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Zhang JJ, Cheng L, Qiao Q, Xiao XL, Lin SJ, He YF, Sha RL, Sha J, Ma Y, Zhang HL, Ye XR. Adenosine triphosphate-induced cell death in heart failure: Is there a link? World J Cardiol 2025; 17:105021. [PMID: 40308621 PMCID: PMC12038699 DOI: 10.4330/wjc.v17.i4.105021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/22/2025] [Accepted: 04/02/2025] [Indexed: 04/21/2025] Open
Abstract
Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.
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Affiliation(s)
- Jing-Jing Zhang
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Lu Cheng
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Qian Qiao
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Xue-Liang Xiao
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Shao-Jun Lin
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yue-Fang He
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Ren-Luo Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Jun Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yin Ma
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia.
| | - Xue-Rui Ye
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
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Hao Z, Guan W, Wei W, Li M, Xiao Z, Sun Q, Pan Y, Xin W. Unlocking the therapeutic potential of tumor-derived EVs in ischemia-reperfusion: a breakthrough perspective from glioma and stroke. J Neuroinflammation 2025; 22:84. [PMID: 40089793 PMCID: PMC11909855 DOI: 10.1186/s12974-025-03405-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Accepted: 03/04/2025] [Indexed: 03/17/2025] Open
Abstract
Clinical studies have revealed a bidirectional relationship between glioma and ischemic stroke, with evidence of spatial overlap between the two conditions. This connection arises from significant similarities in their pathological processes, including the regulation of cellular metabolism, inflammation, coagulation, hypoxia, angiogenesis, and neural repair, all of which involve common biological factors. A significant shared feature of both diseases is the crucial role of extracellular vesicles (EVs) in mediating intercellular communication. Extracellular vesicles, with their characteristic bilayer structure, encapsulate proteins, lipids, and nucleic acids, shielding them from enzymatic degradation by ribonucleases, deoxyribonucleases, and proteases. This structural protection facilitates long-distance intercellular communication in multicellular organisms. In gliomas, EVs are pivotal in intracranial signaling and shaping the tumor microenvironment. Importantly, the cargos carried by glioma-derived EVs closely align with the biological factors involved in ischemic stroke, underscoring the substantial impact of glioma on stroke pathology, particularly through the crucial roles of EVs as key mediators in this interaction. This review explores the pathological interplay between glioma and ischemic stroke, addressing clinical manifestations and pathophysiological processes across the stages of hypoxia, stroke onset, progression, and recovery, with a particular focus on the crucial role of EVs and their cargos in these interactions.
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Affiliation(s)
- Zhongnan Hao
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Department of Neurology, The Affiliated Hospital of Qingdao University, Medical School of Qingdao University, Qingdao, 266100, Shandong Province, China
| | - Wenxin Guan
- Queen Mary School, Nanchang University, Xuefu Avenue, Nanchang, Jiangxi, China
| | - Wei Wei
- Department of Neurology, the Affiliated Hospital of Southwest Jiaotong University & The Third People's Hospital of Chengdu, Chengdu, 610031, Sichuan, PR China
| | - Meihua Li
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Zhipeng Xiao
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qinjian Sun
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China
| | - Yongli Pan
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China.
| | - Wenqiang Xin
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Podyacheva E, Snezhkova J, Onopchenko A, Dyachuk V, Toropova Y. The Role of MicroRNAs in the Pathogenesis of Doxorubicin-Induced Vascular Remodeling. Int J Mol Sci 2024; 25:13335. [PMID: 39769102 PMCID: PMC11728060 DOI: 10.3390/ijms252413335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/06/2024] [Accepted: 12/06/2024] [Indexed: 01/14/2025] Open
Abstract
Doxorubicin (DOX), a cornerstone chemotherapeutic agent, effectively combats various malignancies but is marred by significant cardiovascular toxicity, including endothelial damage, chronic heart failure, and vascular remodeling. These adverse effects, mediated by oxidative stress, mitochondrial dysfunction, inflammatory pathways, and dysregulated autophagy, underscore the need for precise therapeutic strategies. Emerging research highlights the critical role of microRNAs (miRNAs) in DOX-induced vascular remodeling and cardiotoxicity. miRNAs, such as miR-21, miR-22, miR-25, miR-126, miR-140-5p, miR-330-5p, miR-146, miR-143, miR-375, miR-125b, miR-451, miR-34a-5p, and miR-9, influence signaling pathways like TGF-β/Smad, AMPKa/SIRT, NF-κB, mTOR, VEGF, and PI3K/AKT/Nrf2, impacting vascular homeostasis, angiogenesis, and endothelial-to-mesenchymal transition. Despite existing studies, gaps remain in understanding the full spectrum of miRNAs involved and their downstream effects on vascular remodeling. This review synthesizes the current knowledge on miRNA dysregulation during DOX exposure, focusing on their dual roles in cardiovascular pathology and tumor progression. Strategies to reduce DOX cardiotoxicity include modulating miRNA expression to restore signaling balance, targeting pro-inflammatory and pro-fibrotic pathways, and leveraging miRNA inhibitors or mimics. This review aims to organize and integrate the existing knowledge on the role of miRNAs in vascular remodeling, particularly in the contexts of DOX treatment and the progression of various cardiovascular diseases, including their potential involvement in tumor growth.
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Affiliation(s)
| | | | | | | | - Yana Toropova
- Almazov National Medical Research Centre, Ministry of Health of the Russian Federation, 197341 Saint-Petersburg, Russia or (E.P.); (J.S.); (A.O.); (V.D.)
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4
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Song R, Zhang L. MicroRNAs and therapeutic potentials in acute and chronic cardiac disease. Drug Discov Today 2024; 29:104179. [PMID: 39276921 DOI: 10.1016/j.drudis.2024.104179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/23/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024]
Abstract
microRNAs (miRNAs) are small regulatory RNAs implicated in various cardiac disorders. In this review, the role of miRNAs is discussed in relation to acute myocardial infarction and chronic heart failure. In both settings, miRNAs are altered, contributing to injury and adverse remodeling. Notably, miRNA profiles differ between acute ischemic injury and progressive heart failure. Owing to miRNA variabilities between disease stages and delivery difficulties, translation of animal studies to the clinic remains challenging. The identification of distinct miRNA signatures could lead to the development of miRNA therapies tailored to different disease stages. Here, we summarize the current understanding of miRNAs in acute and chronic cardiac diseases, identify knowledge gaps and discuss progress in developing miRNA-based treatment strategies.
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Affiliation(s)
- Rui Song
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
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5
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Ge T, Ning B, Wu Y, Chen X, Qi H, Wang H, Zhao M. MicroRNA-specific therapeutic targets and biomarkers of apoptosis following myocardial ischemia-reperfusion injury. Mol Cell Biochem 2024; 479:2499-2521. [PMID: 37878166 DOI: 10.1007/s11010-023-04876-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/05/2023] [Indexed: 10/26/2023]
Abstract
MicroRNAs are single-stranded non-coding RNAs that participate in post-transcriptional regulation of gene expression, it is involved in the regulation of apoptosis after myocardial ischemia-reperfusion injury. For example, the alteration of mitochondrial structure is facilitated by MicroRNA-1 through the regulation of apoptosis-related proteins, such as Bax and Bcl-2, thereby mitigating cardiomyocyte apoptosis. MicroRNA-21 not only modulates the expression of NF-κB to suppress inflammatory signals but also activates the PI3K/AKT pathway to mitigate ischemia-reperfusion injury. Overexpression of MicroRNA-133 attenuates reactive oxygen species (ROS) production and suppressed the oxidative stress response, thereby mitigating cellular apoptosis. MicroRNA-139 modulates the extrinsic death signal of Fas, while MicroRNA-145 regulates endoplasmic reticulum calcium overload, both of which exert regulatory effects on cardiomyocyte apoptosis. Therefore, the article categorizes the molecular mechanisms based on the three classical pathways and multiple signaling pathways of apoptosis. It summarizes the targets and pathways of MicroRNA therapy for ischemia-reperfusion injury and analyzes future research directions.
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Affiliation(s)
- Teng Ge
- School of Graduate, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Bo Ning
- School of Graduate, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Yongqing Wu
- School of Graduate, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Xiaolin Chen
- School of Pharmacy, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Hongfei Qi
- Shaanxi Key Laboratory of Integrated Traditional and Western Medicine for Prevention and Treatment of Cardiovascular Diseases, Institute of Integrative Medicine, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Haifang Wang
- Shaanxi Key Laboratory of Integrated Traditional and Western Medicine for Prevention and Treatment of Cardiovascular Diseases, Institute of Integrative Medicine, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Mingjun Zhao
- Department of Cardiology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Deputy 2, Weiyang West Road, Weicheng District, Xianyang, 712000, China.
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6
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Qin S, Liu JY, Wang XQ, Feng BH, Ren YC, Zheng J, Yu K, Yu H, Li K, Zhu F, Chen M, Fu X, Chen T, Xing ZX, Mei H. ROS-mediated MAPK activation aggravates hyperoxia-induced acute lung injury by promoting apoptosis of type II alveolar epithelial cells via the STAT3/miR-21-5p axis. Mol Immunol 2023; 163:207-215. [PMID: 37839259 DOI: 10.1016/j.molimm.2023.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 09/13/2023] [Accepted: 09/28/2023] [Indexed: 10/17/2023]
Abstract
Inhibition of type II alveolar epithelial (AE-II) cell apoptosis is a critical way to cure hyperoxia-induced acute lung injury (HALI). It has been reported that miR-21-5p could reduce H2O2-induced apoptosis in AE-II cells. However, the upstream molecular mechanism remains unclear. Herein, we established a cellular model of HALI by exposing AE-II cells to H2O2 treatment. It was shown that miR-21-5p alleviated H2O2-induced apoptosis in AE-II cells. ROS inhibition decreased apoptosis of H2O2-evoked AE-II cells via increasing miR-21-5p expression. In addition, ROS induced MAPK and STAT3 phosphorylation in H2O2-treated AE-II cells. MAPK inactivation reduces H2O2-triggered AE-II cell apoptosis. MAPK activation inhibits miR-21-5p expression by promoting STAT3 phosphorylation in H2O2-challenged AE-II cells. Furthermore, STAT3 activation eliminated MAPK deactivation-mediated inhibition on the apoptosis of AE-II cells under H2O2 condition. In conclusion, ROS-mediated MAPK activation promoted H2O2-triggered AE-II cell apoptosis by inhibiting miR-21-5p expression via STAT3 phosphorylation, providing novel targets for HALI treatment.
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Affiliation(s)
- Song Qin
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Jun-Ya Liu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Xiao-Qin Wang
- Department of Pediatric, The second affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Bang-Hai Feng
- Department of Critical Care Medicine, Zunyi Hospital of Traditional Chinese Medicine, Zunyi 563000, PR China
| | - Ying-Cong Ren
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Jie Zheng
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Kun Yu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Hong Yu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Kang Li
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Feng Zhu
- Department of Respiratory and Critical Care Medicine, The Fifth People's Hospital of Wuxi Affiliated to Jiangnan University, Wuxi 214016, PR China
| | - Miao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Xiaoyun Fu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Tao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China
| | - Zhou-Xiong Xing
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China.
| | - Hong Mei
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, PR China.
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Wang X, Zhang T, Zhai J, Wang Z, Wang Y, He L, Ma S, Xing H, Guo Y. MiR-21 attenuates FAS-mediated cardiomyocyte apoptosis by regulating HIPK3 expression. Biosci Rep 2023; 43:BSR20230014. [PMID: 37581369 PMCID: PMC10500225 DOI: 10.1042/bsr20230014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 08/03/2023] [Accepted: 08/15/2023] [Indexed: 08/16/2023] Open
Abstract
MicroRNA-21 (miR-21) plays an anti-apoptotic role following ischemia-reperfusion (I/R) injury (IRI) in vivo; however, its underlying mechanism remains unclear. The present study explored the effects of miR-21 and homeodomain interacting protein kinase 3 (HIPK3) on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in vitro. To this end, the rat cardiomyocyte H9C2 cell line was exposed to H/R and the roles of miR-21 and HIPK3 in regulating cell viability and apoptosis were evaluated by cell counting kit-8 assay, terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling, and flow cytometry. Immunofluorescence and Western blotting were performed to detect the expression/phosphorylation of apoptosis-related proteins. miR-21 expression was measured with quantitative real-time polymerase chain reaction. The putative interaction between miR-21 and HIPK3 was evaluated using the luciferase reporter assay. Our results showed that (i) miR-21 overexpression or HIPK3 down-regulation significantly attenuated H9C2 cells apoptosis after H/R, (ii) suppression of miR-21 expression promoted apoptosis, (iii) miR-21 overexpression inhibited HIPK3 expression, (iv) HIPK3 was the direct and main target of miR-21, (v) miR-21/HIPK3 formed part of a reciprocal, negative feedback loop, and (vi) HIPK3 down-regulation decreased FAS-mediated apoptosis by inhibiting the phosphorylation of FADD, which subsequently inhibited the expression of BAX and cleaved caspase-3 and increased the expression of BCL2. Our study indicates that miR-21 attenuates FAS-mediated cardiomyocyte apoptosis by regulating HIPK3 expression, which could eventually have important clinical implications for patients with acute myocardial infarction.
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Affiliation(s)
- Xinyu Wang
- College of Postgraduate, Hebei North University, Zhangjiakou, Hebei, China
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Tingting Zhang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jianlong Zhai
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Zhongli Wang
- Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yan Wang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Lili He
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Sai Ma
- Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, China
| | - Hanying Xing
- Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yifang Guo
- College of Postgraduate, Hebei North University, Zhangjiakou, Hebei, China
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
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8
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Farzaei MH, Ramezani-Aliakbari F, Ramezani-Aliakbari M, Zarei M, Komaki A, Shahidi S, Sarihi A, Salehi I. Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1633-1646. [PMID: 36971866 DOI: 10.1007/s00210-023-02469-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/19/2023] [Indexed: 03/29/2023]
Abstract
Ischemia/reperfusion (I/R) injury is a tissue damage during reperfusion after an ischemic condition. I/R injury is induced by pathological cases including stroke, myocardial infarction, circulatory arrest, sickle cell disease, acute kidney injury, trauma, and sleep apnea. It can lead to increased morbidity and mortality in the context of these processes. Mitochondrial dysfunction is one of the hallmarks of I/R insult, which is induced via reactive oxygen species (ROS) production, apoptosis, and autophagy. MicroRNAs (miRNAs, miRs) are non-coding RNAs that play a main regulatory role in gene expression. Recently, there are evidence, which miRNAs are the major modulators of cardiovascular diseases, especially myocardial I/R injury. Cardiovascular miRNAs, specifically miR-21, and probably miR-24 and miR-126 have protective effects on myocardial I/R injury. Trimetazidine (TMZ) is a new class of metabolic agents with an anti-ischemic activity. It has beneficial effects on chronic stable angina by suppressing mitochondrial permeability transition pore (mPTP) opening. The present review study addressed the different mechanistic effects of TMZ on cardiac I/R injury. Online databases including Scopus, PubMed, Web of Science, and Cochrane library were assessed for published studies between 1986 and 2021. TMZ, an antioxidant and metabolic agent, prevents the cardiac reperfusion injury by regulating AMP-activated protein kinase (AMPK), cystathionine-γ-lyase enzyme (CSE)/hydrogen sulfide (H2S), and miR-21. Therefore, TMZ protects the heart against I/R injury by inducing key regulators such as AMPK, CSE/H2S, and miR-21.
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Affiliation(s)
- Mohammad Hosein Farzaei
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Maryam Ramezani-Aliakbari
- Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Zarei
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Siamak Shahidi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Abdolrahman Sarihi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Salehi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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9
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Wang Q, Jiang F, Zhao C, Song J, Hu M, Lv Y, Duan Y, Fang W, Ding R, Qiu Y. miR-21-5p prevents doxorubicin-induced cardiomyopathy by downregulating BTG2. Heliyon 2023; 9:e15451. [PMID: 37131441 PMCID: PMC10149273 DOI: 10.1016/j.heliyon.2023.e15451] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/27/2023] [Accepted: 04/10/2023] [Indexed: 05/04/2023] Open
Abstract
Cardiomyocyte apoptosis has been characterized as one of the major mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy. MicroRNA-21-5p (miR-21-5p) was reported to mitigate ischemia-induced cardiomyocyte apoptosis and cardiac injury. However, to our knowledge, the functional role of miR-21-5p in DOX-induced cardiomyopathy is unclear. In this study, we explored the role of miR-21-5p in DOX-induced cardiac injury. The expression level of miR-21-5p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Dual luciferase reporter assay was used to verify the potential target gene of miR-21-5p. The apoptosis rate of NRCMs was detected by TUNEL staining assay. Western blot analysis was used to detect the protein expression levels of Bax, Bcl-2, Caspase3, cleaved-Caspase3 and BTG2. For animal studies, mice were injected with AAV9-miR-21-5p or AAV9-Empty viruses, and treated with DOX at a dose of 5 mg/kg per week through intraperitoneally administration. After 4 weeks of DOX treatment, mice were subjected to echocardiography to measure the left ventricular ejection fraction (EF) and fractional shortening (FS). Results showed that miR-21-5p was upregulated in both DOX-treated primary cardiomyocytes and mouse heart tissues. Interestingly, enhanced miR-21-5p expression inhibited DOX-induced cardiomyocyte apoptosis and oxidative stress, while decreased miR-21-5p expression promoted cardiomyocyte apoptosis and oxidative stress. Furthermore, cardiac overexpression of miR-21-5p protected against DOX-induced cardiac injury. The mechanistic study indicated that BTG2 was a target gene of miR-21-5p. The anti-apoptotic effect of miR-21-5p could be inhibited by BTG2 overexpression. Conversely, inhibition of BTG2 rescued the pro-apoptotic effect of miR-21-5p inhibitor. Taken together, our study showed that miR-21-5p could prevent DOX-induced cardiomyopathy by downregulating BTG2.
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Affiliation(s)
- Qingwei Wang
- Department of Cardiology, People's Hospital, Peking University, Beijing, 100044, China
| | - Fei Jiang
- Heart Medicine Research Center, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
| | - Chenglin Zhao
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Jiaxin Song
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Meiyu Hu
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Yicheng Lv
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Yi Duan
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Wenqian Fang
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Rongjing Ding
- Cardiac Rehabilitation Center, Department of Rehabilitation Medicine, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Yan Qiu
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
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10
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Natural Monoterpenes as Potential Therapeutic Agents against Atherosclerosis. Int J Mol Sci 2023; 24:ijms24032429. [PMID: 36768748 PMCID: PMC9917110 DOI: 10.3390/ijms24032429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/28/2023] Open
Abstract
Traditional herbal medicines based on natural products play a pivotal role in preventing and managing atherosclerotic diseases, which are among the leading causes of death globally. Monoterpenes are a large class of naturally occurring compounds commonly found in many aromatic and medicinal plants. Emerging evidence has shown that monoterpenes have many biological properties, including cardioprotective effects. Remarkably, an increasing number of studies have demonstrated the therapeutic potential of natural monoterpenes to protect against the pathogenesis of atherosclerosis. These findings shed light on developing novel effective antiatherogenic drugs from these compounds. Herein, we provide an overview of natural monoterpenes' effects on atherogenesis and the underlying mechanisms. Monoterpenes have pleiotropic and multitargeted pharmacological properties by interacting with various cell types and intracellular molecular pathways involved in atherogenesis. These properties confer remarkable advantages in managing atherosclerosis, which has been recognized as a multifaceted vascular disease. We also discuss limitations in the potential clinical application of monoterpenes as therapeutic agents against atherosclerosis. We propose perspectives to give new insights into future preclinical research and clinical practice regarding natural monoterpenes.
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11
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Kawano I, Adamcova M. MicroRNAs in doxorubicin-induced cardiotoxicity: The DNA damage response. Front Pharmacol 2022; 13:1055911. [PMID: 36479202 PMCID: PMC9720152 DOI: 10.3389/fphar.2022.1055911] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/11/2022] [Indexed: 10/17/2023] Open
Abstract
Doxorubicin (DOX) is a chemotherapeutic drug widely used for cancer treatment, but its use is limited by cardiotoxicity. Although free radicals from redox cycling and free cellular iron have been predominant as the suggested primary pathogenic mechanism, novel evidence has pointed to topoisomerase II inhibition and resultant genotoxic stress as the more fundamental mechanism. Recently, a growing list of microRNAs (miRNAs) has been implicated in DOX-induced cardiotoxicity (DIC). This review summarizes miRNAs reported in the recent literature in the context of DIC. A particular focus is given to miRNAs that regulate cellular responses downstream to DOX-induced DNA damage, especially p53 activation, pro-survival signaling pathway inhibition (e.g., AMPK, AKT, GATA-4, and sirtuin pathways), mitochondrial dysfunction, and ferroptosis. Since these pathways are potential targets for cardioprotection against DOX, an understanding of how miRNAs participate is necessary for developing future therapies.
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Affiliation(s)
| | - Michaela Adamcova
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czechia
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12
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Sothivelr V, Hasan MY, Mohd Saffian S, Zainalabidin S, Ugusman A, Mahadi MK. Revisiting miRNA-21 as a Therapeutic Strategy for Myocardial Infarction: A Systematic Review. J Cardiovasc Pharmacol 2022; 80:393-406. [PMID: 35767710 DOI: 10.1097/fjc.0000000000001305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/11/2022] [Indexed: 01/31/2023]
Abstract
Several types of cardiovascular cells use microRNA-21 ( miR-21 ), which has been linked to cardioprotection. In this study, we systematically reviewed the results of published papers on the therapeutic effect of miR-21 for myocardial infarction. Studies described the cardioprotective effects of miR-21 to reduce infarct size by improving angiogenesis, antiapoptotic, and anti-inflammatory mechanisms. Results suggest that cardioprotective effects of miR-21 may work synergistically to prevent the deterioration of cardiac function during postischemia. However, there are other results that indicate that miR-21 positively regulates tissue fibrosis, potentially worsening a postischemic injury. The dual functionalities of miR-21 occur through the targeting of genes and signaling pathways, such as PTEN , PDCD4 , KBTBD7 , NOS3 , STRN , and Spry-1 . This review provides insights into the future advancement of safe miR-21 -based genetic therapy in the treatment of myocardial infarction.
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Affiliation(s)
- Vivisana Sothivelr
- Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan, Malaysia
| | - Mohammad Y Hasan
- Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan, Malaysia
| | - Shamin Mohd Saffian
- Centre for Quality Management of Medicine, Faculty of Pharmacy, Universiti Kebangsaan, Malaysia
| | - Satirah Zainalabidin
- Centre of Toxicology and Health Risk Study, Faculty of Health Sciences, Universiti Kebangsaan, Malaysia; and
| | - Azizah Ugusman
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan, Malaysia
| | - Mohd K Mahadi
- Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan, Malaysia
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13
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Sayed-Pathan NI, Kumar P, Paknikar KM, Gajbhiye V. MicroRNAs: A Neoteric Approach to Understand Pathogenesis, Diagnose, and Treat Myocardial Infarction. J Cardiovasc Pharmacol 2021; 78:773-781. [PMID: 34882110 DOI: 10.1097/fjc.0000000000001141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 09/12/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Myocardial infarction is a substantial contributor to ischemic heart diseases, affecting a large number of people leading to fatal conditions worldwide. MicroRNAs (miRNAs) are explicitly emerging as excellent modulators of pathways involved in maintaining cardiomyocyte survival, repair, and regeneration. Altered expression of genes in cardiomyocytes postinfarction can lead to the disordered state of the myocardium, such as cardiac hypertrophy, ischemia-reperfusion injury, left ventricular remodeling, and cardiac fibrosis. Therapeutic targeting of miRNAs in cardiomyocytes can potentially reverse the adverse effects in the heart postinfarction. This review aims to understand the role of several miRNAs involved in the regeneration and repair of cardiomyocytes postmyocardial infarction and presents comprehensive information on the subject.
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Affiliation(s)
- Nida Irfan Sayed-Pathan
- Nanobioscience Group, Agharkar Research Institute, Pune, India; and
- Savitribai Phule Pune University, Ganeshkhind, Pune, India
| | - Pramod Kumar
- Nanobioscience Group, Agharkar Research Institute, Pune, India; and
- Savitribai Phule Pune University, Ganeshkhind, Pune, India
| | - Kishore M Paknikar
- Nanobioscience Group, Agharkar Research Institute, Pune, India; and
- Savitribai Phule Pune University, Ganeshkhind, Pune, India
| | - Virendra Gajbhiye
- Nanobioscience Group, Agharkar Research Institute, Pune, India; and
- Savitribai Phule Pune University, Ganeshkhind, Pune, India
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14
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Friedrich J, Hammes HP, Krenning G. miRetrieve-an R package and web application for miRNA text mining. NAR Genom Bioinform 2021; 3:lqab117. [PMID: 34988440 PMCID: PMC8696973 DOI: 10.1093/nargab/lqab117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 11/01/2021] [Accepted: 12/03/2021] [Indexed: 12/30/2022] Open
Abstract
microRNAs (miRNAs) regulate gene expression and thereby influence biological processes in health and disease. As a consequence, miRNAs are intensely studied and literature on miRNAs has been constantly growing. While this growing body of literature reflects the interest in miRNAs, it generates a challenge to maintain an overview, and the comparison of miRNAs that may function across diverse disease fields is complex due to this large number of relevant publications. To address these challenges, we designed miRetrieve, an R package and web application that provides an overview on miRNAs. By text mining, miRetrieve can characterize and compare miRNAs within specific disease fields and across disease areas. This overview provides focus and facilitates the generation of new hypotheses. Here, we explain how miRetrieve works and how it is used. Furthermore, we demonstrate its applicability in an exemplary case study and discuss its advantages and disadvantages.
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Affiliation(s)
- Julian Friedrich
- Cardiovascular Regenerative Medicine (CAVAREM), Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1 (EA11), 9713 GZ Groningen, The Netherlands
- 5th Medical Department, Section of Endocrinology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Hans-Peter Hammes
- 5th Medical Department, Section of Endocrinology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- European Center of Angioscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Guido Krenning
- Cardiovascular Regenerative Medicine (CAVAREM), Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1 (EA11), 9713 GZ Groningen, The Netherlands
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15
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Du L, Chen J, Wu Y, Xia G, Chen M, Zhao P, Wang Y, Yao D, Liu F, Zhang L, Wang X, Yang Y, Wang L. Long Non-coding RNA N1LR Protects Against Myocardial Ischemic/Reperfusion Injury Through Regulating the TGF-β Signaling Pathway. Front Cardiovasc Med 2021; 8:654969. [PMID: 34485393 PMCID: PMC8414635 DOI: 10.3389/fcvm.2021.654969] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 07/12/2021] [Indexed: 11/13/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have been shown to play critical roles in various cell biological processes. However, the mechanism of lncRNAs in acute myocardial infarction (AMI) is not fully understood. Previous studies showed that lncRNA N1LR was down-regulated in ischemic cerebral stroke and its up-regulation was protective. The current study was designed to assess the protective effect of N1LR and further to explore potential mechanisms of N1LR in ischemic/reperfusion (I/R) injury after AMI. Male C57BL/6J mice and H9c2 cardiomyocytes were selected to construct in vivo and in vitro pathological models. In H9c2 cell line, N1LR expression was markedly decreased after H2O2 and CoCl2 treatments and N1LR overexpression alleviated apoptosis, inflammation reaction, and LDH release in cardiomyocytes treated with H2O2 and CoCl2. Mouse in vivo study showed that overexpression of N1LR enhanced cardiac function and suppressed inflammatory response and fibrosis. Mechanistically, we found that the expression of transforming growth factor (TGF)-β1 and smads were significantly decreased in the N1LR overexpression group exposed to H2O2. In a summary, our study indicated that N1LR can act as a protective factor against cardiac ischemic-reperfusion injury through regulating the TGF-β/Smads signaling pathway.
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Affiliation(s)
- Lin Du
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.,Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Jie Chen
- Department of Gastroenterology, Northern Jiangsu Province People's Hospital, Yangzhou University, Yangzhou, China
| | - Yong Wu
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Guangwei Xia
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Mingxing Chen
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Pei Zhao
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Yao Wang
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Deshan Yao
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Fan Liu
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Lina Zhang
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Xue Wang
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Yi Yang
- Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Liansheng Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
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16
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Gholaminejad A, Zare N, Dana N, Shafie D, Mani A, Javanmard SH. A meta-analysis of microRNA expression profiling studies in heart failure. Heart Fail Rev 2021; 26:997-1021. [PMID: 33443726 DOI: 10.1007/s10741-020-10071-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 12/20/2022]
Abstract
Heart failure (HF) is a major consequence of many cardiovascular diseases with high rate of morbidity and mortality. Early diagnosis and prevention are hampered by the lack of informative biomarkers. The aim of this study was to perform a meta-analysis of the miRNA expression profiling studies in HF to identify novel candidate biomarkers or/and therapeutic targets. A comprehensive literature search of the PubMed for miRNA expression studies related to HF was carried out. The vote counting and robust rank aggregation meta-analysis methods were used to identify significant meta-signatures of HF-miRs. The targets of HF-miRs were identified, and network construction and gene set enrichment analysis (GSEA) were performed to identify the genes and cognitive pathways most affected by the dysregulation of the miRNAs. The literature search identified forty-five miRNA expression studies related to CHF. Shared meta-signature was identified for 3 up-regulated (miR-21, miR-214, and miR-27b) and 13 down-regulated (miR-133a, miR-29a, miR-29b, miR-451, miR-185, miR-133b, miR-30e, miR-30b, miR-1, miR-150, miR-486, miR-149, and miR-16-5p) miRNAs. Network properties showed miR-29a, miR-21, miR-29b, miR-1, miR-16, miR-133a, and miR-133b have the most degree centrality. GESA identified functionally related sets of genes in signaling and community pathways in HF that are the targets of HF-miRs. The miRNA expression meta-analysis identified sixteen highly significant HF-miRs that are differentially expressed in HF. Further validation in large patient cohorts is required to confirm the significance of these miRs as HF biomarkers and therapeutic targets.
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Affiliation(s)
- Alieh Gholaminejad
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasrin Zare
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran
| | - Nasim Dana
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran
| | - Davood Shafie
- Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arya Mani
- Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran.
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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17
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Ionescu RF, Cretoiu SM. MicroRNAs as monitoring markers for right-sided heart failure and congestive hepatopathy. J Med Life 2021; 14:142-147. [PMID: 34104236 PMCID: PMC8169151 DOI: 10.25122/jml-2021-0071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The last decades showed a worrying increase in the evolution of cardiovascular diseases towards different stages of heart failure (HF), as a stigma of the western lifestyle. MicroRNAs (miRNAs), non-coding RNAs, which are approximately 22-nucleotide long, were shown to regulate gene expression at the post-transcriptional level and play a role in the pathogenesis and progression of HF. miRNAs research is of high interest nowadays, as these molecules display mechanisms of action that can influence the course of evolution of common chronic diseases, including HF. The potential of post-transcriptional regulation by miRNAs concerning the diagnosis, management, and therapy for HF represents a new promising approach in the accurate assessment of cardiovascular diseases. This review aims to assess the current knowledge of miRNAs in cardiovascular diseases, especially right-sided heart failure and hepatomegaly. Moreover, attention is focused on their role as potential molecular biomarkers and more promising aspects involving miRNAs as future therapeutic targets in the pathophysiology of HF.
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Affiliation(s)
- Ruxandra Florentina Ionescu
- Department of Cardiology I, Central Military Emergency University Hospital Dr. Carol Davila, Bucharest, Romania
| | - Sanda Maria Cretoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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18
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Liu B, Wang B, Zhang X, Lock R, Nash T, Vunjak-Novakovic G. Cell type-specific microRNA therapies for myocardial infarction. Sci Transl Med 2021; 13:eabd0914. [PMID: 33568517 PMCID: PMC8848299 DOI: 10.1126/scitranslmed.abd0914] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 01/19/2021] [Indexed: 12/13/2022]
Abstract
Current interventions fail to recover injured myocardium after infarction and prompt the need for development of cardioprotective strategies. Of increasing interest is the therapeutic use of microRNAs to control gene expression through specific targeting of mRNAs. In this Review, we discuss current microRNA-based therapeutic strategies, describing the outcomes and limitations of key microRNAs with a focus on target cell types and molecular pathways. Last, we offer a perspective on the outlook of microRNA therapies for myocardial infarction, highlighting the outstanding challenges and emerging strategies.
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Affiliation(s)
- Bohao Liu
- Department of Medicine, Columbia University, New York, NY 10032, USA
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Bryan Wang
- Department of Medicine, Columbia University, New York, NY 10032, USA
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Xiaokan Zhang
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Roberta Lock
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Trevor Nash
- Department of Medicine, Columbia University, New York, NY 10032, USA
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Gordana Vunjak-Novakovic
- Department of Medicine, Columbia University, New York, NY 10032, USA.
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
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19
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Huang J, Qi Z. MiR-21 mediates the protection of kaempferol against hypoxia/reoxygenation-induced cardiomyocyte injury via promoting Notch1/PTEN/AKT signaling pathway. PLoS One 2020; 15:e0241007. [PMID: 33151961 PMCID: PMC7644004 DOI: 10.1371/journal.pone.0241007] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Kaempferol, a natural flavonoid compound, possesses potent myocardial protective property in ischemia/reperfusion (I/R), but the underlying mechanism is not well understood. The present study was aimed to explore whether miR-21 contributes to the cardioprotective effect of kaempferol on hypoxia/reoxygenation (H/R)-induced H9c2 cell injury via regulating Notch/phosphatase and tensin homologue (PTEN)/Akt signaling pathway. Results revealed that kaempferol obviously attenuates H/R-induced the damages of H9c2 cells as evidence by the up-regulation of cell viability, the down-regulation of lactate dehydrogenase (LDH) activity, the reduction of apoptosis rate and pro-apoptotic protein (Bax) expression, and the increases of anti-apoptotic protein (Bcl-2) expression. In addition, kaempferol enhanced miR-21 level in H9c2 cells exposed to H/R, and inhibition of miR-21 induced by transfection with miR-21 inhibitor significantly blocked the protection of kaempferol against H/R-induced H9c2 cell injury. Furthermore, kaempferol eliminated H/R-induced oxidative stress and inflammatory response as illustrated by the decreases in reactive oxygen species generation and malondialdehyde content, the increases in antioxidant enzyme superoxide dismutase and glutathione peroxidase activities, the decreases in pro-inflammatory cytokines interleukin (IL)-1β, IL-8 and tumor necrosis factor-alpha levels, and an increase in anti-inflammatory cytokine IL-10 level, while these effects of kaempferol were all reversed by miR-21 inhibitor. Moreover, results elicited that kaempferol remarkably blocks H/R-induced the down-regulation of Notch1 expression, the up-regulation of PTEN expression, and the reduction of P-Akt/Akt, indicating that kaempferol promotes Notch1/PTEN/AKT signaling pathway, and knockdown of Notch1/PTEN/AKT signaling pathway induced by Notch1 siRNA also abolished the protection of kaempferol against H/R-induced the damage of H9c2 cells. Notably, miR-21 inhibitor alleviated the promotion of kaempferol on Notch/PTEN/Akt signaling pathways in H9c2 cells exposed to H/R. Taken together, these above findings suggested thatmiR-21 mediates the protection of kaempferol against H/R-induced H9c2 cell injuryvia promoting Notch/PTEN/Akt signaling pathway.
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Affiliation(s)
- Jinxi Huang
- Department of Cardiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, P.R. China
- * E-mail:
| | - Zhenhui Qi
- Department of Cardiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, P.R. China
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20
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Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4894625. [PMID: 33110473 PMCID: PMC7578723 DOI: 10.1155/2020/4894625] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/07/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022]
Abstract
Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart failure (HF), arrhythmias, cardiac ischemia, valve disease, pericarditis, and fibrosis of the pericardium and myocardium. The molecular mechanisms of cardiotoxicity caused by cancer treatment have not yet been elucidated, and they may be both varied and complex. By identifying the functional genetic variations responsible for this toxicity, we may be able to improve our understanding of the potential mechanisms and pathways of treatment, paving the way for the development of new therapies to target these toxicities. Data from studies on genetic defects and pharmacological interventions have suggested that many molecules, primarily those regulating oxidative stress, inflammation, autophagy, apoptosis, and metabolism, contribute to the pathogenesis of cardiotoxicity induced by cancer treatment. Here, we review the progress of genetic research in illuminating the molecular mechanisms of cancer treatment-mediated cardiotoxicity and provide insights for the research and development of new therapies to treat or even prevent cardiotoxicity in patients undergoing cancer treatment. The current evidence is not clear about the role of pharmacogenomic screening of susceptible genes. Further studies need to done in chemotherapy-induced cardiotoxicity.
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21
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Yuan M, Yang X, Duscher D, Xiong H, Ren S, Xu X, Wang C, Chen J, Liu Y, Machens HG, Chen Z. Overexpression of microRNA-21-5p prevents the oxidative stress-induced apoptosis of RSC96 cells by suppressing autophagy. Life Sci 2020; 256:118022. [PMID: 32610163 DOI: 10.1016/j.lfs.2020.118022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/08/2020] [Accepted: 06/24/2020] [Indexed: 10/24/2022]
Abstract
AIM We aim to study the anti-apoptotic effect of microRNA-21-5p (miR-21-5p) in the oxidative stress-induced apoptosis of Schwann cells and the relevant mechanism in this research, laying a foundation for the treatment of peripheral neuropathy (PNP). METHODS AND MATERIALS The oxidative stress model was established by using hydrogen peroxide (H2O2). ROS level were detected by DCFH-DA (2,7-Dichlorodi-hydrofluorescein diacetate). Western blot and fluorescence staining were used to detect the apoptosis and autophagy level. The miR-21-5p overexpression model was established by transfection of miR-21-5p mimics into RSC96 cells. Five groups of control group, H2O2 group, H2O2 + chloroquine (CQ) group, H2O2 + miR-21-5p mimics group, and H2O2 + miR-21-5p mimics+rapamycin (RAPA) group were included in our experiment. KEY FINDINGS Compared with control group, miR-21-5p was decreased in H2O2-treated RSC96 cells, while autophagy and apoptosis were both promoted. The result revealed that apoptosis was probably triggered by activation of autophagy in H2O2-treated group. In order to verify the relationship between autophagy and apoptosis more accurately, we used CQ to inhibit autophagy. Compared with H2O2-treated group, autophagy and apoptosis were both weakened in H2O2 + CQ group. Subsequently, we found the antiapoptotic effect of miR-21-5p in this model, overexpression of miR-21-5p prevented cells from being damaged by oxidative stress, it induced the decrease of PTEN and the level of autophagy, leading to decreased level of apoptosis. SIGNIFICANCE The identified relationship between miR-21-5p, apoptosis, and autophagy promotes us to find a new mechanism to improve the treatment for PNP.
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Affiliation(s)
- Meng Yuan
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaofan Yang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dominik Duscher
- Department of Plastic and Hand Surgery, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany
| | - Hewei Xiong
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Sen Ren
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiang Xu
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cheng Wang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yang Liu
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hans-Günther Machens
- Department of Plastic and Hand Surgery, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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22
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Liu X, Zhang Y, Jiang P, Cai J, Fu Q, Li X, Li Z. Ultrasonic cardiogram and MiRNA-21 analysis of cardiac dysfunction in patients with cardiac arrest following cardiopulmonary resuscitation. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2020; 190:105284. [PMID: 32018074 DOI: 10.1016/j.cmpb.2019.105284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/08/2019] [Accepted: 12/12/2019] [Indexed: 06/10/2023]
Abstract
PURPOSE To explore correlations between the serum level of miRNA-21 expression and cardiac dysfunction severity after cardiopulmonary resuscitation (CPR) using ultrasonic cardiogram. METHODS Thirty-nine patients with cardiopulmonary arrest receiving successful CPR and forty-one healthy participants were recruited in the study. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunochemiluminometric assays was used to examine the serum miRNA-21 level and the concentration of cardiac troponins T and I, respectively. Indices of Electrocardiogram (ECG) and cardiac dysfunction measured by ultrasound of patients in the case group were used to assess cardiac function after CPR. Furthermore, the correlation between the serum level of miRNA-21 expression and severity of cardiac dysfunction was analyzed by Spearman correlation analysis. RESULTS As compared to the control group, the serum level of miRNA-21 expression, as well as cardiac troponin T and I levels in the case group were significantly higher (p = 0.000). The miRNA-21 expression level in the patients at IV grade of cardiac function were substantially higher than patients at III grade (p = 0.015). There was no significant difference in level of cardiac troponins T and I between patients at III grade and patients at IV grade (p > 0.05). Further, Spearman correlation analysis revealed that the level of miRNA-21 expression was negatively correlated with cardiac function index in the ultrasound imaging: E peak, E/A value, LVEF and LVEDD (r = 0.617, 0.535, 0.612, 0.573, P = 0.012, 0.009, 0.008, 0.011), but was positively correlated with the level of cardiac troponins T and I (r = 0.546,0.582, P = 0.006,0.007) and the severity of cardiac dysfunction (r = 0.859, p < 0.05). CONCLUSION The level of miRNA-21 is higher after CPR is closely related to the severity of cardiac dysfunction that is measured by ultrasound, suggesting that it may serve as a potential biomarker.
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Affiliation(s)
- Xing Liu
- Department of Emergency. Shenzhen Longhua District Center Hospital, Shenzhen, Guangdong 518110, PR China
| | - Yongguang Zhang
- Department of Medicine, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510000, PR China
| | - Peng Jiang
- Department of Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China
| | - Jiachen Cai
- Department of Medicine, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510000, PR China
| | - Qiuhong Fu
- Department of Emergency. Shenzhen Longhua District Center Hospital, Shenzhen, Guangdong 518110, PR China
| | - Xiaolei Li
- Department of Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China
| | - Zhou Li
- Department of Medicine, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510000, PR China.
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Meta-Analysis of the Potential Role of miRNA-21 in Cardiovascular System Function Monitoring. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4525410. [PMID: 32337248 PMCID: PMC7150722 DOI: 10.1155/2020/4525410] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/17/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are short and noncoding RNA fragments that bind to the messenger RNA. They have different roles in many physiological or pathological processes. MicroRNA-21, one of the first miRNAs discovered, is encoded by the MIR21 gene and is located on the chromosomal positive strand 17q23.2. MicroRNA-21 is transcribed by polymerase II and has its own promoter sequence, although it is in an intron. It is intra- and extracellular and can be found in many body fluids, alone or combined with another molecule. It regulates many signalling pathways and therefore plays an important role in the cardiovascular system. Indeed, it is involved in the differentiation and migration of endothelial cells and angiogenesis. It contributes to the reconstruction of a myocardial infarction, and it can also act as a cellular connector or as an antagonist to cardiac cell apoptosis. By playing all these roles, it can be interesting to use it as a biomarker, especially for cardiovascular diseases.
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Zhou S, Sun Y, Zhao K, Gao Y, Cui J, Qi L, Huang L. miR‑21/PTEN pathway mediates the cardioprotection of geniposide against oxidized low‑density lipoprotein‑induced endothelial injury via suppressing oxidative stress and inflammatory response. Int J Mol Med 2020; 45:1305-1316. [PMID: 32323738 PMCID: PMC7138279 DOI: 10.3892/ijmm.2020.4520] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 11/21/2019] [Indexed: 12/22/2022] Open
Abstract
Oxidized low‑density lipoprotein (ox‑LDL)‑induced vascular endothelial damage, oxidative stress and inflammation play a vital role in the pathophysiology of atherosclerosis. Geniposide is the primary active ingredient from Gardenia jasminoides Ellis associated with anti‑oxidative properties and cardioprotective action. However, the therapeutic mechanism of geniposide in atherosclerosis remains unclear. Hence, the present study aimed to elucidate the underlying mechanisms of geniposide in oxidative stress and inflammatory response during ox‑LDL injury in human umbilical vein endothelial cells (HUVECs), focusing particularly on the microRNA (miR)‑21/PTEN pathway. The results demonstrated that geniposide pretreatment significantly increased cell viability, decreased lactate dehydrogenase release, increased miR‑21 level and decreased PTEN expression under ox‑LDL condition. Subsequently, transfection with miR‑21 mimic enhanced the protection of geniposide on ox‑LDL‑induced cytotoxicity and apoptosis (mediated by the upregulation of apoptotic rate and caspase‑3 activity), whereas miR‑21 inhibitor reversed these effects of geniposide. In addition, geniposide resulted in an anti‑oxidant effect as evidenced by the decrease in reactive oxygen species generation, malondialdehyde content and NADPH oxidase 2 expression, and the increase in superoxide dismutase, glutathione peroxidase and catalase activities in ox‑LDL‑treated HUVECs, which were exacerbated by miR‑21 mimic and reversed by miR‑21 inhibitor. Furthermore, geniposide mitigated the ox‑LDL‑induced inflammatory response, demonstrated by a downregulation of pro‑inflammatory cytokine (IL‑1β, IL‑6, and TNF‑α) levels and an upregulation of anti‑inflammatory cytokine (IL‑10) level. However, miR‑21 mimic enhanced, whereas miR‑21 inhibitor attenuated, these effects of geniposide. In conclusion, the present results indicated that geniposide protects HUVECs from ox‑LDL injury by inhibiting oxidative stress and inflammation, and that these effects are partly due to the enhancement of the miR‑21/PTEN pathway.
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Affiliation(s)
- Song Zhou
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
| | - Yunjing Sun
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
| | - Kai Zhao
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
| | - Yanzhou Gao
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
| | - Jiangman Cui
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
| | - Liping Qi
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
| | - Lingfang Huang
- Department of Cardiology, The Third Hospital of Xingtai City, Xingtai, Hebei 054000, P.R. China
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Chen YC, Hsu PY, Su MC, Chin CH, Liou CW, Wang TY, Lin YY, Lee CP, Lin MC, Hsiao CC. miR-21-5p Under-Expression in Patients with Obstructive Sleep Apnea Modulates Intermittent Hypoxia with Re-Oxygenation-Induced-Cell Apoptosis and Cytotoxicity by Targeting Pro-Inflammatory TNF-α-TLR4 Signaling. Int J Mol Sci 2020; 21:ijms21030999. [PMID: 32028672 PMCID: PMC7037842 DOI: 10.3390/ijms21030999] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 01/30/2020] [Accepted: 02/01/2020] [Indexed: 02/07/2023] Open
Abstract
The purpose of this study is to explore the anti-inflammatory role of microRNAs (miR)-21 and miR-23 targeting the TLR/TNF-α pathway in response to chronic intermittent hypoxia with re-oxygenation (IHR) injury in patients with obstructive sleep apnea (OSA). Gene expression levels of the miR-21/23a, and their predicted target genes were assessed in peripheral blood mononuclear cells from 40 treatment-naive severe OSA patients, and 20 matched subjects with primary snoring (PS). Human monocytic THP-1 cell lines were induced to undergo apoptosis under IHR exposures, and transfected with miR-21-5p mimic. Both miR-21-5p and miR-23-3p gene expressions were decreased in OSA patients as compared with that in PS subjects, while TNF-α gene expression was increased. Both miR-21-5p and miR-23-3p gene expressions were negatively correlated with apnea hypopnea index and oxygen desaturation index, while TNF-α gene expression positively correlated with apnea hypopnea index. In vitro IHR treatment resulted in decreased miR-21-5p and miR-23-3p expressions. Apoptosis, cytotoxicity, and gene expressions of their predicted target genes—including TNF-α, ELF2, NFAT5, HIF-2α, IL6, IL6R, EDNRB, and TLR4—were all increased in response to IHR, while all were reversed with miR-21-5p mimic transfection under IHR condition. The findings provide biological insight into mechanisms by which IHR-suppressed miRs protect cell apoptosis via inhibit inflammation, and indicate that over-expression of the miR-21-5p may be a new therapy for OSA.
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Affiliation(s)
- Yung-Che Chen
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
- Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Po-Yuan Hsu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
| | - Mao-Chang Su
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
- Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Respiratory Therapy, Chang Gung University of Science and Technology, Chia-Yi 61363, Taiwan
| | - Chien-Hung Chin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
- Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Medicine, Chung Shan Medical University School of Medicine, Taichung 40201, Taiwan
| | - Chia-Wei Liou
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Ting-Ya Wang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
| | - Yong-Yong Lin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
| | - Chiu Ping Lee
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
| | - Meng-Chih Lin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
- Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Correspondence: (M.-C.L.); (C.-C.H.); Tel.: +886-7-731-7123 (ext 8199) (M.-C.L.); +886-7-731-7123 (ext. 8979) (C.-C.H.)
| | - Chang-Chun Hsiao
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (Y.-C.C.); (P.-Y.H.); (M.-C.S.); (C.-H.C.); (T.-Y.W.); (Y.-Y.L.); (C.P.L.)
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Correspondence: (M.-C.L.); (C.-C.H.); Tel.: +886-7-731-7123 (ext 8199) (M.-C.L.); +886-7-731-7123 (ext. 8979) (C.-C.H.)
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Role of HIF-1α in Cold Ischemia Injury of Rat Donor Heart Via the miR-21/PDCD4 Pathway. Transplant Proc 2020; 52:383-391. [PMID: 31959353 DOI: 10.1016/j.transproceed.2019.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 10/19/2019] [Accepted: 11/10/2019] [Indexed: 11/21/2022]
Abstract
BACKGROUND Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that plays a major role under hypoxia conditions. Cold storage during heart transplantation causes the donor heart long-term hypoxia. There is some evidence indicating a conceivable HIF-1α/microRNA-21 (miR-21)/phosphatase and tensin homolog (PTEN)/programmed cell death 4 (PDCD4) pathway. We assessed the hypothesis that HIF-1α has a positive effect during donor heart cold storage by making the miR-21 upregulate to reduce the expression of PDCD4. METHODS We established the rat heart cold storage model and stratified it into 6-hour groups from 0 to 24 hours. Western blot and quantitative reverse transcription polymerase chain reaction were performed to detect the expression of HIF-1α, miR-21, PDCD4, and PTEN. RESULTS After cold storage the expression of HIF-1α increased from 0 to 6 hours and then gradually decreased, but the expression level was relatively higher compared with the control group. The miR-21 was upregulated from 0 to 12 hours then downregulated. The messenger RNA expression of PDCD4 was upregulated gradually, but the protein expression was significantly downregulated at 12th hour then continued to upregulate. Interestingly, the expression level of miR-21 was highest in the 12th hour, which indicated miR-21 could inhibit the PDCD4. We subsequently detected the messenger RNA of PTEN, which can inhibit HIF-1α and be inhibited by miR-21. The expression of PTEN was also significantly downregulated at the 12th hour. CONCLUSION In conclusion, there is possible interaction between HIF-1α and miR-21, and the conceivable HIF-1α/miR-21/PTEN/PDCD4 pathway plays a protective role in cold storage of the heart.
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Ma J, Chen Z, Ma Y, Xia Y, Hu K, Zhou Y, Chen A, Qian J, Ge J. MicroRNA‐19a attenuates hypoxia‐induced cardiomyocyte apoptosis by downregulating NHE‐1 expression and decreasing calcium overload. J Cell Biochem 2019; 121:1747-1758. [PMID: 31633225 DOI: 10.1002/jcb.29411] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 10/04/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Jiaqi Ma
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Zhangwei Chen
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Yuanji Ma
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Yan Xia
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Kai Hu
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - You Zhou
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Ao Chen
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Juying Qian
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
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Zheng T, Shi Y, Zhang J, Peng J, Zhang X, Chen K, Chen Y, Liu L. MiR-130a exerts neuroprotective effects against ischemic stroke through PTEN/PI3K/AKT pathway. Biomed Pharmacother 2019; 117:109117. [DOI: 10.1016/j.biopha.2019.109117] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/07/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023] Open
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MicroRNA-21 Mediates the Protective Effect of Cardiomyocyte-Derived Conditioned Medium on Ameliorating Myocardial Infarction in Rats. Cells 2019; 8:cells8080935. [PMID: 31430983 PMCID: PMC6721717 DOI: 10.3390/cells8080935] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/13/2019] [Accepted: 08/16/2019] [Indexed: 01/07/2023] Open
Abstract
Conditioned medium derived from ischemic myocardium improves rodent cardiac function after myocardial infarction. Exosomal miRNA-mediated intercellular communication is considered to mediate the protective effect of conditioned medium against ischemic injury. Oxygen–glucose-deprivation (OGD)-treated cardiac cells and a rat model with acute myocardial infarction (AMI) were applied. The expression profiles of myocardial-disease-associated miRNAs in cardiomyocytes, cardiac fibroblasts, ventricular myocardium, and conditioned medium derived from cardiomyocytes under ischemic stresses were analyzed. Primary cultured cell model and a rat model with myocardial infarction were applied to examine the role of miRNA in regulating cardiomyocyte apoptosis, fibroblast activation, immune cell infiltration, and myocardial infarction. Results showed that expression levels of miR-21 in cardiomyocytes, cardiac fibroblasts, and conditioned medium (CM) derived from cardiomyocytes were up-regulated with OGD treatment. With the depletion of miR-21, the protective effect of CM on cardiomyocytes against oxidative stress, enhanced fibroblast activation, and promotion of angiogenesis in endothelial cells were reduced. Administration of CM reduced the infarcted size and immune cell infiltration in myocardium of rats with AMI, while depletion of miR-21 reduced the effect of CM. In conclusion, miR-21 plays a role in intercellular communication among ischemic cardiac cells. The expression of miR-21 is important for the protective effect of conditioned medium against myocardial infarction.
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Long Noncoding RNA Expression Profile in BV2 Microglial Cells Exposed to Lipopolysaccharide. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5387407. [PMID: 31309106 PMCID: PMC6594345 DOI: 10.1155/2019/5387407] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 05/26/2019] [Indexed: 02/07/2023]
Abstract
Neuropathic pain, which is one of the most common forms of chronic pain, seriously increases healthcare costs and impairs patients' quality of life with an incidence of 7–10% worldwide. Microglia cell activation plays a key role in the progression of neuropathic pain. Better understanding of novel molecules modulating microglia cell activation and these underlying functions will extremely benefit the exploration of new treatment. Recent studies suggested long noncoding RNAs may be involved in neuropathic pain. However, its underlying functions and mechanisms in microglia cell activation remain unclear. To identify the differentially expressed lncRNAs and predict their functions in the progression of microglia cell activation, GSE103156 was analyzed using integrated bioinformatics methods. The expression levels of selected lncRNAs and mRNAs were determined by real-time PCR. In the present study, a total of 56 lncRNAs and 298 mRNAs were significantly differentially expressed. The differentially expressed mRNAs were mainly enriched in NF-kappa B signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and NOD-like receptor signaling pathway. The top 10 hub genes were Tnf, Il6, Stat1, Cxcl10, Il1b, Tlr2, Irf1, Ccl2, Irf7, and Ccl5 in the PPI network. Our results showed that Gm8989, Gm8979, and AV051173 may be involved in the progression of microglia cell activation. Taken together, our findings suggest that lots of lncRNAs may be involved in BV2 microglia cell activation in vitro. The findings may provide relevant information for the development of promising targets for the microglial cells activation of neuropathic pain in vivo in the future.
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Yin Y, Yang C. miRNA‐30‐3p improves myocardial ischemia via the PTEN/PI3K/AKT signaling pathway. J Cell Biochem 2019; 120:17326-17336. [PMID: 31131466 DOI: 10.1002/jcb.28996] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 02/10/2019] [Accepted: 02/14/2019] [Indexed: 01/28/2023]
Affiliation(s)
- Yugang Yin
- Department of Geriatric Cardiology Nanjing Jinling Hospital Nanjing China
| | - Chun Yang
- Department of Geriatric Cardiology Nanjing Jinling Hospital Nanjing China
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Xu HX, Pan W, Qian JF, Liu F, Dong HQ, Liu QJ. MicroRNA‑21 contributes to the puerarin‑induced cardioprotection via suppression of apoptosis and oxidative stress in a cell model of ischemia/reperfusion injury. Mol Med Rep 2019; 20:719-727. [PMID: 31115556 DOI: 10.3892/mmr.2019.10266] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 04/05/2019] [Indexed: 11/05/2022] Open
Abstract
Puerarin, a major bioactive constituent of the Radix puerariae, can ameliorate myocardial ischemia/reperfusion (I/R) injury. Emerging evidence supports that microRNA (miR)‑21 functions as a protective factor against I/R and/or hypoxia‑reperfusion (H/R)‑induced myocardial injury. However, the role of miR‑21 in the cardioprotective effect of puerarin remains unclear. Therefore, the purpose of the present study was to demonstrate the involvement of miR‑21 in the cardioprotective mechanisms of puerarin using a cell model of I/R injury, generated by culturing rat H9c2 cardiomyocytes under H/R conditions. The results demonstrated that pre‑treatment with puerarin significantly increased cell viability, decreased lactate dehydrogenase activity and upregulated miR‑21 expression in H/R‑treated H9c2 cells. Transfection of an miR‑21 inhibitor led to an increase in H/R‑induced cytotoxicity and reversed the protective effects of puerarin. Additionally, miR‑21 inhibition attenuated the puerarin‑induced decrease in the rate of apoptosis, caspase‑3 activity and the expression of apoptosis regulator Bax, and increased apoptosis regulator Bcl‑2 expression, under H/R conditions. Furthermore, puerarin mitigated H/R‑induced oxidative stress as evidenced by the decrease in endogenous reactive oxygen species production, malondialdehyde content and NADPH oxidase 2 expression, and enhanced the antioxidative defense system as illustrated by the increase in superoxide dismutase activity, catalase and glutathione peroxidase levels. These effects were all eliminated by miR‑21 inhibitor transfection. Furthermore, the miR‑21 inhibitor exacerbated the H/R‑induced oxidative stress and attenuated the antioxidative defense system in H/R‑treated H9c2 cells. Taken together, the results suggested that miR‑21 mediated the cardioprotective effects of puerarin against myocardial H/R injury by inhibiting apoptosis and oxidative stress.
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Affiliation(s)
- Hai-Xiang Xu
- Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, P.R. China
| | - Wen Pan
- Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, P.R. China
| | - Jian-Feng Qian
- Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, P.R. China
| | - Feng Liu
- Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, P.R. China
| | - Hai-Qi Dong
- Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, P.R. China
| | - Qing-Jun Liu
- Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, P.R. China
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Xing Y, Li L. RETRACTED: Gastrodin protects rat cardiomyocytes H9c2 from hypoxia-induced injury by up-regulation of microRNA-21. Int J Biochem Cell Biol 2019; 109:8-16. [PMID: 30684569 DOI: 10.1016/j.biocel.2019.01.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/21/2018] [Accepted: 01/21/2019] [Indexed: 12/21/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Author. The journal contacted the authors for their response to the following remark from Dr Elisabeth Bik regarding this paper: ‘This paper belongs to a set of over 400 papers (as per February 2020) that share very similar Western blots with tadpole-like shaped bands, the same background pattern, and striking similarities in title structures, paper layout, bar graph design, and - in a subset - flow cytometry panels. Despite these similarities, these papers are authored by researchers from different departments and institutes, with almost no overlap in authors’. The authors failed to respond to this directly but instead requested the journal to retract the paper on the basis that the data were not represented accurately and new results have shown inconsistency with what has been reported in this paper. The authors apologise for any misconceptions that this paper may have resulted in.
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Affiliation(s)
- Yu Xing
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Ling Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
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Kumar S, Williams D, Sur S, Wang JY, Jo H. Role of flow-sensitive microRNAs and long noncoding RNAs in vascular dysfunction and atherosclerosis. Vascul Pharmacol 2019; 114:76-92. [PMID: 30300747 PMCID: PMC6905428 DOI: 10.1016/j.vph.2018.10.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/19/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is the primary underlying cause of myocardial infarction, ischemic stroke, and peripheral artery disease. The disease preferentially occurs in arterial regions exposed to disturbed blood flow, in part, by altering expression of flow-sensitive coding- and non-coding genes. In this review, we summarize the role of noncoding RNAs, [microRNAs (miRNAs) and long noncoding RNAs(lncRNAs)], as regulators of gene expression and outline their relationship to the pathogenesis of atherosclerosis. While miRNAs are small noncoding genes that post-transcriptionally regulate gene expression by targeting mRNA transcripts, the lncRNAs regulate gene expression by diverse mechanisms, which are still emerging and incompletely understood. We focused on multiple flow-sensitive miRNAs such as, miR-10a, -19a, -23b, -17~92, -21, -663, -92a, -143/145, -101, -126, -712, -205, and -155 that play a critical role in endothelial function and atherosclerosis by targeting inflammation, cell cycle, proliferation, migration, apoptosis, and nitric oxide signaling. Flow-dependent regulation of lncRNAs is just emerging, and their role in vascular dysfunction and atherosclerosis is unknown. Here, we discuss the flow-sensitive lncRNA STEEL along with other lncRNAs studied in the context of vascular pathophysiology and atherosclerosis such as MALAT1, MIAT1, ANRIL, MYOSLID, MEG3, SENCR, SMILR, LISPR1, and H19. Also discussed is the use of these noncoding RNAs as potential biomarkers and therapeutics to reduce and regress atherosclerosis.
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Affiliation(s)
- Sandeep Kumar
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Darian Williams
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Sanjoli Sur
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Jun-Yao Wang
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Hanjoong Jo
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA; Division of Cardiology, Emory University, Atlanta, USA.
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Zhang CJ, Huang Y, Lu JD, Lin J, Ge ZR, Huang H. Retracted: Upregulated microRNA-132 rescues cardiac fibrosis and restores cardiocyte proliferation in dilated cardiomyopathy through the phosphatase and tensin homolog-mediated PI3K/Akt signal transduction pathway. J Cell Biochem 2019; 120:1232-1244. [PMID: 30216493 DOI: 10.1002/jcb.27081] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 04/26/2018] [Indexed: 02/02/2023]
Abstract
Cardiac fibrosis is known to be present in dilated cardiomyopathy (DCM) and it predicts the occurrence of sudden death and congestive heart failure. The aim of our study is to investigate the expression of microRNA-132 (miR-132) and its effect on cardiocyte proliferation, apoptosis, and cardiac fibrosis by binding to phosphatase and tensin homolog (PTEN) through the phosphateidylinositol 3-kinase (PI3K)/protein kinase (Akt) signal transduction pathway in DCM rats. DCM rat models induced by doxorubicin were established and confirmed by an ultrasonic cardiogram. Epithelial cells were treated with inhibitors, activators, and small interfering RNAs to identify the mechanisms by which miR-132 controls cardiocyte activity and cardiac fibrosis. Angiotensin II (Ang II) and aldosterone (ALD) expressions were detected by an enzyme-linked immunosorbent assay. The relationship between PTEN and miR-132 was verified by a dual-luciferase reporter assay. Cell proliferation and apoptosis were tested by the MTT assay and flow cytometry. PTEN was determined to be the target gene of miR-132. Rat models of DCM exhibited a lower level of miR-132, PI3K, Akt, B-cell lymphoma 2, collagen I, and collagen III, but a higher level of PTEN, Bcl-2-associated X protein, and proliferating cell nuclear antigen as well as inflammatory response (Ang II and ALD), accompanied by declined cardiocyte proliferation and elevated apoptosis and cardiac fibrosis. Upregulated miR-132 or silenced PTEN activated the PI3K/Akt pathway, thus facilitating cardiocyte proliferation and repressing cardiocyte apoptosis and cardiac fibrosis, as well as inflammatory responses. Downregulated miR-132 reversed this tendency. These findings indicate that miR-132 activates the PI3K/Akt pathway by inhibiting PTEN expression, thus facilitating cardiocyte proliferation and inhibiting apoptosis and cardiac fibrosis in DCM rats.
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Affiliation(s)
- Chen-Jun Zhang
- Department of Cardiology, Gongli Hospital, Shanghai, China
| | - Yu Huang
- Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ji-De Lu
- Department of Cardiology, Gongli Hospital, Shanghai, China
| | - Jie Lin
- Department of Cardiology, Gongli Hospital, Shanghai, China
| | - Zhi-Ru Ge
- Department of Cardiology, Gongli Hospital, Shanghai, China
| | - Hui Huang
- Department of Cardiology, Gongli Hospital, Shanghai, China
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Chen W, Sinha B, Li Y, Benowitz L, Chen Q, Zhang Z, Patel NJ, Aziz-Sultan AM, Chiocca AE, Wang X. Monogenic, Polygenic, and MicroRNA Markers for Ischemic Stroke. Mol Neurobiol 2019; 56:1330-1343. [PMID: 29948938 PMCID: PMC7358039 DOI: 10.1007/s12035-018-1055-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 03/29/2018] [Indexed: 02/08/2023]
Abstract
Ischemic stroke (IS) is a leading disease with high mortality and disability, as well as with limited therapeutic window. Biomarkers for earlier diagnosis of IS have long been pursued. Family and twin studies confirm that genetic variations play an important role in IS pathogenesis. Besides DNA mutations found previously by genetic linkage analysis for monogenic IS (Mendelian inheritance), recent studies using genome-wide associated study (GWAS) and microRNA expression profiling have resulted in a large number of DNA and microRNA biomarkers in polygenic IS (sporadic IS), especially in different IS subtypes and imaging phenotypes. The present review summarizes genetic markers discovered by clinical studies and discusses their pathogenic molecular mechanisms involved in developmental or regenerative anomalies of blood vessel walls, neuronal apoptosis, excitotoxic death, inflammation, neurogenesis, and angiogenesis. The possible impact of environment on genetics is addressed as well. We also include a perspective on further studies and clinical application of these IS biomarkers.
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Affiliation(s)
- Wu Chen
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- Department of Clinical Laboratory, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, Hubei, China.
| | - Bharati Sinha
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Department of Newborn Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Yi Li
- Department of Clinical Laboratory, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, Hubei, China
| | - Larry Benowitz
- Department of Neurosurgery, Boston Children's Hospital, F.M. Kirby Neurobiology Center for Life Science, Harvard Medical School, Boston, MA, 02115, USA
| | - Qinhua Chen
- Experimental Center, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, Hubei, China
| | - Zhenghong Zhang
- Department of Neurology, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, Hubei, China
| | - Nirav J Patel
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Ali M Aziz-Sultan
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Antonio E Chiocca
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
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Panagal M, Biruntha M, Vidhyavathi RM, Sivagurunathan P, Senthilkumar SR, Sekar D. Dissecting the role of miR-21 in different types of stroke. Gene 2019; 681:69-72. [PMID: 30267810 DOI: 10.1016/j.gene.2018.09.048] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/19/2018] [Accepted: 09/25/2018] [Indexed: 12/21/2022]
Abstract
Stroke is an important neurological disease in which blood flow to the brain is interrupted and it is becoming an increasing non-communicable disease in developing countries. Current treatment options for stroke is modifying lifestyle practice, diabetes treatment, drugs, and other factors management, but yet no cure is available in sight for the disease, despite it requires new insight into the molecular and therapeutic targets. In general, MicroRNAs (miRNAs) are small noncoding RNAs considered as of greater biological importance and controls molecular signaling pathways in diabetic pathogenesis. Among the reported MiRNAs, MIR-21 is considered to be an important MiRNA, which is frequently elevated in many types of types of strokes, suggesting that it plays an important role in cell proliferation, and apoptosis. Until now, there is no research paper that signifying the role of miR-21 in all types of strokes and the number of studies on the different category of strokes is limited, so in this paper, we are highlighting the recent investigations related to the significance of miR-21 in different types of strokes based on the up-to-date reports. It was found that MiR-21 was found to be normally up and down regulated in all types of strokes, however; we summarize the important research findings related to the role of miR-21 in different types of strokes.
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Affiliation(s)
- Mani Panagal
- Department of Biotechnology, Annai College of Arts and Science, Kumbakonam, Tamil Nadu 612001, India
| | - M Biruntha
- Department of Animal Health and Management, Alagappa University, Tamil Nadu 630003, India
| | - R M Vidhyavathi
- Department of Bioinformatics, Alagappa University, Tamil Nadu 630003, India
| | - P Sivagurunathan
- Department of Microbiology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu 608002, India
| | - S R Senthilkumar
- School of Biological Science, St. Joseph's College, Tiruchirappalli 620002, India
| | - Durairaj Sekar
- Department of Life Science, Centre for Research and PG Studies, Kristu Jayanti College (Autonomous), Bangalore University, Bangalore 560064, India.
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Abstract
Cardiotoxicity is a well-known side effect of doxorubicin (DOX), but the mechanisms leading to this phenomenon are still not completely clear. Prediction of drug-induced dysfunction onset is difficult and is still largely based on detection of cardiac troponin (cTn), a circulating marker of heart damage. In the last years, several investigations focused on the possible involvement of microRNAs (miRNAs) in DOX-induced toxicity in vitro, with contrasting results. Recently, several groups employed animal models to mimic patient’s condition, investigate the biological pathways perturbed by DOX, and identify diagnostic markers of cardiotoxicity. We reviewed the results from several studies investigating cardiac miRNAs expression in rodent models of DOX-treatment. We also discussed the data from two publications indicating the possible use of circulating miRNA as biomarkers of DOX-induced cardiotoxicity. Unfortunately, limited information was derived from these studies, as selection methods of candidate-miRNAs and heterogeneity in cardiotoxicity assessment greatly hampered the novelty and robustness of the findings. Nevertheless, at least one circulating miRNA, miR-1, showed a good potential as early biomarker of drug-mediated cardiac dysfunction onset. The use of animal models to investigate DOX-induced cardiotoxicity surely helps narrowing the gap between basic research and clinical practice. Despite this, several issues, including selection of relevant miRNAs and less-than-optimal assessment of cardiotoxicity, greatly limited the results obtained so far. Nonetheless, the association of patients-based studies with the use of preclinical models may be the key to address the many unanswered questions regarding the pathophysiology and early detection of cardiotoxicity.
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Liu Z, Wang H, Hou G, Cao H, Zhao Y, Yang B. Notoginsenoside R1 protects oxygen and glucose deprivation‐induced injury by upregulation of miR‐21 in cardiomyocytes. J Cell Biochem 2018; 120:9181-9192. [PMID: 30552708 DOI: 10.1002/jcb.28194] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/12/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Zengjia Liu
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University Jining Shandong China
- Forensic Science Center of Jining Medical University Jining Shandong China
| | - Haiyang Wang
- Department of Cardiology Qingdao Municipal Hospital Qingdao Shandong China
| | - Guoliang Hou
- Department of Cardiovascular Medicine Tengzhou Central People's Hospital Tengzhou Shandong China
| | - Honglei Cao
- Department of Cardiology Jining No. 1 People's Hospital Jining Shandong China
| | - Yan Zhao
- Department of Pain Treatment Jining No. 1 People's Hospital Jining Shandong China
| | - Baofa Yang
- Department of Cardiology Jining No. 1 People's Hospital Jining Shandong China
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Sun H, Tong Z, Fang Y, Jiang B, Liang P, Tang Y, Li Y, Wu Y, Xiao X. Nucleolin protects against doxorubicin-induced cardiotoxicity via upregulating microRNA-21. J Cell Physiol 2018; 233:9516-9525. [PMID: 29968904 DOI: 10.1002/jcp.26854] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/10/2018] [Indexed: 12/11/2022]
Abstract
Nucleolin is a multifunctional protein and participates in many important biological processes. Our previous study found that nucleolin protects the heart against myocardial ischemia-reperfusion injury. In this study, we aimed to investigate the role of nucleolin in doxorubicin (DOX)-induced cardiotoxicity. The expression pattern of nucleolin in hearts subjected to DOX injury was investigated, and we found that administration of DOX induced nucleolin expression significantly in vivo and in vitro. Gene transfection and RNA interference approaches were used in cardiomyocytes to investigate the function of nucleolin. Nucleolin overexpression protects cardiomyocytes against DOX-induced injury. Nucleolin-ablated cardiomyocytes become susceptible to the injury induced by DOX. The hearts of cardiac-myocyte-specific nucleolin transgenic mice are more resistant to DOX injury. Furthermore, nucleolin upregulates microRNA(miRNA)-21 expression in vivo and in vitro, and the miRNA-21 inhibitor negates the protective effect of nucleolin against injury induced by DOX. These results have demonstrated that nucleolin is involved in the regulation of DOX-induced cardiac injury and dysfunction via the regulation of miRNA-21 expression, and may be a novel therapeutic target for DOX-induced cardiotoxicity.
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Affiliation(s)
- Hui Sun
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Department of Pathophysiology, Institute of Cardiovascular Disease and Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China
| | - Zhongyi Tong
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yeqing Fang
- Department of Cardiology, Shenzhen Nanshan People's Hospital, Shenzhen, Guangdong, China
| | - Bimei Jiang
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Pengfei Liang
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuting Tang
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yuanbin Li
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yanyang Wu
- Food Science and Technology College, Hunan Agricultural University, Changsha, Hunan, China
| | - Xianzhong Xiao
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
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Zhai CL, Tang GM, Qian G, Hu HL, Wang SJ, Yin D, Zhang S. MicroRNA-98 attenuates cardiac ischemia-reperfusion injury through inhibiting DAPK1 expression. IUBMB Life 2018; 71:166-176. [PMID: 30419147 DOI: 10.1002/iub.1879] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 03/07/2018] [Indexed: 02/04/2023]
Abstract
Cardiovascular ischemic disease is a large class of diseases that are harmful to human health. The significant role of microRNAs (miRNAs) in terms of controlling cardiac injury has been reported in latest studies. MiR-98 is very important in regulating the apoptosis, the differentiation, the growth as well as the metastasis of cells. Nevertheless, the effect of miR-98 in the cardiac ischemia reperfusion (I/R) injury has rarely been investigated. In the current research, we found that the miR-98 expression was down-regulated in the cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and in the myocardium of the I/R rats. In addition, over-expression of miR-98 could significantly reduce the myocardial oxidative stress and ischemic injury as well as cell apoptosis. In agreement, similar findings were demonstrated in H9c2 cells subjected to H/R injury. Bioinformatic analysis using MiRanda and TargetScan and luciferase activity assay confirmed death-associated protein kinase 1 (DAPK1) as a direct target of miR-98. These findings suggest that miR-98 may be exploited as a novel molecular marker or therapeutic target for myocardial I/R injury. © 2018 IUBMB Life, 71(1):166-176, 2019.
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Affiliation(s)
- Chang-Lin Zhai
- Department of Cardiovascular Diseases, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, People's Republic of China.,Department of Cardiovascular Diseases, The Frist Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China
| | - Guan-Min Tang
- Department of Cardiovascular Diseases, The Frist Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China
| | - Gang Qian
- Department of Cardiovascular Diseases, The Frist Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China
| | - Hui-Lin Hu
- Department of Cardiovascular Diseases, The Frist Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China
| | - Shi-Jun Wang
- Department of Cardiovascular Diseases, The Frist Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China
| | - Dong Yin
- Department of Cardiovascular Diseases, The Frist Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China
| | - Song Zhang
- Department of Cardiovascular Diseases, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, People's Republic of China
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Wang J, Duan L, Gao Y, Zhou S, Liu Y, Wei S, An S, Liu J, Tian L, Wang S. Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice. Mol Cell Endocrinol 2018; 472:149-158. [PMID: 29233785 DOI: 10.1016/j.mce.2017.12.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 11/29/2017] [Accepted: 12/08/2017] [Indexed: 12/21/2022]
Abstract
Cardiac fibrosis with diabetic nephropathy (DN) is one of major diabetic complications. miR-21 and MMP-9 were closely associated with fibrosis diseases. Angiotensin II receptor blockers (ARB) have cardioprotective effects. However, it remains unclear whether miR-21 was involved in the mechanism of cardiac fibrosis with DN by target MMP-9 and ARB ameliorates cardiac fibrosis partly by inhibiting miR-21 expression. In this study, In Situ Hybridization(ISH), RT-PCR, cell transfection, western blotting and laser confocal telescope were used, respectively. ISH showed that miR-21, concentrated in cytoplasmic foci in the proximity of the nucleus, was mainly localized in cardiac fibroblasts and at relatively low levels in cardiomyocytes within cardiac tissue with DN. RT-PCR showed that miR-21 expression was significantly enhanced in cardiac tissue with DN, accompanied by the increase of col-IV, FN, CVF, PVCA, LVMI, HWI and NT-pro-BNP (p < 0.05). Bioinformatics analysis and Luciferase reporter gene assays showed that MMP-9 was a validated target of miR-21. Furthermore, cell transfection experiments showed that miR-21 overexpression directly decreased MMP-9 expression. Interestingly, miR-21 levels in cardiac tissue was positively correlated with ACR (r = -0.870, P = 0.003), whereas, uncorrelated with SBP, HbA1C and T-Cho (p > 0.05). More importantly, ARB can significantly decrease miR-21 expression in cardiac tissue, cardiac fibroblasts and serum. Overall, our results suggested that miR-21 may contribute to the pathogenesis of cardiac fibrosis with DN by target MMP-9, and that miR-21 may be a new possible therapeutic target for ARB in cardiac fibrosis with DN.
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Affiliation(s)
- Jinyang Wang
- Department of Endocrinology, Gansu Provincial People's Hospital, Gansu Key Laboratory of Endocrine and Metabolism, 204 Donggang West Road, Lanzhou, 730000, PR China.
| | - Lijun Duan
- Department of Gynecology and Obstetrics, Gansu Provincial People's Hospital, 204 Donggang West Road, Lanzhou 730000, PR China.
| | - Yanbin Gao
- Metabolic Disease Center, School of Traditional Chinese Medical, Capital Medical University, Beijing Key Laboratory of TCM Collateral Disease Theory Research, Beijing, 100069, PR China
| | - Shuhong Zhou
- Department of Rheumatology and Immunology, Gansu Provincial People's Hospital, 204 Donggang West Road, Lanzhou, 730000, PR China
| | - Yongming Liu
- Department of Geriatric Endocrinology, The First Hospital of Lanzhou University, 1 Donggang West Road, Lanzhou, 730000, PR China
| | - Suhong Wei
- Department of Endocrinology, Gansu Provincial People's Hospital, Gansu Key Laboratory of Endocrine and Metabolism, 204 Donggang West Road, Lanzhou, 730000, PR China
| | - Siqin An
- Department of Endocrinology, Gansu Provincial People's Hospital, Gansu Key Laboratory of Endocrine and Metabolism, 204 Donggang West Road, Lanzhou, 730000, PR China
| | - Jing Liu
- Department of Endocrinology, Gansu Provincial People's Hospital, Gansu Key Laboratory of Endocrine and Metabolism, 204 Donggang West Road, Lanzhou, 730000, PR China
| | - Liming Tian
- Department of Endocrinology, Gansu Provincial People's Hospital, Gansu Key Laboratory of Endocrine and Metabolism, 204 Donggang West Road, Lanzhou, 730000, PR China
| | - Shaocheng Wang
- Clinical College of Ophthalmology, Tianjin Medical University, Tianjin Eye Hospital, Tianjin, 300070, PR China
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Cai M, Wang YW, Xu SH, Qiao S, Shu QF, Du JZ, Li YG, Liu XL. Regulatory effects of the long non‑coding RNA RP11‑543N12.1 and microRNA‑324‑3p axis on the neuronal apoptosis induced by the inflammatory reactions of microglia. Int J Mol Med 2018; 42:1741-1755. [PMID: 29956723 DOI: 10.3892/ijmm.2018.3736] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 06/15/2018] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to examine how the long non‑coding RNA (lncRNA) RP11‑543N12.1 interacted with microRNA (miR)‑324‑3p to modify microglials (MIs)‑induced neuroblastoma cell apoptosis, which may pose benefits to the treatment of Alzhemier's disease (AD). The cell model of AD was established by treating SH‑SY5Y cells with amyloid β (Aβ)25‑35, and MI were acquired using primary cell culture technology. The lncRNAs that were differentially expressed between SH‑SY5Y and control cells were screened through a microarray assay and confirmed via polymerase chain reaction. In addition, overexpression of RP11‑543N12.1 and miR‑324‑3p was established by transfection of SH‑SY5Y cells with pcDNA3.1(+)‑RP11‑543N12.1 and miR‑324‑3p mimics, respectively, while downregulation of RP11‑543N12.1 and miR‑324‑3p was achieved by transfection with RP11‑543N12.1‑small interfering RNA (siRNA) and miR‑324‑3p inhibitor, respectively. The interaction between RP11‑543N12.1 and miR‑324‑3p was confirmed with a dual‑luciferase reporter gene assay. The results revealed that the expression levels of total and phosphorylated tau in SH‑SY5Y cells were significantly elevated following Aβ25‑35 treatment (P<0.05), and RP11‑543N12.1 was found to be differentially expressed between the control and Aβ25‑35‑treated cells (P<0.05). Furthermore, the targeted association of RP11‑543N12.1 and miR‑324‑3p was predicted based on miRDB4.0 and PITA databases, and then validated via the dual‑luciferase reporter gene assay. SH‑SY5Y cells transfected with siRNA or inhibitor, and treated with Aβ25‑35 displayed cellular survival and apoptosis that were similar to the normal levels (P<0.05). Finally, co‑culture of MI and SH‑SY5Y cells transfected with RP11‑543N12.1‑siRNA/miR‑324‑3p inhibitor significantly enhanced cell apoptosis (P<0.05). In conclusion, RP11‑543N12.1 targeted miR‑324‑3p to suppress proliferation and promote apoptosis in the AD cell model, suggesting that RP11‑543N12.1 and miR‑324‑3p may be potential biomarkers and therapeutic targets for AD.
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Affiliation(s)
- Miao Cai
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Yan-Wen Wang
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Shan-Hu Xu
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Song Qiao
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Qin-Fen Shu
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Jian-Zong Du
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Ya-Guo Li
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
| | - Xiao-Li Liu
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
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microRNA-21 Confers Neuroprotection Against Cerebral Ischemia-Reperfusion Injury and Alleviates Blood-Brain Barrier Disruption in Rats via the MAPK Signaling Pathway. J Mol Neurosci 2018; 65:43-53. [DOI: 10.1007/s12031-018-1067-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 04/11/2018] [Indexed: 02/02/2023]
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45
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Zeng YL, Zheng H, Chen QR, Yuan XH, Ren JH, Luo XF, Chen P, Lin ZY, Chen SZ, Wu XQ, Xiao M, Chen YQ, Chen ZZ, Hu JD, Yang T. Bone marrow-derived mesenchymal stem cells overexpressing MiR-21 efficiently repair myocardial damage in rats. Oncotarget 2018; 8:29161-29173. [PMID: 28418864 PMCID: PMC5438721 DOI: 10.18632/oncotarget.16254] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/08/2017] [Indexed: 01/08/2023] Open
Abstract
Objective We investigated the ability of bone marrow derived mesenchymal stem cells (BMSCs) overexpressing microRNA-21 (miR-21) to repair cardiac damage induced by anthracyclines in rats. Methods Sprague-Dawley (SD) rats of 2~3 weeks old were selected to isolate and culture BMSCs. A lentivirus harboring pLVX-miR-21 was generated and transfected into rat BMSCs. The rats were assigned into an untreated negative control group, and groups injected with adriamycin alone or with adriamycin followed by BMSCs, pLVX-BMSCs or pLVX-miR-21-BMSCs (n = 10 each). Proliferation and migration of cells were detected by cholecystokinin-8 (CCK- 8) and transwell. MiR-21 expression, mRNA expressions of B cell lymphoma 2 (Bcl2), BAX (BCL-2-associated X protein) and vascular endothelial growth factor (VEGF) were tested by qRT-PCR. Western blotting was applied to detect protein expressions of Bcl-2, Bax and VEGF. Results Using CCK- 8 and transwell assays, we found that pLVX-miR-21-BMSCs, which overexpressed miR-21, exhibited greater proliferation and migration than untransfected BMSCs or pLVX-BMSCs. Ultrasonic cardiograms and immunohistochemical analysis demonstrated that among the five groups, the pLVX-miR-21-BMSC group exhibited the most improved heart function and enhanced angiogenesis. Moreover, the pLVX-miR-21-BMSC group showed enhanced expression of Bcl-2, VEGF and Cx43 and reduced expression of Bax, BNP and troponin T. Conclusion These findings suggest miR-21 overexpression enhanced the proliferation, invasiveness and differentiation of BMSCs as well as expression of key factors (Bcl-2, VEGF and Bax) essential for repairing the cardiac damage induced by anthracyclines and restoring heart function.
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Affiliation(s)
- Yan-Ling Zeng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China.,Department of Hematology, Affiliated Nanping First Hospital of Fujian Medical University, Nanping 353000, P. R. China
| | - Hao Zheng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Qiu-Ru Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Xiao-Hong Yuan
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Jin-Hua Ren
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Xiao-Feng Luo
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Ping Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Zhe-Yao Lin
- Department of Hematology, Affiliated Nanping First Hospital of Fujian Medical University, Nanping 353000, P. R. China
| | - Shao-Zhen Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Xue-Qiong Wu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Min Xiao
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Yong-Quan Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Zhi-Zhe Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Jian-Da Hu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Ting Yang
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
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miR-21 suppression prevents cardiac alterations induced by d-galactose and doxorubicin. J Mol Cell Cardiol 2018; 115:130-141. [PMID: 29329959 DOI: 10.1016/j.yjmcc.2018.01.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 01/01/2018] [Accepted: 01/08/2018] [Indexed: 01/02/2023]
Abstract
d-galactose (d-gal)-induced cardiac alterations and Doxorubicin (Dox)-induced cardiomyocyte senescence are commonly used models to study cardiac aging. Accumulating evidence has suggested that microRNAs (miRNAs, miRs) are critically involved in the regulation of cellular and organismal aging and age-related diseases. However, little has been revealed about the roles of miRNAs in cardiac alterations induced by d-gal and Dox. In this study, we used miRNA arrays to investigate the dysregulated miRNAs in heart samples from 15month-old versus 2month-old male C57BL/6 mice and further validated them in d-gal-induced pseudo-aging mouse model and Dox-induced cardiomyocyte senescence in vitro model. We confirmed a significant increase of miR-21 in all these models by quantitative reverse transcription polymerase chain reactions. We further demonstrated that miR-21 was able to promote Dox-induced cardiomyocyte senescence whereas suppression of miR-21 could prevent that, as determined by percentage of β-gal-positive cells and gene markers of aging. Phosphatase and tensin homolog (PTEN) was identified as a target gene of miR-21, mediating its effect in increasing cardiomyocyte senescence. Finally, we found that miR-21 knockout mice were resistant to d-gal-induced alterations in aging-markers and cardiac function. Collectively, this study provides direct evidence that inhibition of miR-21 is protective against d-gal-induced cardiac alterations and Dox-induced cardiomyocyte senescence via targeting PTEN. Inhibition of miR-21 might be a novel strategy to combat cardiac aging.
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Ke ZP, Xu P, Shi Y, Gao AM. MicroRNA-93 inhibits ischemia-reperfusion induced cardiomyocyte apoptosis by targeting PTEN. Oncotarget 2018; 7:28796-805. [PMID: 27119510 PMCID: PMC5045357 DOI: 10.18632/oncotarget.8941] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 04/04/2016] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs have been implicated in some biological and pathological processes, including the myocardial ischemia/reperfusion (I/R) injury. Recent findings demonstrated that miR-93 might provide a potential cardioprotective effect on ischemic heart disease. This study was to investigate the role of miR-93 in I/R-induced cardiomyocyte injury and the potential mechanism. In this study, we found that hypoxia/reoxygenation (H/R) dramatically increased LDH release, MDA contents, ROS generation, and endoplasmic reticulum stress (ERS)-mediated cardiomyocyte apoptosis, which were attenuated by co-transfection with miR-93 mimic. Phosphatase and tensin homolog (PTEN) was identified as the target gene of miR-93. Furthermore, miR-93 mimic significantly increased p-Akt levels under H/R, which was partially released by LY294002. In addtion, Ad-miR-93 also attenuated myocardial I/R injury in vivo, manifested by reduced LDH and CK levels, infarct area and cell apoptosis. Taken together, our findings indicates that miR-93 could protect against I/R-induced cardiomyocyte apoptosis by inhibiting PI3K/AKT/PTEN signaling.
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Affiliation(s)
- Zun-Ping Ke
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Peng Xu
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Yan Shi
- Department of Emergency, The Affiliated Huai'an Hospital of Xuzhou Medical College and The Second People's Hospital of Huai'an, Huai'an, China
| | - Ai-Mei Gao
- Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
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Sun G, Lu Y, Li Y, Mao J, Zhang J, Jin Y, Li Y, Sun Y, Liu L, Li L. miR-19a protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis via PTEN/PI3K/p-Akt pathway. Biosci Rep 2017; 37:BSR20170899. [PMID: 29054970 PMCID: PMC5715126 DOI: 10.1042/bsr20170899] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 11/10/2017] [Accepted: 10/18/2017] [Indexed: 12/24/2022] Open
Abstract
miRNAs have been implicated in processing of cardiac hypoxia/reoxygenation (H/R)-induced injury. Recent studies demonstrated that miR-19a might provide a potential cardioprotective effect on myocardial disease. However, the effect of miR-19a in regulating myocardial ischemic injury has not been previously addressed. The present study was to investigate the effect of miR-19a on myocardial ischemic injury and identified the potential molecular mechanisms involved. Using the H/R model of rat cardiomyocytes H9C2 in vitro, we found that miR-19a was in low expression in H9C2 cells after H/R treatment and H/R dramatically decreased cardiomyocyte viability, and increased lactate dehydrogenase (LDH) release and cardiomyocyte apoptosis, which were attenuated by co-transfection with miR-19a mimic. Dual-luciferase reporter assay and Western blotting assay revealed that PTEN was a direct target gene of miR-19a, and miR-19a suppressed the expression of PTEN via binding to its 3'-UTR. We further identified that overexpression of miR-19a inhibited the expression of PTEN at the mRNA and protein levels. Moreover, PTEN was highly expressed in H/R H9C2 cells and the apoptosis induced by H/R was associated with the increase in PTEN expression. Importantly, miR-19a mimic significantly increased p-Akt levels under H/R. In conclusion, our findings indicate that miR-19a could protect against H/R-induced cardiomyocyte apoptosis by inhibiting PTEN /PI3K/p-Akt signaling pathway.
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Affiliation(s)
- Guochao Sun
- Deparment of Pathology and Forensics, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Ying Lu
- Teaching Laboratory of Morphology, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Yingxia Li
- Department of Spine Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Jun Mao
- Deparment of Pathology and Forensics, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Jun Zhang
- Teaching Affairs Department, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Yanling Jin
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Yan Li
- Department of Anatomy, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Yan Sun
- Deparment of Pathology and Forensics, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Lei Liu
- Deparment of Pathology and Forensics, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
| | - Lianhong Li
- Deparment of Pathology and Forensics, Dalian Medical University, No.9 West Section, Lvshun Road, Dalian 116044, China
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Razavi-Azarkhiavi K, Jaafari MR, Abnous K, Razavi BM, Jafarian AH, Hassani FV, Shirani K, Karimi G. The Cardiotoxic Mechanism of Doxorubicin (DOX) and Pegylated Liposomal DOX in Mice Bearing C-26 Colon Carcinoma: a Study Focused on microRNA Role for Toxicity Assessment of New Formulations. Pharm Res 2017; 34:1849-1856. [PMID: 28560697 DOI: 10.1007/s11095-017-2194-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 05/23/2017] [Indexed: 01/25/2023]
Abstract
PURPOSE MicroRNAs (miRs) are a group of small non-coding RNAs that regulate transcriptional or post-transcriptional gene expression. The aim of the present study was to investigate the role of miR -1, -21 and -145 and their targets in cardiotoxicity-induced by DOX and pegylated liposomal DOX. METHODS BALB/c mice subjected to subcutaneous injection of C-26 tumor cells. Eight days after tumor inoculation, animals were divided into 6 groups: control, liposome, DOX (6 and 9 mg/kg) and PL-DOX (6 and 9 mg/kg). The formulations were administered one time per week for four weeks. 24 h after the last injection, mice were sacrificed; blood and heart samples were taken. Western blot analysis was done on protein extracts to investigate the expression of cardiac caspase-3, -8, Bax, Bcl2, Programmed cell death 4 (PDCD4) and BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3). The expression levels of miR -1, -21 and -145 were also evaluated by quantitative real-time PCR. RESULTS Mice treated with both DOX formulations showed a marked inhibition in tumor growth. Western blot analysis indicated that the expression level of cardiac caspase-3, caspase-8, Bax and BNIP3 were up-regulated due to DOX injection (9 mg/kg). Exposure of mice with DOX resulted in a significant increase in cardiac miR-1 and miR-21 expression level. PL-DOX treatment did not change the proteins and miRs expression. CONCLUSION The results suggest that miR -1, -21 and -145 may involve in cardiotoxicity induced by DOX. Evaluation of miRs signaling pathways might be of potential value for toxicity assessment of new formulations. Graphical Abstract The cardiotoxic mechanism of doxorubicin (DOX) and pegylated liposomal DOX (PL-DOX).
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Affiliation(s)
- Kamal Razavi-Azarkhiavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khalil Abnous
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box, 1365-91775, I.R., Mashhad, Iran
| | - Bibi Marjan Razavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Hossein Jafarian
- Cancer Molecular Research Center, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Vahdati Hassani
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kobra Shirani
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamreza Karimi
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box, 1365-91775, I.R., Mashhad, Iran.
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Liu K, Du J, Ruan L. MicroRNA-21 regulates the viability and apoptosis of diffuse large B-cell lymphoma cells by upregulating B cell lymphoma-2. Exp Ther Med 2017; 14:4489-4496. [PMID: 29067124 DOI: 10.3892/etm.2017.5021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 12/19/2016] [Indexed: 12/31/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL), one of the most frequently diagnosed non-Hodgkin lymphoma (NHL), is partly attributed to hereditary factors. MicroRNA-21 (miR-21) is an oncogenic substance that induces NHL and primarily targets tumor-suppressive molecules, such as B cell lymphoma-2 (Bcl-2). The present study explored whether Bcl-2, targeted by miR-21, would affect the development of NHL. Specimens were harvested from 55 patients with DLBCL who had undergone surgical treatment. Expression levels of miR-21 and Bcl-2 were evaluated through reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting. Luciferase-reporter assays were performed to investigate the potential association between miR-21 and Bcl-2. MTT assays, flow cytometric analysis and caspase-3 activity assays were used to evaluate cell viability and apoptosis of DLBCL cells, respectively. Furthermore, statistical analysis was conducted using SPSS 19.0 software and the expression levels of miR-21 and Bcl-2 within DLBCL tissues were significantly upregulated when compared to those in normal tissues (P<0.01). As predicted by TargetScan, perfect base pairing was observed between the seed sequence of mature miR-21 and the 3' untranslated region of Bcl-2 mRNA. Dual luciferase reporter gene assays also revealed that miR-21 significantly facilitated the luciferase activity of Bcl-2 wild-type, with 61% upregulation (P<0.01) observed. MTT assays demonstrated that the viability of OCI-LY3 cells was decreased when cells were transfected with miR-21 inhibitor or Bcl-2 small interfering RNA and compared with those of control and negative control groups (all P<0.05). The apoptosis rate and caspase-3 activity level of the miR-21 group were 2.73±0.48 and 0.47±0.05, respectively, which were both significantly different from the groups with lower levels of miR-21 expression levels (all P<0.01). Since miR-21 may contribute to increased viability and decreased apoptosis of DLBCL cells through targeting Bcl-2, both Bcl-2 and miR-21 are likely to serve as effective targets for developing novel DLBCL treatments in the future.
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Affiliation(s)
- Ke Liu
- Department of Hematology, The First Affiliated Hospital and College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Jingxia Du
- Department of Pharmacology, Medical College, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Linhai Ruan
- Department of Hematology, The First Affiliated Hospital and College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
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