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1.
Article in Chinese | WPRIM | ID: wpr-1016440

ABSTRACT

ObjectiveTo investigate the regulatory effect of circular RNA circ_0120051 on the fibrotic phenotype of cardiac fibroblasts and the potential mechanism involved. MethodsThe expression of circ_0120051 and its host gene of solute carrier family 8 member A1(SLC8A1) mRNA in the myocardium of healthy organ donors (n=24) and heart failure (HF) patients (n=21) were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) assay. RNA stability of circ_0120051 was identified by RNase R exonuclease digestion assay. The cytoplasmic and nuclear distribution of circ_0120051 in human cardiomyocyte AC16 was detected by RT-qPCR assay. The expression of fibrosis-related genes in mouse cardiac fibroblasts (mCFs) with adenovirus-mediated overexpression of circ_0120051 was detected by RT-qPCR and Western blot assay, respectively. The effect of overexpression of circ_0120051 on the migration activity of mCFs was evaluated by wound-healing assay. RNA co-immunoprecipitation (RIP) was conducted to detect the interaction between circ_0120051 and miR-144-3p. The binding site of miR-144-3p in the 3'-UTR of isocitrate dehydrogenase 2 (Idh2) mRNA was identified by the dual luciferase reporter gene assay. ResultsCirc_0120051 was significantly up-regulated in the myocardium of HF patients, while the mRNA expression of its host gene SLC8A1 was not changed. Circ_0120051 was mainly located in the cytoplasm of human AC16 cells. Results of RNase R exonuclease digestion revealed that circ_0120051 possesses the characteristic stability of circular RNA compared to the linear SLC8A1 mRNA. Overexpression of circ_0120051 could inhibit the expression of fibrosis-related gene in mCFs and mCFs migration. RIP assay confirmed the specific interaction between circ_0120051 and miR-144-3p. Transfection of miR-144-3p mimic could efficiently promote the expression of fibrosis-related genes in mCFs and reverse the inhibitory effect of circ_0120051 on the fibrotic phenotype of mCFs. Results of the dual luciferase reporter gene assay confirmed the interaction between miR-144-3p and the 3'-UTR of Idh2. Transfection of miR-144-3p transcriptionally inhibited Idh2 expression, and overexpression of circ_0120051 enhanced IDH2 expression in mCFs. MiR-144-3p mimic and Idh2 small interfering RNA (siRNA) could consistently reverse the inhibitory effects of circ_0120051 on fibrosis-related genes expression in mCFs and mCFs migration. ConclusionsCirc_0120051 inhibits the fibrotic phenotype of cardiac fibroblasts via sponging miR-144-3p to enhance the target gene of IDH2 expression.

2.
Article in Chinese | WPRIM | ID: wpr-1007272

ABSTRACT

ObjectiveTo investigate the effect of circSLC8A1_005 on the fibrotic phenotype of cardiac fibroblasts and the potential mechanism involved. MethodsThe effect of adenovirus-mediated overexpression of circSLC8A1_005 on the expression of fibrosis-related genes, collagen type I alpha 1 chain (Col1a1), collagen type Ⅲ alpha 1 chain (Col3a1) and smooth muscle actin alpha 2 (Acta2), in mouse cardiac fibroblasts (mCFs) were detected. The proliferation and migration activities of mCFs were detected by EdU and wound-healing assay, respectively. Dual luciferase reporter gene assay was performed to detect the activity of potential internal ribozyme entry site (IRES) in circSLC8A1_005. CircSLC8A1_005-translated protein, SLC8A1-605aa, and its intracellular distribution was identified by Western blot assay. The effect of SLC8A1-605aa protein on transcription activity of Sod2 gene was detected by the dual luciferase reporter gene assay. RNA binding protein immunoprecipitation (RIP) was utilized to verify the interaction between SLC8A1-605aa and superoxide dismutase 2 (Sod2) mRNA. Actinomycin D treatment was used to detect the effect of SLC8A1-605aa on Sod2 mRNA stability in mCFs. ResultsAn efficient adenovirus-mediated overexpression of circSLC8A1_005 was achieved in mCFs. The enforced expression of circSLC8A1_005 suppressed proliferation and migration of mCFs, and inhibited the expression of fibrosis-related genes in mCFs. The dual luciferase reporter gene assay revealed the activities of 2 IRES in circSLC8A1_005. Results of Western blot assay showed that circSLC8A1_005 could translate protein SLC8A1-605aa with the prospected molecular weight of 70 ku, which is predominantly distributed in the nucleus. Overexpression of the circSLC8A1_005 and SLC8A1-605aa could consistently inhibit the fibrotic phenotype of mCFs. SLC8A1-605aa could up-regulate superoxide dismutase 2 (Sod2) expression, but not at the transcriptional level. RIP assay indicated that SLC8A1-605aa could specifically interact with Sod2 mRNA, and the results of actinomycin D assay showed that SLC8A1-605aa could enhance the stability of Sod2 mRNA in mCFs. ConclusionCircSLC8A1_005 inhibits the fibrotic phenotype of cardiac fibroblasts via translating SLC8A1-605aa protein, and SLC8A1-605aa may be a potential target for the treatment of myocardial fibrosis.

3.
Journal of Medical Biomechanics ; (6): 178-184, 2024.
Article in Chinese | WPRIM | ID: wpr-1023790

ABSTRACT

During the occurrence and development of various heart diseases,continuous deterioration of myocardial fibrosis leads to remodeling and dysfunction of the cardiac structure.As a newly discovered mechanically sensitive ion channel,Piezo1 has opened up a new field of research on cellular mechanical transduction.Piezo1 combines a fine force transducer with Ca2+ influx and participates in the regulation of cellular mechanical transduction,thereby regulating cellular biological functions.Recent studies have shown that the biomechanical changes induced by myocardial injury regulate the expression of Piezo1 in cardiomyocytes and cause an imbalance in calcium homeostasis,which plays an important role in the positive feedback loop of myocardial fibrosis.This review summarizes the theoretical basis and related studies of Piezo1 in regulating cardiac fibrosis and suggests that the Piezo1 channel may become a new target for the treatment of cardiac fibrosis,thereby providing a new research horizon for the prevention and treatment of cardiac fibrosis.

4.
Article in Chinese | WPRIM | ID: wpr-1025863

ABSTRACT

OBJECTIVE Based on fibroblast activation protein(FAP)gene promoter as the response element,to develop a new dual luciferase reporting system for the screening of drugs related to myocardial fibrosis.METHODS The promoter fragment of mouse FAP gene was synthesized in vitro and cloned into plasmid psiCHECK2 to replace HSV-TK promoter,and then a new recombinant plasmid psiCHECK2-FAP was obtained.After the recombinant plasmid psiCHECK2-FAP was digested by restriction endonucliase Hind Ⅲ,the product digested was identified by agar-gel electrophoresis and sequencing.After psiCHECK2-FAP was transient transfected into mouse cardiac fibroblasts(MCFs),and continued cultured for 24 h,and MCFs were treated with Ransforming growth factor β1(TGF-β1,5 μg·L-1)or angiotensinⅡ(Ang Ⅱ,1 μmol·L-1)or palmitic acid(PA,100 μmol·L-1)for 0,12,24,48 h,respectively,the double luciferase reporter gene assay was used to detect luciferase activity;After psiCHECK2-FAP was transient transfected into MCFs,the cells were pretreated with Dapa(1 μmol·L-1)for 1 h,and supplemented with TGF-β1(5 μg·L-1)or AngⅡ(1 μmol·L-1)or PA(100 μmol·L-1),continued treatment for 24 h,the double luciferase reporter gene assay was used to detect luciferase activity,and the expression of collagenⅠand collagen Ⅲ protein was detected with Western blotting.RESULTS The recombinant plasmid psiCHECK2-FAP was digested into two fragments by Hind Ⅲ with the expected strip size,and the sequencing results were completely consistent with the theoretical sequence;Compared with control group,the collagenⅠand collagen Ⅲ protein expression were significantly increased by TGF-β1 or Ang Ⅱ or PA in MCFs(P<0.05,P<0.01).However,compared with TGF-β1 or Ang Ⅱ or PA group,the intervention of Dapa significantly alleviated the promoter activity of FAP gene and the expression of collagenⅠand collagen Ⅲ protein(P<0.05,P<0.01);Compared with control group,luciferase activity was significantly increased by TGF-β1 or Ang Ⅱ or PA(P<0.05,P<0.01),reaching the peak at 24 h.Compared with TGF-β1 or AngⅡ or PA group,the intervention of Dapa significantly decreased luciferase activity(P<0.05,P<0.01).CONCLUSSION Based on the promoter of FAP gene as the response element,a noval dual luciferase reporter gene system was established and showed a good sensitivity to the promyocardial fibrosis factor in MCFs,which can provide strategies for the development of antimyocar-dial fibrosis drugs.

5.
Article in Chinese | WPRIM | ID: wpr-1036527

ABSTRACT

Objective @#To explore the role of secreted frizzled ⁃related protein 3 ( sFRP3) , a regulator of the Wnt signaling pathway , in the activation and proliferation of murine cardiac fibroblasts ( CFs ) . @*Methods @#Neonatalmice aged 1 -3 days were obtained for surgical procedures to collect heart tissues. After digestion, CFs were isola.ted and cultured. Transforming growth factor-beta 1 (TGF-β1 ) stimulation was used to induce activation and prolif.eration in CF's after they adhered to the culture dish. Once the model was confirmed, experimental and controlgroups were transfected with sFRP3 overexpression plasmids and empty plasmids for 24 -48 hours. Expression lev.els of sFRP3, Periostin (POSTN), Type I collagen ( Collagen I ), and proliferating cell nuclear antigen ( PCNA) were assessed at the molecular level using Westerm blot and qR'T-PCR. Changes in cell proliferation capacitywere examined using M'TT, CCK-8, and EdU staining methods.@*Results@#In the TGF-β1-induced activation andproliferation model of CFs, compared to the control group, the model group exhibited decreased expression of sFRP3 protein and mRNA , while the expression of activation and proliferation-related proteins PCNA, POSTN, andCollagen I was upregulated. Furthermore, in CFs overexpressing sFRP3 through plasmid transfection, the proteinand mRNA expression of PCNA, POSTN, and Collagen I decreased compared to the empty vector group. MTTCCK-8, and EdU experiments indicated a significant decrease in the proliferative activity of CFs in the sFRP3 over0verexpression of sFRP3 markedly inhibits theexpression group compared to the empty vector group. @*Conclusion@#Overexpression of sFRP3 markedly inhibits theactivation and proliferation of CFs, suggesting that sFRP3 may be a key gene involved in the regulation of CF activation and proliferation.

6.
Article in Chinese | WPRIM | ID: wpr-965563

ABSTRACT

As a natural compound with high efficiency and low toxicity, cryptotanshinone (CTS) has a good anti-fibrosis effect in various organs and tissues. However, its mechanism of action has not been clearly defined, and there is no systematic literature review to describe its potential anti-fibrosis mechanism. The efficacy and mechanism of cryptotanshinone in the treatment of fibrosis in various organs were summarized and the use prospects were put forward in this paper.

7.
Article in Chinese | WPRIM | ID: wpr-979218

ABSTRACT

ObjectiveTo investigate the effect of myosin heavy chain 7 gene-derived miRNA-208b-3p on the fibrotic phenotype of cardiac fibroblasts. MethodsmiRNA chip array was performed to detect the dysregulated miRNAs in the myocardium of diabetic db/db mice and db/m control mice. Neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs) were isolated from C57BL/6 mice and cultured. Real-time quantitative PCR (RT-qPCR) was conducted to determine the expression of miR-208b-3p in mouse CFs and NMVCs subjected to angiotensinⅡ(AngⅡ) and high glucose plus glucose oxidase (G/Go) treatment, respectively. Cell counting kit 8(CCk8) assay, flow cytometry and determination of fibrosis-related protein, including COL1A1, COL3A1and α-SMA, were performed in mCFs transfected with miR-208b-3p. Dual luciferase reporter assay was performed to confirm the interaction between miR-208b-3p and the 3'-UTR of metal response element binding transcription factor 2 (Mtf2) and progesterone receptor membrane component 1(Pgrmc1), respectively. The expressions of Mtf2 and Pgrmc1 at the mRNA and protein levels in mCFs after miR-208b-3p mimic transfection were determined using RT-qPCR and Western blot assay, respectively. The small interfering RNA (siRNA) was used to inhibit Mtf2 and Pgrmc1 expression in mCFs, and the effects of Mtf2 siRNA, Pgrmc1 siRNA and miR-208b-3p on fibrosis-related protein expression in mCFs were investigated. ResultsResults of miRNA chip array and RT-qPCR assay showed that miR-208b-3p was up-regulated in the myocardium of the diabetic db/db mice. miR-208b precursor and the host gene of Myh7 were consistently increased in db/db mice. miR-208b-3p and Myh7 mRNA were expressed in mCFs and NMVCs, but the levels of miR-208b-3p and Myh7 mRNA in NMVCs were much higher than those in mCFs. miR-208b-3p was up-regulated in mCFs and NMVCs subjected to Ang Ⅱ and G/Go treatment, respectively. miR-208b-3p could significantly enhance fibrosis-related protein, including COL1A1, COL3A1 and α-SMA, in mCFs, without affecting the proliferation activity and cell cycle distribution of mCFs. Dual luciferase reporter assay revealed the interactions of miR-208b-3p with the 3'-UTR of Mtf2 and Pgrmc1. The results of RT-qPCR and Western blotting confirmed that miR-208b-3p inhibited Mtf2 and Pgrmc1 expression at the post- transcriptional level. Transfection with miR-208b-3p mimic, Mtf2 siRNA and Pgrmc1 siRNA could consistently enhance the fibrosis-related protein expression in the cardiac fibroblasts. ConclusionsmiR-208b-3p enhances fibrosis-related gene expression by targeting Mtf2 and Pgrmc1in mCFs.

8.
Article in Chinese | WPRIM | ID: wpr-992809

ABSTRACT

Objective:To evaluate the effect of cinacalcet on right ventricular function in rats with MCT-induced arterial pulmonary hypertension by echocardiography.Methods:Thirty male SD rats were randomly divided into control group, PAH group, and cinacalcet group, with 10 rats in each group. Rats in the cinacalcet group were given intraperitoneal injection of cinacalcet hydrochloride with 30 mg/kg, and the control group and the PAH group were given equal-volume of solvent. Echocardiographic parameters: right ventricular wall thickness (RVWT), right ventricular basal dimension (RVD), left ventricular eccentricity index (EI), tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RVFAC), tricuspid lateral annular systolic velocity (s′), right ventricular global longitudinal strain (RV4CSL), and right ventricular free wall longitudinal strain (RVFWSL), etc. Histopathological parameters: pulmonary arteriole wall thickness (WT), right ventricular cardiomyocyte mean diameter (RV cell-D), collagen volume fraction (CVF) and right ventricular hypertrophy index (RVI). Echocardiographic and pathological parameters were compared among three groups, and the correlation between right ventricular pathological changes and strain parameters was analyzed.Results:①Compared with the control group, WT, RV cell-D, CVF and RVI in PAH group were increased (all P<0.01), the size of right ventricle and thickness of RV wall were increased (all P<0.05), and the right ventricular longitudinal strain was reduced ( P<0.01). ②Compared with the PAH group, rats in the cinacalcet group showed reduced WT, RV cell-D, CVF and RVI (all P<0.01), as well as improved structure and function of the right ventricle (all P<0.05). There was no statistical difference of the above parameters between cinacalcet and control group (all P>0.05). ③Correlation analysis: the right chamber remodeling parameters CVF and RV cell-D were positively correlated with WT ( rs=0.706 3, 0.629 4; both P<0.05); and RVFWSL correlated well with CVF, RV cell-D ( rs=-0.685 3, r=-0.767 2; both P<0.05). Conclusions:The right ventricular inverse remodeling of PAH rats with the intervention of cinacalcet was retained, suggesting that cinacalcet had a protective effect on the structure and function of the right ventricle in rats with PAH.

9.
Chinese Pharmacological Bulletin ; (12): 1450-1456, 2023.
Article in Chinese | WPRIM | ID: wpr-1013735

ABSTRACT

Aim To explore the effect of astragaloside IV (AS-IV) on cell proliferation and collagen expression in cardiac fibroblasts (CFs) of rats induced with angiotensin II (Ang II) and its mechanism. Methods CFs were pretreated with short-chain acyl-CoA dehydrogenase (SCAD) siRNA1186 for 12 h and then co-treated with Ang TJ and AS-IV for 36 h. The expressions of SCAD, α-SMA, collagen I and collagen III in CFs were detected by Western blot. mRNA expression levels of SCAD, a-SMA, collagen I and collagen III in CFs were detected by quantitative real-time PCR. The SCAD enzymatic activity, the content of ATP, hydroxyproline and free fatty acid were measured by detection kits. Results The expression of α-SMA, collagen I and collagen III were up-regulated (all P < 0. 01) in CFs induced by Ang II compared with the control cells, and the expression and enzymatic activity of SCAD significantly decreased (P < 0. 01, P< 0. 05). The content of ATP decreased (P < 0.01), and the content of hydroxyproline and free fatty acids increased (all P < 0.01). Compared with Ang II group, SCAD expression and enzymatic activity, and ATP content were significantly increased (all P < 0.01) in Ang II + AS-TV group, but the content of hydroxyproline and free fatty acids, and the expression of α-SMA, collagen I and collagen III significantly decreased (all P < 0.01). However, compared with the Ang II + NC group, there was no significant difference in all indices in the Ang II + SiRNA1186 + AS-TV group. The protective effect of AS-TV on Ang II -induced cell proliferation and collagen expression in CFs was eliminated by the interference of SCAD SiRNA1186. Conclusions AS-IV may inhibit Ang II-induced cell proliferation and collagen expression in CFs by activating SCAD.

10.
Chinese Pharmacological Bulletin ; (12): 229-238, 2023.
Article in Chinese | WPRIM | ID: wpr-1013848

ABSTRACT

Aim To explore the effect of ZLY18 on angiotensin II-induced cardiac fibrosis and the underlying mechanism. Methods Ang II was used to induce cardiac fibrosis in vitro and in vivo. Cardiac fibroblasts were divided into blank control group, model group and medicine group. The medicine group was subdivided into ZLY18(L)group, ZLY18(M)group and ZLY18(H)group. Compound ZLY18 was given 1, 2, 5 μmol·L-1 respectively. C57BL/6 mice were randomly divided into control group, model group and medicine group. The medicine group were subdivided into ZLY18(L)group, ZLY18(M)group and ZLY18(H)group. Compound ZLY18 was given 10,20 and 50 mg·kg-1 respectively. Both the model group and the medicine group were given with Ang II to induce cardiac fibrosis. The changes of protein levels were detected by Western blot and immunofluorescence. The changes of cardiac function indexes in C57BL/6 mice were detected by small animal echocardiography. The morphology, cell arrangement and collagen fibers of cardiac fibroblasts were observed by tissue section staining and other methods. Results The model of Ang II-induced myocardial fibrosis was successfully established at the cell and animal levels, and ZLY18 treatment improved the elevated fibrosis-related protein caused by Ang II and abnormal cardiac function in mice. Moreover, ZLY18 was able to inhibit the increased phosphorylation of TGF-1 and Smad3 caused by Ang II and increased Smad2/3 nuclear entry, suggesting that the antifibrotic effect of ZLY18 might be related to the activation of TGF-1/Smads signaling pathway. Conclusions ZLY18 has a protective effect on Ang II-induced cardiac fibrosis. ZLY18 may inhibit TGF-β/Smads signaling pathway activation to exert anti-fibrotic effects.

11.
Article in English | WPRIM | ID: wpr-1010563

ABSTRACT

Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease. Anti-fibrosis treatment is a significant therapy for heart disease, but there is still no thorough understanding of fibrotic mechanisms. This study was carried out to ascertain the functions of cytokine receptor-like factor 1 (CRLF1) in cardiac fibrosis and clarify its regulatory mechanisms. We found that CRLF1 was expressed predominantly in cardiac fibroblasts. Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction, but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-‍β1 (TGF‍-‍β1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-‍β1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF‍-‍β1 stimulation, while silencing of CRLF1 had the opposite effects. An inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and different inhibitors of TGF-‍β1 signaling cascades, comprising mothers against decapentaplegic homolog (SMAD)‍-dependent and SMAD-independent pathways, were applied to investigate the mechanisms involved. CRLF1 exerted its functions by activating the ERK1/2 signaling pathway. Furthermore, the SMAD-dependent pathway, not the SMAD-independent pathway, was responsible for CRLF1 up-regulation in NMCFs treated with TGF-‍β1. In summary, activation of the TGF-‍β1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression. CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway. CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.


Subject(s)
Animals , Humans , Mice , Disease Models, Animal , Fibroblasts/metabolism , Fibrosis , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase 3/metabolism , Myocardial Infarction/metabolism , Receptors, Cytokine/metabolism , Signal Transduction , Transforming Growth Factor beta1/pharmacology
12.
Acta Pharmaceutica Sinica B ; (6): 291-307, 2022.
Article in English | WPRIM | ID: wpr-929294

ABSTRACT

Bromodomain containing protein 4 (BRD4), as an epigenetic reader, can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various diseases, including cancer, cardiac remodeling and heart failure. Herein, we described the discovery of hit 5 bearing 4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 compound library (enamine). Then, structure-activity relationship (SAR) study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed, synthesized and evaluated, using HTRF assay set up in our lab. Eventually, we identified compound C-34, which possessed better pharmacokinetic and physicochemical properties as well as lower cytotoxicity against NRCF and NRCM cells, compared to the positive control JQ1. Using computer-based molecular docking and cellular thermal shift assay, we further verified that C-34 could target BRD4 at molecular and cellular levels. Furthermore, treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo, which was correlated with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF-β1/Smad2/3 signaling pathway. Taken together, our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead compound for further development to treat fibrotic cardiovascular disease.

13.
Article in English | WPRIM | ID: wpr-974549

ABSTRACT

@#Cardiovascular disease (CVD) is the leading cause of death worldwide and in New Zealand. However, a significant inequality in the burden of CVD amongst different ethnic groups exists with a 2 - 3-times higher CVD mortality rate in Pasifika compared to Pākehā. It is unknown whether a difference in cardiac fibrosis might underly this ethnic inequality in CVD mortality. To address this, we determined cardiac fibrosis, myocardial fat infiltration, and the expression of some key miRNAs (miR-15a, miR-15b, miR- 34a and miR-153) in right atrial appendages of Pacific Islanders and New Zealand European patients (n=21) undergoing cardiopulmonary bypass surgery. Cardiac fibrosis was measured by total collagen deposition identified by Picro Sirius Red staining, whereas fat accumulation was determined via Oil-Red-O staining. No differences in cardiac fibrosis were observed between ethnic groups (Collagen: Pasifika 23.4±12.5% vs. New Zealand European 29.4±13.2%, one-way ANOVA, p=0.17). Similarly, no differences were observed in accumulation of lipid nor the expression of the miRNAs examined (-15a, - 15b, -34a and -153) between different groups. In conclusion, the earlier requirements for surgical intervention for CVD of Pasifika in Aotearoa might not be explained by differences in miRNAs associated with cardiomyocyte loss, fibrosis or myocardial lipid infiltration. New and Noteworthy Despite the established significant inequality in the burden of CVD amongst the Pasifika compared to the Pākehā (New Zealand European) populations in Aotearoa, we found no difference inhistopathological (cardiac fibrosis, lipid infiltration, or associated pro- or anti-f

14.
J. biomed. eng ; Sheng wu yi xue gong cheng xue za zhi;(6): 574-582, 2021.
Article in Chinese | WPRIM | ID: wpr-888215

ABSTRACT

Long non-coding RNA (lncRNA) Dnm3os plays a critical role in peritendinous fibrosis and pulmonary fibrosis, but its role in the process of cardiac fibrosis is still unclear. Therefore, we carried out study by using the myocardial fibrotic tissues obtained by thoracic aortic constriction (TAC) in an early study of our group, and the


Subject(s)
Humans , Fibroblasts , Fibrosis , Myocardium/pathology , RNA, Long Noncoding , Signal Transduction , Transforming Growth Factor beta1
15.
Article in English | WPRIM | ID: wpr-922544

ABSTRACT

OBJECTIVES@#Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by angiotensin II (AngII). Low-intensity pulsed ultrasound (LIPUS) has been reported to ameliorate cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechano-transduction and its downstream pathways. In this study, we aimed to investigate whether LIPUS could exert a protective effect by ameliorating AngII-induced cardiac hypertrophy and fibrosis and if so, to further elucidate the underlying molecular mechanisms.@*METHODS@#We used AngII to mimic animal and cell culture models of cardiac hypertrophy and fibrosis. LIPUS irradiation was applied in vivo for 20 min every 2 d from one week before mini-pump implantation to four weeks after mini-pump implantation, and in vitro for 20 min on each of two occasions 6 h apart. Cardiac hypertrophy and fibrosis levels were then evaluated by echocardiographic, histopathological, and molecular biological methods.@*RESULTS@#Our results showed that LIPUS could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-induced release of inflammatory cytokines, but the protective effects on cardiac hypertrophy were limited in vitro. Given that LIPUS increased the expression of caveolin-1 in response to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vivo and in vitro. LIPUS-induced downregulation of inflammation was reversed and the anti-fibrotic effects of LIPUS were absent.@*CONCLUSIONS@#These results indicated that LIPUS could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeutic apparatus in clinical practice.

16.
Chinese Pharmacological Bulletin ; (12): 922-928, 2021.
Article in Chinese | WPRIM | ID: wpr-1014460

ABSTRACT

Aim To investigate the mechanism of TET1 in cardiac fibrosis induced by high pressure. Methods Wistar rats and spontaneous hypertension rats(SHR) were selected to detected the expression of TET1, TGF-β, COL-1 and COL-3 in myocardium by Western blot; HE and Masson staining were used to detect myocardial pathological changes. Neonatal rat cardiac fibroblasts (NRCFs) were isolated from the ventricles of neonatal Sprague-Dawley rats and stimulated by 0 mm-Hg, 120 mmHg and 180 mmHg high pressure. Immunofluorescence was used to detect the changes of 5-hmC in the NRCFs. The changes of 5-hmC and 5-mC in TGF-β promoter region were detected by qRT-PCR. The expressions of TET1, TGF-β, COL-1 and COL-3 were detected by Western blot. Results Compared with Wistar rats, SHR showed increased blood pressure, increased fibrous collagen in ventricular tissues, and significantly increased expressions of TET1, TGF-P, COL-1 and COL-3. Compared with the 0 mmHg group, 120 mmHg and 180 mmHg group significantly induced the increase of TET1, 5-hmC, TGF-p, COL-1 and COL-3. TET1 knockdown significantly reduced the increase of 5-hmC, TGF-β, COL-1 and COL-3 under 180 mmHg pressure. Besides, knockdown TET1 significantly reduced the level of 5-hmC and increased the level of 5-mC and 5-hmC in the TGF-β promoter region. Conclusions High pressure induced cardiac fibrosis is associated with the promotion of TGF-β promoter demethylation and the increased of TGF-β expression by TET1.

17.
Chin. j. integr. med ; Chin. j. integr. med;(12): 424-431, 2021.
Article in English | WPRIM | ID: wpr-880554

ABSTRACT

OBJECTIVE@#To evaluate the effects of Huoxin Pill (, HXP) on cardiac fibrosis and heart failure (HF) in isoproterenol (ISO)-induced HF rats.@*METHODS@#Thirty Wistar rats were randomly divided into 5 groups including control, HF, isosorbide mononitrate (ISMN), HXP low (HXP-L), and HXP high (HXP-H) groups (n=6 for each group) according to the complete randomization method. Rats were pretreated with ISMN (5 mg/kg daily), low concentration of HXP (10 mg/kg daily) or high concentration of HXP (30 mg/kg daily) or equal volume of saline by intragastric administration for 1 week, followed by intraperitoneal injection of ISO (10 mg/kg, 14 days), and continually intragastric administrated with above medicines or saline for additional 6 weeks. The effects of HXP treatment on the cardiac function, heart weight index (HWI), pathological changes, and collagen content were further assessed. Moreover, the role of HXP on activation of transforming growth factor- β 1 (TGF-β 1)/Smads pathway was further explored using immunohistochemistry (IHC) and Western-blot assay.@*RESULTS@#HXP treatment significantly alleviated the decrease of ejection fraction (EF) and fractional shortening (FS), while decreased the elevation of left ventricular end-systolic volume (LVESV) in ISO-induced HF rats (P<0.05). Moreover, HXP treatment obviously attenuated the increase of HWI and serum level of creatine kinase MB (CK-MB, P<0.05), as well as pathological changes in ISO-induced HF rats. Further determination indicated that HXP treatment alleviated the elevation of collagen I and collagen III protein expression in cardiac tissues of ISO-induced HF rats. Furthermore, HXP treatment significantly down-regulated the increase of TGF-β 1 and p-Smad2/3 protein expression in cardiac tissues of HF rats (P<0.05), while did not affect the expression of total Smad2/3.@*CONCLUSIONS@#HXP attenuated heart failure and cardiac fibrosis in ISO-induced HF rats by suppression of TGF-β 1/Smad2/3 pathway.

18.
Protein & Cell ; (12): 194-212, 2021.
Article in English | WPRIM | ID: wpr-880909

ABSTRACT

Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction (MI). MicroRNA-146b (miR-146b) is an active regulator of immunomodulation, but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic remodeling following MI remain largely unknown. Herein, miR-146b-5p was found to be upregulated in the infarcted myocardium of mice and the serum of myocardial ischemia patients. Gain- and loss-of-function experiments demonstrated that miR-146b-5p was a hypoxia-induced regulator that governed the pro-fibrotic phenotype transition of cardiac cells. Overexpression of miR-146b-5p activated fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition, impaired endothelial cell function and stress survival, and disturbed macrophage paracrine signaling. Interestingly, the opposite effects were observed when miR-146b-5p expression was inhibited. Luciferase assays and rescue studies demonstrated that the miR-146b-5p target genes mediating the above phenotypic modulations included interleukin 1 receptor associated kinase 1 (IRAK1) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). Local delivery of a miR-146b-5p antagomir significantly reduced fibrosis and cell death, and upregulated capillary and reparative macrophages in the infarcted myocardium to restore cardiac remodeling and function in both mouse and porcine MI models. Local inhibition of miR-146b-5p may represent a novel therapeutic approach to treat cardiac fibrotic remodeling and dysfunction following MI.

19.
J. biomed. eng ; Sheng wu yi xue gong cheng xue za zhi;(6): 450-459, 2020.
Article in Chinese | WPRIM | ID: wpr-828147

ABSTRACT

Calnexin is a lectin-like molecular chaperone protein on the endoplasmic reticulum, mediating unfolded protein responses, the endoplasmic reticulum Ca homeostasis, and Ca signals conduction. In recent years, studies have found that calnexin plays a key role in the heart diseases. This study aims to explore the role of calnexin in the activation of cardiac fibroblasts. A transverse aortic constriction (TAC) mouse model was established to observe the activation of cardiac fibroblasts , and the cardiac fibroblasts activation model was established by transforming growth factor β1 (TGFβ1) stimulation. The adenovirus was respectively used to gene overexpression and silencing calnexin in cardiac fibroblasts to elucidate the relationship between calnexin and cardiac fibroblasts activation, as well as the possible underlying mechanism. We confirmed the establishment of TAC model by echocardiography, hematoxylin-eosin, Masson, and Sirius red staining, and detecting the expression of cardiac fibrosis markers in cardiac tissues. After TGFβ1 stimulation, markers of the activation of cardiac fibroblast, and proliferation and migration of cardiac fibroblast were detected by quantitative PCR, Western blot, EdU assay, and wound healing assay respectively. The results showed that the calnexin expression was reduced in both the TAC mice model and the activated cardiac fibroblasts. The overexpression of calnexin relieved cardiac fibroblasts activation, in contrast, the silencing of calnexin promoted cardiac fibroblasts activation. Furthermore, we found that the endoplasmic reticulum stress was activated during cardiac fibroblasts activation, and endoplasmic reticulum stress was relieved after overexpression of calnexin. Conversely, after the silencing of calnexin, endoplasmic reticulum stress was further aggravated, accompanying with the activation of cardiac fibroblasts. Our data suggest that the overexpression of calnexin may prevent cardiac fibroblasts against activation by alleviating endoplasmic reticulum stress.

20.
Acta Pharmaceutica Sinica B ; (6): 724-733, 2019.
Article in English | WPRIM | ID: wpr-774948

ABSTRACT

Excess activation of cardiac fibroblasts inevitably induces cardiac fibrosis. Emodin has been used as a natural medicine against several chronic diseases. The objective of this study is to determine the effects of emodin on cardiac fibrosis and the underlying molecular mechanisms. Intragastric administration of emodin markedly decreased left ventricular wall thickness in a mouse model of pathological cardiac hypertrophy with excess fibrosis induced by transaortic constriction (TAC) and suppressed activation of cardiac fibroblasts induced by angiotensin II (AngII). Emodin upregulated expression of metastasis associated protein 3 (MTA3) and restored the MTA3 expression in the setting of cardiac fibrosis. Moreover, overexpression of MTA3 promoted cardiac fibrosis; in contrast, silence of MTA3 abrogated the inhibitory effect of emodin on fibroblast activation. Our findings unraveled the potential of emodin to alleviate cardiac fibrosis upregulating MTA3 and highlight the regulatory role of MTA3 in the development of cardiac fibrosis.

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