|
1
|
Wei XC, Xia YR, Zhou P, Xue X, Ding S, Liu LJ, Zhu F. Hepatitis B core antigen modulates exosomal miR-135a to target vesicle-associated membrane protein 2 promoting chemoresistance in hepatocellular carcinoma. World J Gastroenterol 2021; 27:8302-8322. [PMID: 35068871 PMCID: PMC8717014 DOI: 10.3748/wjg.v27.i48.8302] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The association of hepatitis B virus (HBV) infection with HCC is hitherto documented. Exosomal miRNAs contribute to cancer progression and chemoresistance. HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis. However, there has been no report on hepatitis B core antigen (HBc) regulating exosomal miRNAs to induce drug resistance of HCC cells. AIM To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride (Dox) resistance in HCC. METHODS Exosomes were isolated by ultracentrifugation. The morphology and size of exosomes were evaluated by Dynamic Light Scattering (DLS) and transmission electron microscopy (TEM). The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas (TCGA) database. The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction. TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p. Finally, we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry, Cell counting kit 8 (CCK-8) assay and western blot. RESULTS We found that HBc increased the expression of exosomal miR-135a-5p. Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues. Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2 (VAMP2) as a novel target gene of miR-135a-5p. Functional assays showed that exosomal miR-135a-5p induced apoptosis protection, cell proliferation, and chemotherapy resistance in HCC. In addition, the rescue experiment demonstrated that VAMP2 reversed apoptosis protection, cell growth, and drug resistance by miR-135a-5p. Finally, HBc promoted HCC anti-apoptosis, proliferation, and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis. CONCLUSION These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis, cell proliferation, and chemical resistance through miR-135a-5p/VAMP2. Thus, our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.
Collapse
Affiliation(s)
- Xiao-Cui Wei
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ya-Ru Xia
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ping Zhou
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xing Xue
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Shuang Ding
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| |
Collapse
|
|
2
|
Chu PY, Hsieh CH, Chen CY, Wu MH. Improvement of Background Solution for Optically Induced Dielectrophoresis-Based Cell Manipulation in a Microfluidic System. Front Bioeng Biotechnol 2021; 9:759205. [PMID: 34881232 PMCID: PMC8645848 DOI: 10.3389/fbioe.2021.759205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/04/2021] [Indexed: 11/25/2022] Open
Abstract
Optically induced dielectrophoresis (ODEP) is effective for cell manipulation. However, its utilization has been limited by the requirement of solution with low conductivity. This issue has been ignored in ODEP-relevant studies. To address this issue, this study aims to investigate to what extent the cell viability and performance of ODEP-based cell manipulation are affected by low conductivity conditions. Additionally, this study aims to modify sucrose solutions to reduce the impacts caused by low-conductivity solutions. Results revealed the use of sucrose solution in ODEP operation could significantly reduce the viability of the manipulated cells by 9.1 and 38.5% after 2- and 4-h incubation, respectively. Prolonged operation time (e.g., 4 h) in sucrose solution could lead to significantly inferior performance of cell manipulation, including 47.2% reduction of ODEP manipulation velocity and 44.4% loss of the cells manipulatable by ODEP. The key finding of this study is that the use of bovine serum albumin (BSA)-supplemented sucrose solution (conductivity: 25–50 μS cm−1) might significantly increase the cell viability by 10.9–14.8% compared with that in sucrose solution after 4 h incubation. Moreover, the ODEP manipulation velocity of cells in the BSA-supplemented sucrose solution (conductivity: 25 μS cm−1) was comparable to that in sucrose solution during 4-h incubation. More importantly, compared with sucrose solution, the use of BSA-supplemented sucrose solution (conductivity: 25–50 μS cm−1) contributed high percentage (80.4–93.5%) of the cells manipulatable by ODEP during 4-h incubation. Overall, this study has provided some fundamental information relevant to the improvement of background solutions for ODEP-based cell manipulation.
Collapse
Affiliation(s)
- Po-Yu Chu
- Ph.D. Program in Biomedical Engineering, Chang Gung University, Taoyuan City, Taiwan
| | - Chia-Hsun Hsieh
- Division of Hematology-Oncology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan.,Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan.,Collage of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chih-Yu Chen
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City, Taiwan
| | - Min-Hsien Wu
- Ph.D. Program in Biomedical Engineering, Chang Gung University, Taoyuan City, Taiwan.,Division of Hematology-Oncology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan.,Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan.,Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City, Taiwan.,Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan
| |
Collapse
|
|
3
|
Ciesielska S, Slezak-Prochazka I, Bil P, Rzeszowska-Wolny J. Micro RNAs in Regulation of Cellular Redox Homeostasis. Int J Mol Sci 2021; 22:6022. [PMID: 34199590 PMCID: PMC8199685 DOI: 10.3390/ijms22116022] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/27/2021] [Accepted: 05/30/2021] [Indexed: 02/08/2023] Open
Abstract
In living cells Reactive Oxygen Species (ROS) participate in intra- and inter-cellular signaling and all cells contain specific systems that guard redox homeostasis. These systems contain both enzymes which may produce ROS such as NADPH-dependent and other oxidases or nitric oxide synthases, and ROS-neutralizing enzymes such as catalase, peroxiredoxins, thioredoxins, thioredoxin reductases, glutathione reductases, and many others. Most of the genes coding for these enzymes contain sequences targeted by micro RNAs (miRNAs), which are components of RNA-induced silencing complexes and play important roles in inhibiting translation of their targeted messenger RNAs (mRNAs). In this review we describe miRNAs that directly target and can influence enzymes responsible for scavenging of ROS and their possible role in cellular redox homeostasis. Regulation of antioxidant enzymes aims to adjust cells to survive in unstable oxidative environments; however, sometimes seemingly paradoxical phenomena appear where oxidative stress induces an increase in the levels of miRNAs which target genes which are supposed to neutralize ROS and therefore would be expected to decrease antioxidant levels. Here we show examples of such cellular behaviors and discuss the possible roles of miRNAs in redox regulatory circuits and further cell responses to stress.
Collapse
Affiliation(s)
- Sylwia Ciesielska
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland; (P.B.); (J.R.-W.)
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland;
| | | | - Patryk Bil
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland; (P.B.); (J.R.-W.)
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland;
| | - Joanna Rzeszowska-Wolny
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland; (P.B.); (J.R.-W.)
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland;
| |
Collapse
|
|
4
|
Zhang Y, Wang J, Ye M, Li G, Zhong M, Guan X. The effect of mechanical stimulation on the expression of apoptosis-related genes in cardiomyocytes. APPLIED NANOSCIENCE 2021. [DOI: 10.1007/s13204-021-01901-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
5
|
Liu P, Li J, Liu M, Zhang M, Xue Y, Zhang Y, Han X, Jing X, Chu L. Hesperetin modulates the Sirt1/Nrf2 signaling pathway in counteracting myocardial ischemia through suppression of oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 2021; 139:111552. [PMID: 33839495 DOI: 10.1016/j.biopha.2021.111552] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/26/2021] [Accepted: 03/27/2021] [Indexed: 11/17/2022] Open
Abstract
Hesperetin (HSP) is a natural flavonoid that offers useful curative effects for cardiovascular diseases, but its effect on myocardial ischemia and its precise mechanism remains unclear. The aim of this study is to explore the potential cardioprotective mechanism of HSP on myocardial ischemia caused by isoproterenol (ISO). Adult male Kunming mice were randomly divided into five groups: control, ISO, low-dose HSP (L-HSP, 25 mg/kg/d), high-dose HSP (H-HSP, 50 mg/kg/d), and verapamil (VER) group. Treatment groups of mice received HSP or VER for seven days, and the groups other than the control group were injected with ISO (100 mg/kg/d) subcutaneously for two consecutive days to establish a model of myocardial ischemia. Electrocardiogram and heart-histology changes were used to assess changes in myocardial architecture. The activities and the content of oxidative stress markers and inflammatory cytokines were determined and assayed using kits respectively. The expressions of proteins associated with apoptosis and the Sirt1/Nrf2 pathway were evaluated by Western blotting. The results demonstrate that VER, L-HSP and H-HSP significantly reduced the J-point displacement, heart rate, cardiac pathomorphological changes, and the levels of creatine kinase, lactated dehydrogenase, malonaldehyde, interleukin-6, and tumor necrosis factor-α in serum while promoting the activation of superoxide dismutase, catalase, glutathione in serum in the ISO-treated animals. Furthermore, L-HSP and H-HSP also reversed the ISO-induced apoptosis and the changes in the Sirt1/Nrf2 signaling pathway, as evident from the levels of proteins Bax, Bcl-2, caspase-3, Sirt1, Nrf2, NQO-1, and HO-1. In conclusion, HSP plays a protective role in ISO-induced myocardial ischemia by modulating oxidative stress, inflammation, and apoptosis via Sirt1/Nrf2 pathway activation.
Collapse
Affiliation(s)
- Panpan Liu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Jinghan Li
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Miaomiao Liu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Muqing Zhang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Yucong Xue
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Yuanyuan Zhang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China
| | - Xue Han
- Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China.
| | - Xuan Jing
- Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China.
| | - Li Chu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, China.
| |
Collapse
|
|
6
|
miR-126-5p regulates H9c2 cell proliferation and apoptosis under hypoxic conditions by targeting IL-17A. Exp Ther Med 2020; 21:67. [PMID: 33365067 DOI: 10.3892/etm.2020.9499] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence has indicated that microRNAs (miRNAs/miRs) regulate the occurrence and development of various diseases, including diabetes, osteoporosis and cardiovascular conditions. However, the role of miRNAs in acute myocardial infarction (AMI) is not completely understood. The present study aimed to evaluate the therapeutic efficacy and mechanisms underlying the effects of miR-126-5p on H9c2 cell proliferation and apoptosis by targeting interleukin (IL)-17A. A total of 40 patients with AMI and 40 healthy volunteers were recruited in the present study and the expression levels of serum miR-126-5p and IL-17A were determined. Following confirmation that IL-17A was a target of miR-126-5p via a dual-luciferase reporter assay, H9c2 cells were exposed to hypoxic conditions. H9c2 cell viability and apoptosis were subsequently assessed. Additionally, the protein expression levels of apoptosis-associated proteins were detected following transfection. Compared with healthy individuals, miR-126-5p expression was significantly decreased in the serum samples of patients with AMI, whereas IL-17A, the target of miR-126-5p, was significantly increased. Following hypoxic treatment, miR-126-5p overexpression enhanced H9c2 cell viability compared with the NC group, which was subsequently reversed following co-transfection with pcDNA3.1-IL-17A. Additionally, the results indicated that hypoxia-induced H9c2 cell apoptosis was significantly reduced following transfection with miR-126-5p mimics via the PI3K/AKT signaling pathway compared with the NC group. The present study indicated that miR-126-5p may serve as a novel miRNA that regulates H9c2 cell viability and apoptosis by targeting IL-17A under hypoxic conditions. Therefore, miR-126-5p may serve as a crucial biomarker for the diagnosis of AMI.
Collapse
|
|
7
|
Wang N, Yang Y, Pang M, Du C, Chen Y, Li S, Tian Z, Feng F, Wang Y, Chen Z, Liu B, Rong L. MicroRNA-135a-5p Promotes the Functional Recovery of Spinal Cord Injury by Targeting SP1 and ROCK. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:1063-1077. [PMID: 33294293 PMCID: PMC7691148 DOI: 10.1016/j.omtn.2020.08.035] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/28/2020] [Indexed: 01/18/2023]
Abstract
Emerging evidence indicates that microRNAs play a pivotal role in neural remodeling after spinal cord injury (SCI). This study aimed to investigate the mechanisms of miR-135a-5p in regulating the functional recovery of SCI by impacting its target genes and downstream signaling. The gene transfection assay and luciferase reporter assay confirmed the target relationship between miR-135a-5p and its target genes (specificity protein 1 [SP1] and Rho-associated kinase [ROCK]1/2). By establishing the H2O2-induced injury model, miR-135a-5p transfection was found to inhibit the apoptosis of PC12 cells by downregulating the SP1 gene, which subsequently induced downregulation of pro-apoptotic proteins (Bax, cleaved caspase-3) and upregulation of anti-apoptotic protein Bcl-2. By measuring the neurite lengths of PC12 cells, miR-135a-5p transfection was found to promote axon outgrowth by downregulating the ROCK1/2 gene, which subsequently caused upregulation of phosphate protein kinase B (AKT) and phosphate glycogen synthase kinase 3β (GSK3β). Use of the rat SCI models showed that miR-135a-5p could increase the Basso, Beattie, and Bresnahan (BBB) scores, indicating neurological function recovery. In conclusion, the miR-135a-5p-SP1-Bax/Bcl-2/caspase-3 and miR-135a-5p-ROCK-AKT/GSK3β axes are involved in functional recovery of SCI by regulating neural apoptosis and axon regeneration, respectively, and thus can be promising effective therapeutic strategies in SCI.
Collapse
Affiliation(s)
- Nanxiang Wang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Yang Yang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Mao Pang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Cong Du
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Yuyong Chen
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Simin Li
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstrasse 12, 04103 Leipzig, Germany
| | - Zhenming Tian
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Feng Feng
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Yang Wang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Zhenxiang Chen
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Bin Liu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Limin Rong
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| |
Collapse
|
|
8
|
Blood levels of microRNAs associated with ischemic heart disease differ between Austrians and Japanese: a pilot study. Sci Rep 2020; 10:13628. [PMID: 32788621 PMCID: PMC7423897 DOI: 10.1038/s41598-020-69332-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 07/08/2020] [Indexed: 01/08/2023] Open
Abstract
Mortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20). Total miRNAs in serum from each participant were analyzed using the 3D-Gene miRNA Oligo chip. Twenty-one miRNAs, previously reported as associated with IHD, were compared between Austrians and Japanese. The expression levels of miR-106a-5p, miR-135a-3p, miR-150-3p, miR-16-5p, miR-17-5p. miR-191-5p, miR-320b, miR-451a, miR-486-5p, miR-663b, and miR-92a-3p were significantly higher, while the miR-2861 expression level was significantly lower in Austrians as compared to Japanese. Both in Austrians and Japanese, there were significant positive correlations between serum expression levels of each pair of the above miRNAs except for miR-2861. The expression level of miR-2861 showed significant positive correlations with the expression levels of miR-106a-5p, miR-150-3p, miR-17-5p, miR-486-5p, miR-663b and miR-92a-3p in Austrians but not in Japanese. In pathway analysis, proinflammatory cytokine production in foam cells and collagen synthesis in vascular smooth muscle cells were associated with differentially expressed miRNAs. Difference in miRNA levels may contribute to lower cardiovascular risk in Japan than in Western countries.
Collapse
|
|
9
|
Li L, Shao Y, Zheng H, Niu H. Kaempferol Regulates miR-15b/Bcl-2/TLR4 to Alleviate OGD-Induced Injury in H9c2 Cells. Int Heart J 2020; 61:585-594. [PMID: 32418959 DOI: 10.1536/ihj.19-359] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Ischemic heart disease (IHD) is one of the world's leading causes of human death. Kaempferol (Kae) was proved to have anti-inflammatory, antioxidant, and anticancer effects. Such properties suggested that it might play protective roles in IHD. In this study, we have attempted to disclose the potential regulating mechanisms of Kae in primary cardiomyocytes and H9c2 cells.Cells were first stimulated by oxygen-glucose deprivation (OGD) and then exposed to Kae. CCK-8 assay and flow cytometry were used to examine cell characteristics. Quantitative reverse-transcription polymerase chain reaction was utilized to test the expression levels of miR-15b and TLR4. Afterward, cell transfection, dual-luciferase activity assay, and western blot were used to explore the potential mechanisms.OGD treatment suppressed cell viability, whereas it enhanced cell apoptosis. Besides, OGD treatment enhanced the expression of apoptosis-associated proteins. Kae exposure, however, attenuated the effects that OGD-induced. Further experiments showed that Kae exposure promoted down-regulation of miR-15b, Bcl-2 and TLR4 were a target of miR-15b. Moreover, Kae enhanced the expression of key factors involved in PI3K/AKT and Wnt/β-catenin pathways, whereas miR-15b mimic reversed the Kae-triggered effects.This investigation revealed that Kae diminished OGD-triggered cell damage through down-regulating miR-15b expression via activating PI3K/AKT and Wnt3a/β-catenin pathways.
Collapse
Affiliation(s)
- Linping Li
- Department of Cardiology, Jining No.1 People's Hospital
| | - Yuanxia Shao
- Department of Cardiology, Jining No.1 People's Hospital
| | | | - Heng Niu
- Department of Cardiology, Jining No.1 People's Hospital
| |
Collapse
|
|
10
|
Hu F, Yang J, Chen X, Shen Y, Chen K, Fu X, Guo S, Jiang Z. LncRNA 1700020I14Rik/miR-297a/CGRP axis suppresses myocardial cell apoptosis in myocardial ischemia-reperfusion injury. Mol Immunol 2020; 122:54-61. [PMID: 32298875 DOI: 10.1016/j.molimm.2020.03.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/09/2020] [Accepted: 03/20/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are closely related to various human diseases, but their role in myocardial injury has not been fully elucidated. In the current study, we found that the expression of lncRNA 1700020I14Rik was significantly down-regulated in myocardial injury tissues and the underlying mechanism by which lncRNA 1700020I14Rik regulated myocardial cell injury was investigated. METHODS The model of myocardial ischemia-reperfusion (I/R) injury and myocardial cells hypoxia/reoxygenation (H/R) injury were established and the expression of 1700020I14Rik, miR-297a or CGRP was analyzed by qRT-PCR or Western blot. Moreover, myocardial cell apoptosis was assessed by TUNEL staining and the concentration of LDH in the mouse plasma sample or myocardial cell culture supernatant was measured by the LDH cytotoxicity test kit. Furthermore, the differences of myocardial cell survival rate after H/R treatment were assessed by MTT assay and the observation of CGRP expression was performed in HL-1 cells overexpressed or silenced with 1700020I14Rik or miR-297a. In addition, the regulating function of miR-297a on 1700020I14Rik and CGRP expression was analyzed by a dual luciferase reporter assay. RESULTS The expressions of 1700020I14Rik and CGRP were abnormally down-regulated in a model of myocardial I/R injury and myocardial cells H/R injury, while miR-297a was up-regulated. By TUNEL staining, the apoptotic rate of myocardial cells in the model of myocardial I/R injury was significantly increased. Furthermore, the concentrations of LDH in the mouse plasma sample or myocardial cell culture supernatant were significantly increased after myocardial cell injury. By MTT assay, the survival rate of cells was decreased after myocardial cells were treated with H/R. In addition, overexpression of 1700020I14Rik or knockdown of miR-297a could up-regulate CGRP protein level, while interference with 1700020I14Rik or overexpression of miR-297a produced the opposite result. Further study confirmed that lncRNA 1700020I14Rik/miR-297a/CGRP axis suppressed myocardial cell apoptosis in myocardial I/R injury. CONCLUSION Our results indicated that 1700020I14Rik was abnormally down-regulated in myocardial injury tissues. In-depth studies manifested that 1700020I14Rik/miR-297a/CGRP axis suppressed myocardial cell apoptosis in myocardial I/R injury.
Collapse
Affiliation(s)
- Fudong Hu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinhua Yang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xi Chen
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yangyang Shen
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kui Chen
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Fu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shengcun Guo
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Zhengming Jiang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| |
Collapse
|
|
11
|
Hu J, Xue Y, Tang K, Fan J, Du J, Li W, Chen S, Liu C, Ji W, Liang J, Zhuang J, Chen K. The protective effects of hydrogen sulfide on the myocardial ischemia via regulating Bmal1. Biomed Pharmacother 2019; 120:109540. [PMID: 31639648 DOI: 10.1016/j.biopha.2019.109540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/24/2019] [Accepted: 10/02/2019] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND To investigate the effect of hydrogen peroxide (H2S) on myocardial clock gene Bmal1 in ischemic cardiomyocytes. MATERIALS & METHODS Quantitative PCR (qPCR) was used to detect the expression of Bmal1 at the mRNA level in H9C2 rat cardiomyocytes. The protein expressions of Bax and Bcl-2, PI3K/Akt, caspase-3 were measured by western blotting. The levels of reactive oxygen species (ROS) were determined by ELISA. RESULTS The expression level of clock gene Bmal1 demonstrated a clock rhythm of periodic oscillation within 24 h. Compared with the control group, H2S treatment maintained the rhythm of the clock gene in ischemic cardiomyocytes and increased the transcription and expression levels of Bmal1. H2S increased cell survival by activating PI3K/Akt signaling pathway, inhibiting mitochondrial apoptosis signaling, and reducing intracellular oxidative stress. PI3K/Akt and Bmal1 were demonstrated to be involved in H2S protection of cardiomyocyte ischemia. Knockout of Bmal1 gene affects the degree of phosphorylation of Akt and Erk proteins, and the level of ROS production, resulting in a decrease in the protective effects of H2S. CONCLUSION The expression level of Bmal1 has effects on the function of cardiomyocytes such as ROS production. The potential mechanism by which H2S regulates clock genes may be related to the effect of clock genes on protein phosphorylation levels in ischemic cardiomyocytes.
Collapse
Affiliation(s)
- Jiaqin Hu
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, PR China
| | - Yan Xue
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou, 510080, China; Department of Anesthesia, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou, 510080, China
| | - Kai Tang
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, PR China
| | - Jing Fan
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, PR China
| | - Junxi Du
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, PR China
| | - Wenfu Li
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, PR China
| | - Siyu Chen
- China Pharmaceutical University, 639 Longmian Ave., Nanjing, Jiangsu, 211198, China
| | - Chang Liu
- China Pharmaceutical University, 639 Longmian Ave., Nanjing, Jiangsu, 211198, China
| | - Wenjin Ji
- Department of Anesthesia, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou, 510080, China
| | - Jiexian Liang
- Department of Anesthesia, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou, 510080, China
| | - Jian Zhuang
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou, 510080, China.
| | - Kun Chen
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, PR China.
| |
Collapse
|
|
12
|
Reigada D, Calderón-García AÁ, Soto-Catalán M, Nieto-Díaz M, Muñoz-Galdeano T, Del Águila Á, Maza RM. MicroRNA-135a-5p reduces P2X 7 -dependent rise in intracellular calcium and protects against excitotoxicity. J Neurochem 2019; 151:116-130. [PMID: 30924927 DOI: 10.1111/jnc.14700] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 01/01/2023]
Abstract
Excitotoxic cell death because of the massive release of glutamate and ATP contributes to the secondary extension of cellular and tissue loss following traumatic spinal cord injury (SCI). Evidence from blockage experiments suggests that over-expression and activation of purinergic receptors, especially P2X7 , produces excitotoxicity in neurodegenerative diseases and trauma of the central nervous system. We hypothesize that the down-regulation of specific miRNAs after the SCI contributes to the over-expression of P2X7 and that restorative strategies can be used to reduce the excitotoxic response. In the present study, we have employed bioinformatic analyses to identify microRNAs whose down-regulation following SCI can be responsible for P2X7 over-expression and excitotoxic activity. Additional luciferase assays validated microRNA-135a-5p (miR-135a) as a posttranscriptional modulator of P2X7 . Moreover, gene expression analysis in spinal cord samples from a rat SCI model confirmed that the decrease in miR-135a expression correlated with P2X7 over-expression after injury. Transfection of cultures of Neuro-2a neuronal cell line with a miR-135a inhibitory sequences (antagomiR-135a), simulating the reduction of miR-135a observed after SCI, resulted in the increase of P2X7 expression and the subsequent ATP-dependent rise in intracellular calcium concentration. Conversely, a restorative strategy employing miR-135a mimicked reduced P2X7 expression, attenuating the increase in intracellular calcium concentration that depends on this receptor and protecting cells from excitotoxic death. Therefore, we conclude that miR-135a is a potential therapeutic target for SCI and that restoration of its expression may reduce the deleterious effects of ATP-dependent excitotoxicity induced after a traumatic spinal cord injury.
Collapse
Affiliation(s)
- David Reigada
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain
| | - Andrés Ángel Calderón-García
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain.,Instituto de Neurociencias de Castilla y León (INCYL), Faculty of Medicine, University of Salamanca. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Manuel Soto-Catalán
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain
| | - Manuel Nieto-Díaz
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain
| | - Teresa Muñoz-Galdeano
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain
| | - Ángela Del Águila
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Rodrigo M Maza
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Toledo, Spain
| |
Collapse
|
|
13
|
Huang YM, Li WW, Wu J, Han M, Li BH. The diagnostic value of circulating microRNAs in heart failure. Exp Ther Med 2019; 17:1985-2003. [PMID: 30783473 PMCID: PMC6364251 DOI: 10.3892/etm.2019.7177] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 01/07/2019] [Indexed: 12/17/2022] Open
Abstract
Heart failure (HF) is a complex clinical syndrome, characterized by inadequate blood perfusion of tissues and organs caused by decreased heart ejection capacity resulting from structural or functional cardiac disorders. HF is the most severe heart condition and it severely compromises human health; thus, its early diagnosis and effective management are crucial. However, given the lack of satisfactory sensitivity and specificity of the currently available biomarkers, the majority of patients with HF are not diagnosed early and do not receive timely treatment. A number of studies have demonstrated that peripheral blood circulating nucleic acids [such as microRNAs (miRs), mRNA and DNA] are important for the diagnosis and monitoring of treatment response in HF. miRs have been attracting increasing attention as promising biomarkers, given their presence in body fluids and relative structural stability under diverse conditions of sampling. The aim of the present review was to analyze the associations between the mechanisms underlying the development of HF and the expression of miRs, and discuss the value of using circulating miRs as diagnostic biomarkers in HF management. In particular, miR-155, miR-22 and miR-133 appear to be promising for the diagnosis, prognosis and management of HF patients.
Collapse
Affiliation(s)
- Yao-Meng Huang
- Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Wei-Wei Li
- Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Jun Wu
- Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Mei Han
- Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Bing-Hui Li
- Department of Oncological Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| |
Collapse
|
|
14
|
MicroRNA-135a inhibits cardiac fibrosis induced by isoproterenol via TRPM7 channel. Biomed Pharmacother 2018; 104:252-260. [PMID: 29775892 DOI: 10.1016/j.biopha.2018.04.157] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 04/23/2018] [Accepted: 04/23/2018] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Cardiac fibrosis is a crucial factor of heart failure. It has been reported that several microRNAs (miRNAs, miRs) were involved in cardiac fibrosis, however, the role and possible regulatory mechanism of microRNA-135a (miR-135a) in cardiac fibrosis have not been investigated. Here, we explored the regulation mechanism of miR-135a on cardiac fibrosis. METHODS AND RESULTS In vitro, cardiac fibroblasts (CFs) from neonatal rats were treated by isoproterenol (ISO) at the final concentration of 10 μM for 24 h and miR-135a expression was decreased obviously. A miR-135a mimic inhibited CFs proliferation and differentiation by down-regulating transient receptor potential melastatin 7 (TRPM7) expression and current, whose effects were reversed by either the addition of miR-135a mimic or silencing TRPM7. In vivo, adult SD rat cardiac fibrosis was induced by subcutaneous administration of ISO (5 mg/kg/day) for 10 days. The expression of Collagen I, α-smooth muscle actin (α-SMA) and TRPM7 were up-regulated while miR-135a was down-regulated. In summary, our results illustrated that TRPM7 channel played an essential role in regulating fibrosis and that miR-135a protected against ISO-induced cardiac fibrosis via TRPM7 channel. CONCLUSION MiR-135a inhibits cardiac fibrosis via miR-135a- TRPM7-collagen production pathway.
Collapse
|
|
15
|
Liu X, Li M, Hou M, Huang W, Song J. MicroRNA-135a alleviates oxygen-glucose deprivation and reoxygenation-induced injury in neurons through regulation of GSK-3β/Nrf2 signaling. J Biochem Mol Toxicol 2018; 32:e22159. [PMID: 29719095 DOI: 10.1002/jbt.22159] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 04/12/2018] [Accepted: 04/13/2018] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs) have been suggested as pivotal regulators in the pathological process of cerebral ischemia and reperfusion injury. In this study, we aimed to investigate the role of miR-135a in regulating neuronal survival in cerebral ischemia and reperfusion injury using an in vitro cellular model induced by oxygen-glucose deprivation and reoxygenation (OGD/R). Our results showed that miR-135a expression was significantly decreased in neurons with OGD/R treatment. Overexpression of miR-135a significantly alleviated OGD/R-induced cell injury and oxidative stress, whereas inhibition of miR-135a showed the opposite effects. Glycogen synthase kinase-3β (GSK-3β) was identified as a potential target gene of miR-135a. miR-135a was found to inhibit GSK-3β expression, but promote the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and downstream signaling. However, overexpression of GSK-3β significantly reversed miR-135a-induced neuroprotective effect. Overall, our results suggest that miR-135a protects neurons against OGD/R-induced injury through downregulation of GSK-3β and upregulation of Nrf2 signaling.
Collapse
Affiliation(s)
- Xiaobin Liu
- Department of Neurosurgery, The Third Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, People's Republic of China
| | - Min Li
- Department of Neurosurgery, The Third Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, People's Republic of China
| | - Mingshan Hou
- Department of Neurosurgery, The Third Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, People's Republic of China
| | - Weidong Huang
- Department of Neurosurgery, The Third Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, People's Republic of China
| | - Jinning Song
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China
| |
Collapse
|
|
16
|
Du XJ, Lu JM. MiR-135a represses oxidative stress and vascular inflammatory events via targeting toll-like receptor 4 in atherogenesis. J Cell Biochem 2018; 119:6154-6161. [PMID: 29663503 DOI: 10.1002/jcb.26819] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 02/28/2018] [Indexed: 12/18/2022]
Abstract
Plenty of microRNAs have been identified as critical mediators in atherosclerosis progression, which is still a great threat to human health. Oxidative stress and inflammation have been implicated to contribute a lot to atherosclerosis development. MiR-135a is abnormally expressed in various cancer types, however its function in atherosclerosis is largely unexplored. Ox-LDL is commonly recognized as a crucial atherosclerosis regulator. In our current study, we observed ox-LDL was able to induce RAW264.7 cell apoptosis and meanwhile miR-135a was restrained by ox-LDL both dose-dependently and time- dependently. CD36 has been reported to participate in atherosclerosis process and miR-135a mimics can inhibit its expression while miR-135a inhibitors exhibited a reverse phenomenon. Meanwhile, miR-135a overexpression can suppress foam cell formation, TC, TG levels, and cell apoptosis induced by 20 µg/mL ox-LDL. Subsequently, it was found that miR-135a overexpression can inhibit oxidative stress by decreasing ROS, MDA levels, and increasing SOD levels. Reversely, miR-135a inhibition demonstrated an inhibitory effect in vitro. Apart from these, miR-135a can also modulate inflammation molecules including IL-6, IL-1β, and TNF-α. TLR4 was predicted as a target of miR-135a and the negative correlation between them was confirmed by dual-luciferase reporter assay in our study. This work improves our understanding of atherosclerosis events mediated by miR-135a/TLR4 and helps to develop new approaches for atherosclerosis.
Collapse
Affiliation(s)
- Xian-Jin Du
- Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing-Min Lu
- Department of Neurology, Huai'an Second People's Hospital, and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| |
Collapse
|
|
17
|
Farías JG, Molina VM, Carrasco RA, Zepeda AB, Figueroa E, Letelier P, Castillo RL. Antioxidant Therapeutic Strategies for Cardiovascular Conditions Associated with Oxidative Stress. Nutrients 2017; 9:nu9090966. [PMID: 28862654 PMCID: PMC5622726 DOI: 10.3390/nu9090966] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidant systems, where ROS overwhelms the antioxidant capacity. Excessive presence of ROS results in irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases related to hypoxia, cardiotoxicity and ischemia-reperfusion. Here, we describe the participation of OS in the pathophysiology of cardiovascular conditions such as myocardial infarction, anthracycline cardiotoxicity and congenital heart disease. This review focuses on the different clinical events where redox factors and OS are related to cardiovascular pathophysiology, giving to support for novel pharmacological therapies such as omega 3 fatty acids, non-selective betablockers and microRNAs.
Collapse
Affiliation(s)
- Jorge G Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
| | - Víctor M Molina
- Unidad de Cuidados Intensivos, Hospital de Niños Roberto del Río, Santiago 7500922, Chile.
- Unidad de Cuidados Intensivos Pediátricos, Hospital Clínico Pontificia Universidad Católica de Chile, Santiago 7500922, Chile.
| | - Rodrigo A Carrasco
- Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile.
- Departamento de Cardiología, Clínica Alemana, Santiago 7500922, Chile.
| | - Andrea B Zepeda
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
| | - Elías Figueroa
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
- Núcleo de Investigación en Producción Alimentaria, BIOACUI, Escuela de Acuicultura, Universidad Católica de Temuco, Temuco 4780000, Chile.
| | - Pablo Letelier
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
- School of Health Sciences, Universidad Católica de Temuco, Temuco 4780000, Chile.
| | - Rodrigo L Castillo
- Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile.
- Programa de Fisiopatología Oriente, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile.
| |
Collapse
|
|
18
|
Peng Q, Wang X, Wu K, Liu K, Wang S, Chen X. Irisin attenuates H 2O 2-induced apoptosis in cardiomyocytes via microRNA-19b/AKT/mTOR signaling pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:7707-7717. [PMID: 31966617 PMCID: PMC6965300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 05/20/2017] [Indexed: 06/10/2023]
Abstract
Irisin, a novel muscle-secreted peptide, has been proposed to play a potential role in improving myocardial remodeling that leads to impaired myocardial function and heart failure. It has been reported that controlling reactive oxygen species (ROS) exposure could increase cardiomyocyte survival and prevent pathological remodeling of the myocardium. Therefore, we aimed to determine the potential protective effects of Irisin pretreatment against ROS in cardiomyocytes and explored the potential mechanisms. H9c2 cells that were subjected to H2O2 in vitro were used to mimic myocardial remodeling. Then, the effects of Irisin on myocardial cell proliferation, apoptosis and cellular ROS levels were evaluated during this process by using MTT assay, flow cytometry analysis and 2'7'-Dichloro fluoresc in diacetate (DCFH-DA). In order to determine whether Irisin could regulate any microRNA (miRNA) during this process, six miRNAs that are known to be involved in apoptosis of cardiomyocytes were assessed by qRT-PCR. The protective effects of Irisin on cardiomyocytes mediated by miR-19b were evaluated by detecting cell proliferation and apoptosis. In addition, the potential target of miR-19b was predicted with bioinformatics tools and verified using dual-luciferase reporter assay. Finally, the protein levels of members of the phosphatidylinositol 3-kinase (PI3K)/Akt/signaling pathway were also examined by Western Blot. Our study showed that Irisin treatment improved H2O2-induced cell viability and attenuated the levels of intracellular ROS and the apoptosis of cardiomyocytes in a dose-dependent manner. We also demonstrated that Irisin promoted cell viability and inhibited cell apoptosis via upregulating miR-19b expression. In addition, PTEN was identified as a functional target gene of miR-19b that was responsible for its anti-apoptotic effects in cardiomyocytes. Further study demonstrated that Irisin-regulated miR-19b could reactivate the AKT/mTOR signaling pathway blocked by H2O2 in H9c2 cells. We demonstrated that Irisin strongly enhances cellular proliferation and preventsapoptosis of cardiomyocytes as well as attenuates the levels of intracellular ROS induced by H2O2. These effects might be mediated through the miR-19b/AKT/mTOR signaling pathway, which provide a new insight into the mechanism by which Irisin may have beneficial effect on myocardial remodeling.
Collapse
Affiliation(s)
- Qing Peng
- Department of Cardiology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
- Department of Cardiology, The Affiliated Hospital of Southwest Medical UniversityLuzhou 646000, Sichuan, China
| | - Xiaojie Wang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical UniversityLuzhou 646000, Sichuan, China
| | - Kai Wu
- Department of Cardiology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Kai Liu
- Department of Cardiology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Si Wang
- Department of Cardiology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Xiaoping Chen
- Department of Cardiology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| |
Collapse
|