normal temperature in a sealing solution containing the fluorescent secondary antibody; PBST is washed 3 times; incubation for 3 min in DAPI-containing staining solution; PBS was washed 2 times; and (5) photographing and analyzing.
2. Experimental results
In order to study the function of TXNDC5 in PH, firstly, the localization of TXNDC5 is explored, and immunofluorescence stained rat lung tissue sections find that the expression level of TXNDC5 in pulmonary artery adventitia fibroblasts and intimal endothelial cells in low-oxygen and low-oxygen +Sugen induced PH rat lung tissues is high. It was shown that TXNDC5 is localized mainly in the pulmonary artery endothelial and adventitial fibroblast layers in lung tissue of Hyp and HySu-induced PH rats (fig. 2A). From FIG. 2B, TGF-beta 1 stimulates the up-regulation of TXNDC5 in HPF and HUVECs. Over-expression of TXNDC5 in HUVECs (fig. 2C), the mesenchymal specific genes (slug, snail, FSP and ZEB 2) were found to be significantly up-regulated, and the endothelial specific genes (CD 31, VE-cadherein and vWF) were significantly down-regulated (fig. 2D), indicating that TXNDC5 is associated with the EndMT procedure.
Example 3:
The present embodiment provides a protein inhibitor comprising a structure of formula I;
the protein inhibitor, designated ZEX, was able to inhibit the expression of TXNDC 5.
This example also investigated ZEX inhibition of bleomycin-induced PH.
1. Experimental animal
To investigate the effect of TXNDC5 on hypoxia-induced PH, C57 mice were randomized into 4 groups, vehicle group (VE), ve+ ZEX group, bleomycin-induced group (BLM-PH) and ZEX-treated group (BLM-ph+ ZEX), bleomycin was induced by tracheal instillation at 8 weeks of age in mice for 3 weeks, ZEX was administered intragastrically for 3 weeks from the first day. The PH related indexes of the model mice are detected, and the specific method is as follows:
① Performing tomography on the lung of the mouse by utilizing micro-CT to obtain a lung image;
② Determination of right ventricular systolic pressure and mean pulmonary artery pressure: groups of mice were anesthetized by intraperitoneal injection and Right Ventricular Systolic Pressure (RVSP) was determined by catheterization. After the pressure measurement is finished, the heart and the lung are completely taken out immediately, the Right Ventricle (RV) and the left ventricle adding chamber interval (LV+S) are separated, the filter paper is used for absorbing the water, the water is respectively weighed, and the ratio RV/(LV+S) of the two is calculated to be used as the right heart hypertrophy index to reflect the right ventricular hypertrophy change.
2. Statistical analysis
The comparison between the two groups was performed using the unpaired t-test and the comparison between the groups was performed using one-way analysis of variance (one-wayANOVA, tukey's multiple comparison test) expressed as mean.+ -. Standard deviation (mean.+ -. SD) using prism9.0 software. Assume that the test level is determined at α=0.05. P is less than or equal to 0.05, and the difference is statistically significant. Correlation analysis the Spearman correlation analysis was used. Assume that the test level is determined at α=0.05. P <0.05 indicates that the difference is statistically significant.
3. Experimental results
To investigate the effect of TXNDC5 inhibitors on bleomycin-induced mouse PH, an inhibitor ZEX of TXNDC5 was obtained from a pre-screen that was covalently bound to TXNDC5 (fig. 3A) while inhibiting tgfβ1-stimulated fibrosis-related protein up-regulation (fig. 3B). As shown in fig. 3C, the inhibitor ZEX reduced the number of bleomycin-induced mice deaths, inhibiting bleomycin-induced increases in RVSP and RV/lv+s in mice (fig. 3d,3 e). At the same time, it was also observed that the inhibitor was effective in alleviating bleomycin-induced lung tissue damage (fig. 3f,3 g).
Taken together, the present invention demonstrates that TXNDC5 is involved in the development of pH. Therefore, TXNDC5 can be used as a drug target point for preparing PH control drugs.
The foregoing examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention, and all designs that are the same or similar to the present invention are within the scope of the present invention.
Claims (7)
- Application of TXNDC5 in preparing medicine for preventing, treating and relieving pulmonary arterial hypertension.
- 2. The use according to claim 1, wherein: the drug is a drug that inhibits transcription of the TXNDC5 gene or expression of a protein.
- 3. The use according to claim 2, wherein: the medicine is one or more of small molecules, chemical agents, antisense oligonucleotides, siRNA, miRNA, ribozymes, polypeptides or protein inhibitors.
- 4. A use according to claim 3, wherein: the protein inhibitors include structures of formula I;The protein inhibitors inhibit the expression of TXNDC 5.
- 5. A pharmaceutical composition for preventing and treating pulmonary arterial hypertension, which is characterized in that: the pharmaceutical composition comprises a pharmaceutically acceptable carrier and an active ingredient comprising the protein inhibitor of claim 4.
- 6. The pharmaceutical composition for preventing and treating pulmonary hypertension according to claim 5, wherein: the pharmaceutically acceptable carrier is injection, capsule, granule, tablet, pill or oral liquid.
- 7. A method of screening for a drug for preventing, treating, alleviating or ameliorating pulmonary hypertension, comprising the steps of:(1) Feeding a pulmonary arterial hypertension animal model under conditions of administration of a candidate agent and non-administration of said candidate agent, respectively;(2) Determining the amount of TXNDC5 expression in the pulmonary artery endothelial layer and adventitia fibroblast layer of a pulmonary artery high pressure animal model with and without administration of the candidate agent;(3) When the amount of expression of TXNDC5 under conditions of administration of the candidate agent is lower than the conditions of no administration of the candidate agent, the candidate agent is used as an indication of a medicament for preventing, treating, alleviating or ameliorating pulmonary arterial hypertension.
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