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Hindawi Journal of Oncology Volume 2021, Article ID 9130650, 12 pages https://doi.org/10.1155/2021/9130650 Research Article Study on the Mechanism of Capillary Leakage Caused by Hypoxia-Inducible Factor-1α through Inducing High Expression of Matrix Metalloproteinase-9 Huili Li, He Huang, Yunliang Cui , Weiwei Li, Shuliu Zhang, and Yugang Chen Department of Critical Care Medicine, e 960th Hospital of the PLA Joint Logistics Support Force, Jinan 250031, Shandong, China Correspondence should be addressed to Yunliang Cui; cuiyunliangicu@163.com Received 17 July 2021; Accepted 17 August 2021; Published 17 September 2021 Academic Editor: Ashok Pandurangan Copyright © 2021 Huili Li et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purposes. )is study mainly explored the mechanism of capillary leakage caused by hypoxia-inducible factor-1α through inducing high expression of matrix metalloproteinase-9. Method. We established a monolayer endothelial cell model by culturing human umbilical vein endothelial cells (HUVEC) in vitro, used tumor necrosis factor (TNFα) and HIF-1α inhibitor 2-methoxyestradiol (2ME2) to act on HUVEC, and at the same time constructed siRNA-transfected HUVEC to interfere with the expression of HIF- 1α. )e permeability of monolayer endothelial cells was measured by transwell chamber method, the concentration of MMP-9 in the supernatant was measured by ELISA method, the expression of key molecules related to permeability (HIF- 1α, MMP-9, claudin-5, and ZO-1) was measured by RT-PCR and Western blot method, and the localization and expression of claudin-5 and ZO-1 were measured by immunofluorescence method. We searched for 7 HIF-1α hypoxia response elements within 4000 bp before the transcription start site in the MMP-9 promoter region, constructed the MMP-9 promoter-luciferase reporter gene recombinant plasmid, transfected and stimulated HUVEC with TNFα, and detected the effect of 7 hypoxia response element plasmids on the transcription activity of MMP-9 promoter. Results. Under the action of TNFα, the permeability of monolayer endothelial cells increased, and the concentration of MMP-9 in the cell supernatant increased. 2ME2 and HIF-1α-siRNA transfection can improve the above situation (P< 0.05). 2ME2 and HIF-1α-siRNA transfection can inhibit the high expression of HIF-1α and MMP-9 caused by TNFα, thereby increasing the expression of claudin-5 and ZO-1 (P< 0.05). 2ME2 and HIF-1α- siRNA transfection can reduce the inhibition of TNFα on the expression of cell membrane protein claudin-5 and tight junction protein ZO-1. Element 1, element 5, and element 7 are the sites where HIF-1α interacts with MMP-9 at the transcription level. Conclusion. )is study shows that HIF-1α can increase the permeability of monolayer epithelial cells by inducing the high expression of MMP-9, leading to capillary leakage. Its target is at the −3798 bp, −1878 bp, and −1489 bp points of the transcription initiation site in the MMP-9 promoter region. therapy to reverse the destruction of the endothelial barrier 1. Introduction [5]. )erefore, it is necessary to study the underlying Vascular leakage is the main reaction of tissue damage [1]. mechanism of vascular leakage. )e destruction of the endothelial barrier and vascular HIF-1 is a heterodimer composed of α subunit and β leakage are characteristics of a variety of life-threatening subunit. HIF-1α (hypoxia-inducible factor-1a) encodes the α diseases, including sepsis, acute respiratory distress syn- subunit of the transcription factor hypoxia-inducible factor- drome (ARDS), and COVID-19, which have an important 1 (HIF-1). HIF-1 activates the transcription of many genes, impact on the morbidity and mortality of critically ill pa- including genes involved in energy metabolism, angiogen- tients [2–4]. Despite the serious adverse clinical results esis, and apoptosis and genes generating other protein associated with vascular leakage, there is currently no products that can increase oxygen transfer or promote 2 Journal of Oncology explored the mechanism of HIF-1α inducing the high ex- metabolism to adapt to hypoxia, as a main regulator in the homeostatic response to cells and the whole body hypoxia. pression of MMP-9 and causing capillary leakage. In this study, a monolayer endothelial cell model was HIF-1 plays an important role in embryonic angiogenesis, tumor angiogenesis, and pathophysiology of ischemic dis- established by culturing human umbilical vein endothelial cells eases. For example, it has been reported that HIF-1α pro- (HUVEC) in vitro, using tumor necrosis factor (TNFα) and motes tumor chemotherapy resistance by recruiting GDF15- HIF-1α inhibitor 2-methoxyestradiol (2ME2) to act on induced tumor-associated macrophages in colorectal cancer HUVEC, and constructing siRNA-transfected HUVEC to [6]; silencing long noncoding RNA NEAT1 stimulates HIF- interfere with the expression of HIF-1α. )e permeability of 1α/NF-kappaB by competitively binding miR-33a-5p to monolayer endothelial cells was measured by transwell chamber method, the concentration of MMP-9 in the super- inhibit the occurrence of infantile hemangioma [7]; under hypoxic conditions, miR-375 impairs the invasion ability of natant was measured by ELISA method, and the expression of key molecules (HIF-1α, MMP-9, claudin-5, and ZO-1) related liver cancer cells through targeted regulation of HIF-1α [8]; in the process of IL-1β-induced chondrocyte degeneration, to permeability was measured by RT-PCR and Western blot method. )e localization of claudin-5 and ZO-1 was observed FBW7 regulates the HIF-1α/VEGF pathway [9]; miR-210 regulates the inflammatory response of exudative otitis and the protein expression was reconfirmed by the immu- media by inhibiting the expression of HIF-1α [10]; extra- nofluorescence method. )e MMP-9 promoter-luciferase re- cellular vesicles from healthy cells activate and improve the porter gene recombinant plasmid was constructed and cell function of progeria stem cells and stem cells themselves transfected, TNFα was used to stimulate HUVEC, and the through miR-302b and HIF-1α [11]. effect of 7 hypoxia response element plasmids on the tran- Proteins of the matrix metalloproteinase (MMP) family scription activity of MMP-9 promoter was detected. are involved in the degradation of extracellular matrix in normal physiological processes, such as embryonic devel- 2. Materials and Methods opment, reproduction and tissue remodeling, and disease processes such as arthritis and metastasis. Most matrix 2.1. Cell Culture and Cell Transfection. HUVEC cells were metalloproteinases are secreted in the form of inactive cultured in DMEM high glucose medium (containing 10% fetal proproteins and are activated when cleaved by extracellular bovine serum) and placed in an incubator (37 C, 5% CO2), and proteases. MMP9 (matrix metallopeptidase 9), as a member the cell culture medium was replaced every 2 days until it grows of the matrix metallopeptidase family, also plays an im- and converges to 70–80% passage. 3–4 times passage was taken portant role in many diseases and life processes. In dentistry, for experiment and divided into 7 groups, namely, the normal MP-8, MMP-9, and BOP can be used to assess the peri- control group, only adding DMEM high glucose medium odontal condition of orthodontic patients [12]; in otology, containing 10% fetal bovine serum; TNFα group, adding the functional polymorphism of MMP9 and BDNF enables DMEM high glucose medium containing 50 ng/ml TNFα; them to be used as potential biomarkers of neuroplasticity in TNFα + 2ME2 (0.1 uM) group, adding DMEM high glucose the cochlear implantation treatment for the prelinguistic medium containing 50 ng/ml TNFα and 0.1 uM 2ME2; deaf [13]. Active MMP-9 increases at 7 and 14 days after TNFα + 2ME2 (0.01 uM) group, adding DMEM high glucose kidney transplantation and returns to baseline level 3 medium containing 50 ng/ml TNFα and 0.01 uM 2ME2; months after kidney transplantation, consistent with the TNFα + 2ME2 (0.001 uM) group, adding DMEM high glucose improvement of renal function and plasma creatinine. In medium containing 50 ng/ml TNFα and 0.001 uM 2ME2; HIF- dialysis patients and kidney transplant recipients, active 1α siRNA-negative control group, negative HIF-1α siRNA was MMP-9 is associated with pulse pressure as an indicator of used to transfect HUVEC, and after monolayer cells were arteriosclerosis. )erefore, active MMP-9 can be used as a formed, 50 ng/ml TNFα was added to act for 24 hours; HIF-1α biomarker of arterial stiffness in renal replacement therapy siRNA-positive transfection group, positive HIF-1α siRNA was [14]; in patients with colorectal liver metastasis, high ex- used to transfect HUVEC, and after monolayer cells were pression of MMP9 indicates that patients can get a better formed, 50 ng/ml TNFα was added to act for 24 hours. )is prognosis [15]; in addition, excessive activation of MMP-9 study was approved by the institutional ethical review board of will hinder the wound healing of diabetic skin. In diabetic the 960th Hospital of the PLA Joint Logistics Support Force, skin tissues, TET2 can induce demethylation of the MMP-9 China. promoter, leading to high expression of MMP9 [16]; in- creased expression levels of MMP2 and MMP9 in the premature myometrium will aggravate uterine contractions 2.2. Transwell Experiment. HUVEC was seeded in the upper [17]; MMP9 can also regulate the integrity of blood-testis chamber of the transwell (1 × 10 /well) to establish a complete barrier to prevent virus invasion and protect the body [18]; monolayer endothelial cell model. After drug action as inhibiting MMP9 can weaken migration, invasion, and grouped, we washed with PBS for 3 times, seeded 100 ul PBS colony formation and promote CD8(+) T cell infiltration which contains FITC-Dextran40 (FD40, dextran labeled with and activation. Interestingly, the primary tumor was not fluorescein isothiocyanate) 100 mg/L in the upper transwell affected, which indicates that inhibiting active MMP9 is chamber, filled the lower chamber with 600 ul PBS for 1hours, mainly effective in the early metastatic cascade. collected the PBS in the lower chamber, measured the intensity However, there are still very few studies on the mech- of FITC fluorescence with a fluorescence spectrometer, anism of HIF-1α on vascular leakage. )erefore, this study established a standard curve between fluorescence intensity Journal of Oncology 3 and FD40 concentration, and used FD40 concentration to then incubated with 1% hydrogen peroxide for 10 minutes. reflect the permeability of monolayer endothelial cells. After two PBS washes, the cells were incubated with blocking solution (PBS containing 1% bovine serum albumin, 0.4% Triton X-100, and 4% normal goat serum) for 20 minutes. 2.3.ELISA. HUVEC was seeded into a 96-well plate (1 × 10 / Next, the cells were incubated with primary antibodies, well). After stimulation with drugs as grouped, we took the claudin-5 antibody (1 :100, ab15106, Abcam), and ZO-1 supernatant and tested the concentration of MMP-9 by antibody (1 : 500, ab221547, Abcam) at 4 C overnight. )en ELISA method. )e kit was purchased from Abcam the cells were washed twice with PBS and labeled with (ab246539) and used following the kit instructions. )e fluorescein isothiocyanate (FITC) to culture secondary absorbance was measured at 450 nm with an ultraviolet antibodies (1 : 500) for 1 hour at room temperature. )e spectrophotometer. cover glass was fixed in a fixed medium, observed with a fluorescence microscope, and stained with DAPI (10 ug/ml). 2.4. RT-PCR. After establishing the monolayer HUVEC model, we added drugs as grouped and extracted total RNA 2.7. Dual-Luciferase Reporter Experiment. By searching with TRIzol reagent for detection. We used ABI Prism 7500 Ensemble and NCBI, two major gene databases, it was found system and 2X premixed SYBR Green (Enzynomics) to that the human MMP-9 genome contains 7 hypoxia re- detect the mRNA abundance by real-time quantitative PCR. sponse elements 4000 bp before the transcription start site in )e PCR conditions are as follows: 95 C (30 s) 1 cycle, and ° ° the promoter region. According to the hypoxia response 95 C (5 s), 60 C (34 s), 40 cycles. )e primers are as follows: element position of the human MMP-9 promoter sequence, HIF-1α upstream primer: 5′-CAGAGCAGGAAAGA- promoter fragments of different lengths were designed, and GAGTCATAGAAC-3′ and HIF-1α downstream primer: 5′- then the PCR primers of each promoter fragment were TTTCGCTT CCTCTGAGCATTC-3′; MMP-9 upstream designed and synthesized. )e whole blood DNA of healthy primer: 5′-GCC TGG CAC ATA GTA GGC CC-3′ and volunteers was extracted by the NaI method, human ge- downstream primer: 5′-CTT CCT AGC CAG CCG GCA nomic DNA was used as a template, the promoter fragment TC-3′; claudin-5 upstream primer: 5′-GAATTCGCCGC- was obtained by PCR amplification, the target DNA was CACCATGGGGTCTGCAGCGTTG-3′ and downstream cloned by T-A and transformed into E. coli Trans5α, and the primer: 5′-GAATTCTCAGACATAGTTCTTCTTGTCGT- plasmid was extracted for enzyme digestion identification. AATCG-3′; ZO-1 upstream primer: 5′-CGA GTT GCAA )e identified target DNA fragments were connected to TGG TTA ACG GA-3′ and downstream primer: 5′-TCA pGL3-Basic vector to construct a luciferase reporter plasmid, GGA TCA GGA CGA CTT ACT GG-3’; β-actin upstream E. coli Trans5α was transformed, amplified, sequenced, and primer: 5′-CCT GGC ACC CAG CAC AAT-3′ and identified, the luciferase reporter plasmid already con- downstream primer: 5′-GGG CGG GAC TCG TCA TAC-3′. structed was extracted, the plasmid was transfected into HUVEC, and the activity of the dual-luciferase reporter gene 2.5. Western Blot. After establishing a monolayer HUVEC after TNFα stimulation was detected. model, we added drugs as grouped and extracted total protein of the cells for detection. An equal volume of 2× Laemmli sample buffer was 2.8. Statistical Analysis. All analyses involved in this study added to the supernatant, and the supernatant mixture was used unpaired t-tests to calculate P values. )e result of ° ° boiled at 100 C for 5 minutes and stored at −20 C. )en, the P< 0.05 has statistical significance. centrifuge tube containing the supernatant mixture was thawed at 37 C. )e same amount of protein and maker was 3. Results loaded into the SDS-PAGE gel wells, with a sample amount of 20–30 μg, and electrophoresis was imposed at 100 V for 1 3.1. Permeability Test of Monolayer Endothelial Cells. In to 2 hours. )e antibody was purchased from Abcam, USA. order to detect the permeability of human monolayer en- )e primary antibodies were rabbit antibodies, anti-MMP-9 dothelial cells (HUVEC) under different treatment condi- antibody (ab76003), with a dilution ratio of 1 :1000, anti- tions, we tested the concentration of FD40 in different HIF-1α antibody (ab51608), with a dilution ratio of 1 : 500, treatment groups. )e concentration of FD40 in the lower anti-claudin 5 antibody (ab131259), with a dilution ratio of chamber of the TNFα group was 2.339± 0.149 mg/l, which 1 : 5000, and the anti-ZO-1 antibody (ab276131), with a was significantly higher than that of the normal control dilution ratio of 1 :1000. )e secondary antibodies were goat group, which was 1.485± 0.137 mg/l. In the TNFα + 2ME2 anti-rabbit antibodies (ab6721), with a dilution ratio of 1 : group, after giving 0.1 uM, 0.01 uM, and 0.001 uM 2ME2 for 3000. ImageJ software was used to quantify the gray value of coculture, the concentrations of FD40 were 1.927± 0.147, the resulting graph and drew a statistical graph. 1.803± 0.136, and 2.057± 0.193 mg/l, respectively. Com- pared with the TNFα group, P< 0.05, suggesting improved 2.6. Immunocytochemistry. )e immunofluorescence ex- permeability (Figure 1(a)). )e concentration of FD40 in the periment was carried out according to the previously lower chamber of the HIF-1α siRNA-positive transfection published method [19]. HUVEC was fixed with 4% para- group was 1.788± 0.088 mg/l, which was lower than formaldehyde for 30 minutes, washed twice with PBS, and 1.99± 0.176 mg/l (P � 0.008) in the HIF-1α siRNA-negative 4 Journal of Oncology ** 2.5 2.0 1.5 1.0 0.5 0 0.0 Negative HIF-1α siRNA (a) (b) 1500 1500 Negative HIF-1α siRNA (c) (d) Figure 1: Permeability test of monolayer endothelial cells. (a) )e effect of TNFα and TNFα combined with different concentrations of 2ME2 on the concentration of FD40. (b) )e effect of HIF-1α siRNA transfection on the concentration of FD40. (c) Using ELISA method to detect the effect of TNFα and TNFα combined with different concentrations of 2ME2 on the concentration of MMP9 protein. P< 0.05; ∗∗ P< 0.01. (d) Using ELISA method to detect the effect of HIF-1α siRNA transfection on the concentration of MMP9 protein. control group, suggesting that after siRNA knocked down 1αsiRNA-negative control group 921.1± 76.48 pg/ml HIF-1α expression, the permeability decreased (Figure 1(b)). (P � 0.03), indicating that after siRNA knocks down the ex- In order to detect the effect of changes in cell perme- pression of HIF-1α, the concentration of MMP9 in the su- ability on the concentration of extracellular MMP9, we pernatant is reduced (Figure 1(d)). tested the concentration of MMP9 in the supernatant. )e results showed that the concentration of MMP9 in the su- pernatant of the TNFα group was 926.6± 322.6 pg/ml, which 3.2. HIF-1α, MMP-9, Claudin-5, and ZO-1 DNA Expression was significantly higher than that of the normal control Changes. )e relative expression of HIF-1α mRNA in the group of 348.2± 130.1 pg/ml. In the TNFα + 2ME2 group, normal control group was 1.006± 0.036, and the relative after giving 0.1 uM, 0.01 uM, and 0.001 uM 2ME2, respec- expression in the TNFα group was 2.080± 0.267, which was tively, for coculture, the concentrations of MMP9 were significantly higher than that in the normal control group, 655.9± 213.66, 696.9± 235.27, and 839.5± 284.28 pg/ml, P< 0.01; in the TNF α + 2ME2 0.1 uM group, the respectively, which were lower than those in the TNFα TNFα + 2ME2 0.01 uM group, and the TNFα + 2ME2 group, P< 0.05 (Figure 1(c)). 0.001 uM group, the relative expression of HIF-1α mRNA )e concentration of MMP9 in the supernatant of was 0.292± 0.099, 1.464± 0.066, and 1.795± 0.172, respec- the HIF-1α siRNA-positive transfection group was tively. 0.1 uM and 0.01 uM 2ME2 can inhibit the high ex- 545.9± 43.82 pg/ml, which was lower than the HIF- pression of HIF-1α caused by TNFα, P< 0.01. )e inhibitory MMP9 (pg/ml) FD40 (mg/l) Normal Normal TNFα TNFα TNFα+ 2ME2 TNFα+ 2ME2 (0.1 μM) (0.1 μM) TNFα+ 2ME2 TNFα+ 2ME2 (0.01 μM) (0.01 μM) TNFα+ 2ME2 TNFα+ 2ME2 (0.001 μM) (0.001 μM) MMP9 (pg/ml) FD40 (mg/l) Journal of Oncology 5 inhibit the high expression of HIF-1α caused by TNFα, effect disappeared with 0.001 uM 2ME2, P � 0.145 (Figure 2(a)). P< 0.01. )e inhibitory effect disappeared with 0.001uM 2ME2, P � 0.288. )e relative expression of MMP9 mRNA in the normal control group was 1.006± 0.036, and the relative expression )e relative expression of MMP-9/β actin protein in the in the TNFα group was 2.237± 0.279, which was signifi- normal control group was 0.276± 0.021, and the relative cantly higher than that in the normal control group, P< 0.01; expression of MMP-9/β actin protein in the TNFα group was in the TNFα + 2ME2 0.1 uM group, the TNFα + 2ME2 0.570± 0.038, which was higher than that in the normal 0.01 uM group, and the TNFα + 2ME2 0.001 uM group, the control group, P< 0.01; after adding 2ME2 for intervention, relative expression of HIF-1α mRNA was 1.440± 0.101, the relative expression of MMP-9/β actin protein in the TNFα + 2ME2 0.1 uM group, the TNFα + 2ME2 0.01 uM 1.437± 0.103, and 2.063± 0.170, respectively. 0.1 uM and 0.01 uM 2ME2 can inhibit the high expression of HIF-1α group, and the TNFα + 2ME2 0.001 uM group was 0.455± 0.032, 0.454± 0.036, and 0.598± 0.018, respectively caused by TNFα, P< 0.01. )e inhibitory effect was not significant with 0.001 uM 2ME2, P � 0.686 (Figure 2(b)). (P< 0.01, P< 0.01, and P � 0.288). Compared with the TNFα group, the expression of MMP-9 protein in the )e relative expression of claudin-5 mRNA in the normal control group was 1.006± 0.036, and the relative TNFα + 2ME2 0.01 uM group and the TNFα + 2ME2 expression of claudin-5 mRNA in the TNFα group was 0.001 uM group was significantly reduced, and the expres- 0.350± 0.080, which was lower than that in the normal sion of MMP-9 protein in the TNFα + 0.001 uM 2ME2 group control group, P< 0.01; after adding 2ME2 for intervention, was slightly increased, P � 0.408 (Figure 4(a)). in the TNFα + 2ME2 0.1 uM group, the TNFα + 2ME2 )e relative expression of claudin-5/β actin protein in 0.01 uM group, and the TNFα + 2ME2 0.001 uM group, the the normal control group was 0.877± 0.026, and the relative expression of claudin-5/β actin protein in the TNFα group relative expression of claudin-5mRNA was 0.580± 0.084, 0.669± 0.073, and 0.679± 0.113, respectively. Compared was 0.199± 0.079, which was lower than that in the normal control group, P< 0.01; after adding 2ME2 for intervention, with the TNFα group, the expression of claudin-5 mRNA was significantly increased, P< 0.01 (Figure 2(c)). the relative expression of claudin-5/β actin protein in the TNFα + 2ME2 0.1 uM group, the TNFα + 2ME2 0.01 uM )e relative expression of ZO-1 mRNA in the normal control group was 1.006± 0.036, and the relative expression group, and the TNFα + 2ME2 0.001 uM group was of ZO-1 mRNA in the TNFα group was 0.350± 0.080, which 0.707± 0.018, 0.591± 0.019, and 0.605± 0.025, respectively. was lower than that in the normal control group, P< 0.01; Compared with the TNFα group, the expression of claudin-5 after adding 2ME2 for intervention, in the TNFα + 2ME2 was significantly increased, P< 0.01 (Figure 4(b)). 0.1 uM group, the TNFα + 2ME2 0.01 uM group, and the )e relative expression of ZO-1/β actin protein in the TNFα + 2ME2 0.001 uM group, the relative expression of normal control group was 0.928± 0.045, and the relative expression of ZO-1/β actin protein in the TNFα group was ZO-1 mRNA was 0.756± 0.079, 0.580± 0.086, and 0.594± 0.088, respectively. Compared with the TNFα group, 0.264± 0.009, which was lower than that in the normal control group, P< 0.01; after adding 2ME2 for intervention, the expression of ZO-1 was significantly increased, P< 0.01 (Figure 2(d)). the relative expression of ZO-1/β actin protein in the )e relative expression of HIF-1α and MMP-9 mRNA in TNFα + 2ME2 0.1 uM group, the TNFα + 2ME2 0.01 uM the HIF-1α siRNA-positive transfection group was group, and the TNFα + 2ME2 0.001 uM group was 0.193± 0.036 and 0.298± 0.047, respectively, which was 0.819± 0.037, 0.462± 0.015, and 0.481± 0.026, respectively. lower than 1.112± 0.307 in the HIF-1α siRNA-negative Compared with the TNFα group, the expression of ZO-1 control group, P< 0.01; the relative expression of claudin-5 protein was increased, P< 0.01 (Figure 4(c)). and ZO-1mRNA was 2.282± 0.158 and 3.021± 0.3259, re- )e relative expression of HIF-1α/β actin protein in the spectively, which was higher than 1.112± 0.307 in the HIF- HIF-1α siRNA-positive transfection group was 0.046± 0.005, which was lower than 0.154± 0.006 in the 1α siRNA-negative control group, P< 0.01. After siRNA interfered with the expression of HIF-1α, the expression of HIF-1α siRNA-negative control group (P< 0.01), suggesting that after siRNA knocked down the HIF-1α expression, the MMP-9 mRNA decreased accordingly, and the expression of claudin-5 and ZO-1 mRNA increased (Figure 3). HIF-1α expression caused by TNFα interfered. )e relative expression of MMP-9/β actin protein in the HIF-1α siRNA- positive transfection group was 0.278± 0.006, which was 3.3. HIF-1α, MMP-9, Claudin-5, and ZO-1 Protein Expression lower than 0.517± 0.021 in the HIF-1α siRNA-negative Changes. )e relative expression of HIF-1α/β actin protein control group (P< 0.01), indicating that after siRNA in- in the normal control group was 0.184± 0.016, and the terfered with the HIF-1α expression, the MMP-9 high ex- relative expression of HIF-1α/β actin protein in the TNFα pression was inhibited. )e relative expression of claudin-5/ group was 0.403± 0.015, which was significantly higher than β actin protein in the HIF-1α siRNA-positive transfection that in the normal control group, P< 0.01; 2ME2 can inhibit group was 0.498± 0.018, which was lower than 0.241± 0.011 HIF-1α expression. )e relative expression of HIF-1α/β in the HIF-1α siRNA-negative control group (P< 0.01), actin protein in the TNFα + 2ME2 0.1 uM group, the suggesting that after siRNA interfered with the HIF-1α TNFα + 2ME2 0.01 uM group, and the TNFα + 2ME2 expression, the expression of claudin-5 was promoted. )e 0.001 uM group was 0.282± 0.015, 0.318± 0.018, and relative expression of ZO-1/β actin protein in the HIF-1α 0.413± 0.030, respectively. 0.1 uM and 0.01 uM 2ME2 can siRNA-positive transfection group was 0.304± 0.004, which 6 Journal of Oncology ns ns ** ** ** ** ** 2.5 ** 2.0 1.5 1.0 0.5 0.0 (a) (b) ** 2.5 1.5 ** ** ** 2.0 ** ** 1.0 1.5 1.0 0.5 0.5 0.0 0.0 (c) (d) Figure 2: Changes in DNA levels of HIF-1α, MMP-9, claudin-5, and ZO-1 RT-PCR detected the effect of TNFα and TNFα combined with different concentrations of 2ME2 on the expression of HIF-1α (a), MMP-9 (b), claudin-5 (c), and ZO-1 (d) DNA levels. P< 0.05; ∗∗ P< 0.01; ns, no significant difference (no significance). ** ** 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0 Negative HIF-1α siRNA Negative HIF-1α siRNA (a) (b) Figure 3: Continued. HIF-1α mRNA expression Claudin-5 mRNA expression HIF-1α mRNA expression Normal Normal TNFα TNFα TNFα+ 2ME2 TNFα+ 2ME2 (0.1 μM) (0.1 μM) TNFα+ 2ME2 TNFα+ 2ME2 (0.01 μM) (0.01 μM) TNFα+ 2ME2 TNFα+ 2ME2 (0.001 μM) (0.001 μM) MMP9 mRNA expression ZO-1 mRNA expression MMP9 mRNA expression Normal Normal TNFα TNFα TNFα+ 2ME2 TNFα+ 2ME2 (0.1 μM) (0.1 μM) TNFα+ 2ME2 TNFα+ 2ME2 (0.01 μM) (0.01 μM) TNFα+ 2ME2 TNFα+ 2ME2 (0.001 μM) (0.001 μM) Journal of Oncology 7 3 4 ** ** 0 0 Negative HIF-1α siRNA Negative HIF-1α siRNA (c) (d) Figure 3: HIF-1α, MMP-9, claudin-5, and ZO-1 DNA expression changes. RT-PCR was used to detect the effect of HIF-1α siRNA ∗∗ transfection on the level of DNA expression of HIF-1α (a), MMP-9 (b), claudin-5 (c), and ZO-1 (d). P< 0.01. ns ns ** ** ** ** 0.8 ** ** 0.4 0.6 0.3 0.4 0.2 0.2 0.1 0.0 0.0 (a) (b) Figure 4: Continued. HIF-1α expression (/β-actin) Claudin-5 mRNA expression Normal TNFα TNFα+ 2ME2 (0.1 μM) TNFα+ 2ME2 (0.01 μM) TNFα+ 2ME2 (0.001 μM) MMP9 expression (/β-actin) Claudin-5 mRNA expression Normal TNFα TNFα+ 2ME2 (0.1 μM) TNFα+ 2ME2 (0.01 μM) TNFα+ 2ME2 (0.001 μM) 8 Journal of Oncology ** ** ** ** 1.5 1.0 ** ** ** 0.8 ** 1.0 0.6 0.4 0.5 0.2 0.0 0.0 (c) (d) Figure 4: HIF-1α, MMP-9, claudin-5, and ZO-1 protein expression changes. Western blot was used to detect the effects of TNFα and TNFα combined with different concentrations of 2ME2 on the protein expression of HIF-1α (a), MMP-9 (b), claudin-5 (c), and ZO-1 ∗∗ (d). P< 0.01, ns (no significance). was lower than 0.032± 0.004 in the HIF-1α siRNA-negative 4. Discussion control group (P< 0.01), suggesting that after siRNA in- )is study found that, under the action of TNFα, the per- terfered with the HIF-1α expression, the expression of ZO-1 meability of the HUVEC monolayer increased and the was promoted (Figure 5). concentration of MMP-9 in the cell supernatant increased (PMID: 30976100). 2ME2 and HIF-1α-siRNA transfection 3.4. Immunofluorescence Detection of the Effect of TNFα on the can improve the above situation (P< 0.05). TNFα is a Expression of Claudin-5 and ZO-1 in Human Umbilical Vein proinflammatory factor secreted by macrophages and en- Endothelial Cells. )e fluorescent pattern of claudin-5 and dothelial cells, which is related to the increase of plaque load ZO-1 proteins in the normal control group was continuous, [20]. Recent literature reported that TNFα can lead to the loss and there were many fluorescent particles. )e fluorescent of adhesion protein, thereby increasing cell permeability [21]. pattern of claudin-5 and ZO-1 proteins in the TNFα group In our results, the extracellular FD40 concentration under the showed an obvious break, and the fluorescent particles were action of TNFα increased significantly, indicating an increase significantly reduced. )e fluorescence pattern of claudin-5 and in cell permeability, which is consistent with previous reports. ZO-1 protein was more continuous than that of the TNFα However, with the addition of the HIF-1α inhibitor 2- group, with more fluorescent particles (Figure 6(a)). )e methoxyestradiol (2ME2), the increasing trend of FD40 con- fluorescent pattern of claudin-5 and ZO-1 proteins in the HIF- centration was inhibited, and with the increase of the 2ME2 1α siRNA-positive transfection group was more continuous concentration, the inhibitory effect gradually increased. Be- than that of the HIF-1α siRNA-negative control group, and the sides, the addition of HIF-1α siRNA would also significantly number of fluorescent particles increased (Figure 6(b)). decrease the concentration of FD40, suggesting that TNFα may affect cell permeability by regulating HIF-1α (Figure 8). 3.5. Mechanism of HIF-1α′s Direct Initiation of MMP-9 at the By investigating the literature, we found that HIF-1α can Transcription Level. In order to explore the mechanism of affect the expression of MMP-9 [22, 23]. )erefore, we HIF-1α′s direct activation of MMP-9 at the transcription hypothesized the influence mechanism of HIF-1α on cell level, we searched Ensemble and NCBI, two major gene permeability. Perhaps HIF-1α affects cell permeability by databases, and found that the human MMP-9 genome has 7 affecting the expression of MMP9. We tested the expression hypoxia response elements in a length of 4000 bp before the of MMP9 through ELISA experiments. )e results showed transcription start site in the promoter region. )rough the that TNFα can induce the expression of MMP9, while the double luciferase reporter gene experiment, it was found that addition of 2ME2 and HIF-1α-siRNA can slow down this the activities of HRE1, HRE5, and HRE7 after TNFα stimu- process, which confirmed our conjecture from the side. lation were significantly higher than those of other HREs Subsequently, we further verified our conjecture through (6.33± 0.482, 7.25± 0.488, and 6.38± 1.010, P< 0.05, Figure 7). RT-PCR and Western blot experiments. )e results showed Claudin-5 expression (/β-actin) Normal TNFα TNFα+ 2ME2 (0.1 μM) TNFα+ 2ME2 (0.01 μM) TNFα+ 2ME2 (0.001 μM) ZO-1 expression (/β-actin) Normal TNFα TNFα+ 2ME2 (0.1 μM) TNFα+ 2ME2 (0.01 μM) TNFα+ 2ME2 (0.001 μM) Journal of Oncology 9 HIF-1α MMP9 β-actin β-actin ** 0.6 0.20 ** 0.15 0.4 0.10 0.2 0.05 0.0 0.00 Negative HIF-1α siRNA Negative HIF-1α siRNA (a) (b) Claudin-5 ZO-1 β-actin β-actin 0.4 0.6 ** ** 0.3 0.4 0.2 0.2 0.1 0.0 0.0 Negative HIF-1α siRNA Negative HIF-1α siRNA (c) (d) Figure 5: HIF1α, MMP-9, claudin-5, and ZO-1 protein expression changes. Western blot was used to detect the effect of HIF-1α siRNA ∗∗ transfection on the protein expression of HIF-1α (a), MMP-9 (b), claudin-5 (c), and ZO-1 (d). P< 0.01. TNFα+ 2ME2 TNFα+ 2ME2 TNFα+ 2ME2 Normal TNFα (0.1 μM) (0.01 μM) (0.001 μM) 400x 400x 400x 400x 400x (a) TNFα+ 2ME2 TNFα+ 2ME2 TNFα+ 2ME2 Normal TNFα (0.1 μM) (0.01 μM) (0.001 μM) 400x 400x 400x 400x 400x (b) Figure 6: Continued. HIF-1α expression (/β-actin) Claudin-5 expression (/β-actin) ZO-1 Claudin-5 ZO-1 expression (/β-actin) MMP9 expression (/β-actin) 10 Journal of Oncology Negative HIF-1α siRNA Negative HIF-1α siRNA 400x 400x 400x 400x (c) (d) Figure 6: Immunofluorescence detection of the effect of TNFα on the expression of claudin-5 and ZO-1 in human umbilical vein en- dothelial cells. (a) and (c) )e effect of TNFα, TNFα combined with 2ME2 and siRNA transfection on the expression of claudin-5. (b, d) )e effect of TNFα, TNFα combined with 2ME2 and siRNA transfection on the expression of ZO-1. 10 * while 2ME2 and HIF-1α-siRNA can inhibit this process. * ZO-1 is involved in cell adhesion and tight junction. As an important structural protein of tight junction, ZO-1 maintains the integrity of the tight junction complex mainly by connecting claudins, occlusion proteins, and cytoskeleton proteins. Abnormal expression of ZO-1 may hinder the formation of tight junction between cells [27, 28]. In our research results, the expression trend of ZO-1 is consistent with claudin-5. )is once again indi- cates from the side that TNFα and HIF-1α will affect the permeability of cell membranes. Control HRE1 HRE2 HRE3 HRE4 HRE5 HRE6 HRE7 In order to have a more intuitive understanding of the Figure 7: Dual-luciferase experiment to explore the mechanism of regulatory relationship between HIF-1α and MMP9, we HIF-1α′s direct activation of MMP-9 at the transcription level. searched the database, designed primers, and used dual-lu- ciferase experiments to explore the possible sites. Finally, it was found that element 1, element 5, and element 7 of HIF-1α HIF-1α were the sites that interact with MMP-9 at the transcription MMP9 level, confirming the interaction between HIF-1α and MMP9. Claudin-5 TNFα HIF-1α 5. Conclusions capillary leakage ZO-1 All in all, this study showed that, under the action of TNFα, the permeability of monolayer endothelial cells Figure 8: Mechanism diagram. increased, and the concentration of MMP-9 in the cell supernatant increased. 2ME2 and HIF-1α-siRNA trans- that TNFα can induce the expression of HIF-1α at the fection can improve the above situation (P< 0.05). 2ME2 mRNA level and protein level, which is consistent with the and HIF-1α-siRNA transfection can inhibit the high ex- report by Tsapournioti et al. [24]. 2ME2 and HIF-1α-siRNA pression of HIF-1α and MMP-9 caused by TNFα, thereby transfection can inhibit the expression of HIF-1α caused by increasing the expression of claudin-5 and ZO-1 TNFα. At the same time, TNFα can also induce the ex- (P< 0.05). 2ME2 and HIF-1α-siRNA transfection can pression of MMP9 at the mRNA level and protein level, improve the inhibition of TNFα on the expression of cell which is also consistent with previous reports [25]. )e membrane protein claudin-5 and tight junction protein addition of 2ME2 and HIF-1α-siRNA can also inhibit the ZO-1. Element 1 (−3798 bp), element 5 (−1878 bp), and ability of TNFα to regulate MMP9, which has once again element 7 (−1489 bp) were the sites where HIF-1α confirmed the regulatory effect of HIF-1α on MMP9. interacted with MMP-9 at the transcription level. In addition, in order to further explore the correlation between TNFα and HIF-1α and cell permeability, we also tested the expression of the membrane protein claudin-5 Data Availability and tight junction protein ZO-1. Claudin-5 is a member of )e data used to support the findings of this study are the intact membrane protein claudins and a key com- available from the corresponding author upon request. ponent of the TJ chain, especially in brain endothelial cells [19]. It has been proved to have mediated changes in endothelial or epithelial permeability in many patho- Conflicts of Interest logical diseases, including ischemia [26]. In our research results, TNFα can increase the expression of claudin-5, )e authors declare that they have no conflicts of interest. Fluorescence activity Claudin-5 ZO-1 Journal of Oncology 11 cochlear implantation-A retrospective cohort analysis,” Authors’ Contributions Trends in Hearing, vol. 25, Article ID 23312165211002140, All the authors contribute the same to this paper. [14] E. Rodriguez-Sanchez, J. A. Navarro-Garcia, J. 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Journal of Oncology – Hindawi Publishing Corporation
Published: Sep 17, 2021
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