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Li L, Zheng Z, Lan W, Tang N, Zhang D, Ling J, Wu Y, Yang P, Fu L, Liu J, Zhang J, Yu P, Huang T. Role of Exosomes in Cardiovascular Disease: A Key Regulator of Intercellular Communication in Cardiomyocytes. ACS OMEGA 2025; 10:18145-18169. [PMID: 40385188 PMCID: PMC12079207 DOI: 10.1021/acsomega.4c11423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/27/2025] [Accepted: 04/22/2025] [Indexed: 05/20/2025]
Abstract
In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.
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Affiliation(s)
- Liuxin Li
- Department of Endocrinology and Metabolism, second Affiliated Hospital
of Nanchang University, Nanchang, People’s Republic of China, The second Clinical Medical College, Nanchang University, Nanchang 330006, Republic of China
| | - Zhidong Zheng
- Department of Endocrinology and Metabolism, second Affiliated Hospital
of Nanchang University, Nanchang, People’s Republic of China, The second Clinical Medical College, Nanchang University, Nanchang 330006, Republic of China
| | - Wenyu Lan
- The
Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Nan Tang
- The
Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Deju Zhang
- Food
and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 0000, Hong Kong
| | - Jitao Ling
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Yuting Wu
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Pingping Yang
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Linhua Fu
- Department
of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Jianping Liu
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Jing Zhang
- Department
of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical
College, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Peng Yu
- Department
of Metabolism and Endocrinology, The Second
Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Tieqiu Huang
- Department
of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
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Fu C, Liu Y, Yang H, Liang Q, Liu W, Guo W. Construction of a miR-15a-based risk prediction model for vascular calcification detection in patients undergoing hemodialysis. Ren Fail 2024; 46:2313175. [PMID: 38419564 PMCID: PMC10906117 DOI: 10.1080/0886022x.2024.2313175] [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: 07/31/2023] [Accepted: 01/27/2024] [Indexed: 03/02/2024] Open
Abstract
Vascular calcification (VC) is highly prevalent in patients undergoing hemodialysis, and is a significant contributor to the mortality rate. Therefore, biomarkers that can accurately predict the onset of VC are urgently required. Our study aimed to investigate serum miR-15a levels in relation to VC and to develop a predictive model for VC in patients undergoing hemodialysis at the Beijing Friendship Hospital hemodialysis center between 1 January 2019 and 31 December 2020. The patients were categorized into two groups: VC and non-VC. Logistic regression (LR) models were used to examine the risk factors associated with VC. Additionally, we developed an miR-15a-based nomogram based on the results of the multivariate LR analysis. A total of 138 patients under hemodialysis were investigated (age: 58.41 ± 13.22 years; 54 males). VC occurred in 79 (57.2%) patients. Multivariate LR analysis indicated that serum miR-15a, age, and WBC count were independent risk factors for VC. A miR-15a-based nomogram was developed by incorporating the following five predictors: age, dialysis vintage, predialysis nitrogen, WBC count, and miR-15a. The receiver operating characteristic (ROC) curve had an area under the curve of 0.921, diagnostic threshold of 0.396, sensitivity of 0.722, and specificity of 0.932, indicating that this model had good discrimination. This study concluded that serum miR-15a levels, age, and white blood cell (WBC) count are independent risk factors for VC. A nomogram constructed by integrating these risk factors can be used to predict the risk of VC in patients undergoing hemodialysis.
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Affiliation(s)
- Chen Fu
- Department of Nephrology, Faculty of Kidney Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Yingjie Liu
- Department of Nephrology, Faculty of Kidney Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Huayu Yang
- Division of Geriatrics, Medical and Health Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Qiaojing Liang
- Division of Geriatrics, Medical and Health Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Wenhu Liu
- Department of Nephrology, Faculty of Kidney Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Weikang Guo
- Department of Nephrology, Faculty of Kidney Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
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Cheng F, Li N, Yang J, Yang J, Yang W, Ran J, Sun P, Liao Y. The effect of resistance training on patients with secondary sarcopenia: a systematic review and meta-analysis. Sci Rep 2024; 14:28784. [PMID: 39567607 PMCID: PMC11579013 DOI: 10.1038/s41598-024-79958-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: 08/04/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024] Open
Abstract
To analyse the effectiveness of resistance training on secondary sarcopenia, we conducted a meta-analysis to elucidate the effects of resistance training (RT) on muscle strength (handgrip strength [HGS]), muscle mass (Skeletal muscle mass index [SMI]), and physical function (Gait speed [GS]) in patients with secondary sarcopenia. All studies published between 2015 and January 2024 on the effects of resistance training on patients with secondary sarcopenia were retrieved from 6 electronic databases: PubMed, Web of Science Core Collection, Embase, the Cochrane Library, the China National Knowledge Infrastructure (CNKI) Core journals and the Wanfang Database. Two researchers independently extracted and evaluated studies that met the inclusion and exclusion criteria. Finally, 12 randomized controlled trials were included. Pooled analyses of baseline data and results were performed using Review Manager 5.3 with standardized mean variance (SMD) and random effects model. The study included 12 randomized controlled trials involving 639 patients (mean age 57.28 ± 2.66 to 79.6 ± 5.4 years). There are five types of complications among the patients: obesity, type 2 diabetes, Alzheimer's disease, hemodiaysis, and pancreatic cancer. Compared with the control group, RT effectively improved HGS [SMD = 2.47, 95% CI (1.50, 3.43), p < 0.01, I2 = 94%]; SMI [SMD = 0.94, 95% CI (0.52, 1.36), p < 0.01, I2 = 56%]; and GS [SMD = 2.18, 95% CI (-0.01, 4.37), p ≥ 0.05, I2 = 97%]. Further subgroup analysis of the results showed that the intervention effect on grip strength was greater for non-elastic band resistance [SMD = 2.40, 95% CI (1.05, 3.75), p < 0.01, I2 = 94%] than for elastic band resistance (EBRT) [SMD = 1.22, 95% CI (-0.14, 2.58), p < 0.01, I2 = 95%]. The intervention effect of RT on grip strength is more significant in patients with T2D [SMD = 0.59, 95%CI (0.26-0.93, p < 0.01, I2 = 27%] and obesity [SMD = 0.74, 95%CI (0.32-1.15, p < 0.01, I2 = 0%]. For patients with secondary sarcopenia, Resistance training (RT) can effectively enhance muscle strength and muscle mass; however, it does not significantly improve physical function. Different RT intervention methods have different effects on patients, such as elastic band training and non-elastic band training (bounce ball RT; equipment RT, etc.). Different types of complications may influence the effectiveness of RT intervention.
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Affiliation(s)
- Fang Cheng
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
- 3Institute of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
| | - Na Li
- Clinical Research Center for Geriatrics Diseases, West China Hospital, Sichuan University, Chengdu, 610065, China
| | - Jinfeng Yang
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
- 3Institute of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
| | - Jinqi Yang
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
| | - Weicheng Yang
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
| | - Jianxin Ran
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
| | - Peijie Sun
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China
| | - Yuanpeng Liao
- Department of Sports Medicine and Health, Chengdu Sport University, Chengdu, 610041, China.
- 4Affiliated Hospital of Chengdu Sport University, Chengdu Sport University, Chengdu, 610041, China.
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Yu Y, Cai Y, Yang F, Yang Y, Cui Z, Shi D, Bai R. Vascular smooth muscle cell phenotypic switching in atherosclerosis. Heliyon 2024; 10:e37727. [PMID: 39309965 PMCID: PMC11416558 DOI: 10.1016/j.heliyon.2024.e37727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/25/2024] [Accepted: 09/09/2024] [Indexed: 09/25/2024] Open
Abstract
Atherosclerosis (AS) is a complex pathology process involving intricate interactions among various cells and biological processes. Vascular smooth muscle cells (VSMCs) are the predominant cell type in normal arteries, and under atherosclerotic stimuli, VSMCs respond to altered blood flow and microenvironment changes by downregulating contractile markers and switching their phenotype. This review overviews the diverse phenotypes of VSMCs, including the canonical contractile VSMCs, synthetic VSMCs, and phenotypes resembling macrophages, foam cells, myofibroblasts, osteoblasts/chondrocytes, and mesenchymal stem cells. We summarize their presumed protective and pro-atherosclerotic roles in AS development. Additionally, we underscore the molecular mechanisms and regulatory pathways governing VSMC phenotypic switching, encompassing transcriptional regulation, biochemical factors, plaque microenvironment, epigenetics, miRNAs, and the cytoskeleton, emphasizing their significance in AS development. Finally, we outline probable future research directions targeting VSMCs, offering insights into potential therapeutic strategies for AS management.
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Affiliation(s)
- Yanqiao Yu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yajie Cai
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
| | - Furong Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
| | - Yankai Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Zhuorui Cui
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Dazhuo Shi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
| | - Ruina Bai
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
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Zhong L, Sun Y, Wang C, Liu R, Ru W, Dai W, Xiong T, Zhong A, Li S. SP1 regulates BMSC osteogenic differentiation through the miR-133a-3p/MAPK3 axis : SP1 regulates osteogenic differentiation of BMSCs. J Orthop Surg Res 2024; 19:396. [PMID: 38982418 PMCID: PMC11232211 DOI: 10.1186/s13018-024-04889-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 06/29/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND The progression of osteoporosis (OP) can dramatically increase the risk of fractures, which seriously disturb the life of elderly individuals. Specific protein 1 (SP1) is involved in OP progression. However, the mechanism by which SP1 regulates OP progression remains unclear. OBJECTIVE This study investigated the mechanism underlying the function of SP1 in OP. METHODS SAMP6 mice were used to establish an in vivo model of age-dependent OP, and BALB/c mice were used as controls. BMSCs were extracted from two subtypes of mice. Hematoxylin and eosin staining were performed to mark the intramedullary trabecular bone structure to evaluate histological changes. ChIP assay was used to assess the targeted regulation between SP1 and miR-133a-3p. The binding sites between MAPK3 and miR-133a-3p were verified using a dual-luciferase reporter assay. The mRNA levels of miR-133a-3p and MAPK3 were detected using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The protein expression of SP1, MAPK3, Colla1, OCN, and Runx2 was examined using Western blotting. Alkaline phosphatase (ALP) kit and Alizarin Red S staining were used to investigate ALP activity and mineralized nodules, respectively. RESULTS The levels of SP1 and miR-133a-3p were upregulated, whereas the expression of MAPK3 was downregulated in BMSCs from SAMP6 mice, and miR-133a-3p inhibitor accelerated osteogenic differentiation in BMSCs. SP1 directly targeted miR-133a-3p, and MAPK3 was the downstream mRNA of miR-133a-3p. Mechanically, SP1 accelerated osteogenic differentiation in BMSCs via transcriptional mediation of the miR-133a-3p/MAPK3 axis. CONCLUSION SP1 regulates osteogenic differentiation by mediating the miR-133a-3p/MAPK3 axis, which would shed new light on strategies for treating senile OP.
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Affiliation(s)
- Liying Zhong
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Yehai Sun
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Cong Wang
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Runzhi Liu
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Wenjuan Ru
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Wei Dai
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Ting Xiong
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Aimin Zhong
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China
| | - Shundong Li
- Department of Geriatrics, The Third Hospital of Changsha, No. 176 Laodongxi Road, Tianxin District, Changsha, Hunan Province, 410015, China.
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Xu C, Xu Z, Li G, Li J, Ye L, Ning Y, Du Y. CircFgfr2 promotes osteogenic differentiation of rat dental follicle cells by targeting the miR-133a-3p/DLX3 signaling pathway. Heliyon 2024; 10:e32498. [PMID: 38912473 PMCID: PMC11193016 DOI: 10.1016/j.heliyon.2024.e32498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 06/25/2024] Open
Abstract
Dental follicle cells (DFCs) promote bone regeneration in vivo and in vitro. Circular RNAs (circRNAs) play crucial roles in bone development and regeneration. Our previous study demonstrated the upregulation of circFgfr2 expression during the osteogenic differentiation of DFCs. However, the molecular mechanisms and functional roles of circFgfr2 in DFCs osteogenesis remain unclear. In this study, we aimed to investigate the subcellular localization of circFgfr2 in DFCs using fluorescence in situ hybridization. In vitro investigations demonstrated that circFgfr2 overexpression promoted osteogenic differentiation, as evidenced by real-time quantitative polymerase chain reaction. By integrating the outcomes of bioinformatics analyses, dual luciferase reporter experiments, and chromatin isolation by RNA purification, we identified circFgfr2 as a sponge for miR-133a-3p, a key regulator of osteogenic differentiation. Moreover, miR-133a-3p suppressed osteogenic differentiation by targeting DLX3 and RUNX2 in DFCs. We validated that circFgfr2 promoted the osteogenic differentiation of DFCs through the miR-133a-3p/DLX3 axis. To further investigate the therapeutic potential of circFgfr2 in bone regeneration, we conducted in vivo experiments and histological analyses. Overall, these results confirmed the crucial role of circFgfr2 in promoting osteogenesis. In summary, our findings demonstrated that the circFgfr2/miR-133a-3p/DLX3 pathway acts as a cascade, thereby identifying circFgfr2 as a promising molecular target for bone tissue engineering.
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Affiliation(s)
- Cheng Xu
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‐sen University, Guangzhou, Guangdong, China
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Reasearch Institute of Stomatology, Nanjing University,Nanjing, Jiangsu, China
| | - Zhiqing Xu
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‐sen University, Guangzhou, Guangdong, China
| | - Guixian Li
- Operative Dentistry and Endodontics, Jiangmen Municipal Stomatological Hospital, Jiangmen, Guangdong, China
| | - Jing Li
- Department of Stomatology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Li Ye
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‐sen University, Guangzhou, Guangdong, China
| | - Yang Ning
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‐sen University, Guangzhou, Guangdong, China
| | - Yu Du
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‐sen University, Guangzhou, Guangdong, China
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Letonja J, Petrovič D. A Review of MicroRNAs and lncRNAs in Atherosclerosis as Well as Some Major Inflammatory Conditions Affecting Atherosclerosis. Biomedicines 2024; 12:1322. [PMID: 38927529 PMCID: PMC11201627 DOI: 10.3390/biomedicines12061322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/05/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
It is generally accepted that atherosclerosis is a chronic inflammatory disease. The link between atherosclerosis and other inflammatory diseases such as psoriasis, type 2 diabetes mellitus (T2DM), and rheumatoid arthritis (RA) via metabolic, inflammatory, and immunoregulatory pathways is well established. The aim of our review was to summarize the associations between selected microRNAs (miRs) and long non-coding RNAs (lncRNAs) and atherosclerosis, psoriasis, T2DM, and RA. We reviewed the role of miR-146a, miR-210, miR-143, miR-223, miR-126, miR-21, miR-155, miR-145, miR-200, miR-133, miR-135, miR-221, miR-424, let-7, lncRNA-H19, lncRNA-MEG3, lncRNA-UCA1, and lncRNA-XIST in atherosclerosis and psoriasis, T2DM, and RA. Extracellular vesicles (EVs) are a method of intracellular signal transduction. Their function depends on surface expression, cargo, and the cell from which they originate. The majority of the studies that investigated lncRNAs and some miRs had relatively small sample sizes, which limits the generalizability of their findings and indicates the need for more research. Based on the studies reviewed, miR-146a, miR-155, miR-145, miR-200, miR-133, and lncRNA-H19 are the most promising potential biomarkers and, possibly, therapeutic targets for atherosclerosis as well as T2DM, RA, and psoriasis.
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Affiliation(s)
- Jernej Letonja
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia;
- Laboratory for Histology and Genetics of Atherosclerosis and Microvascular Diseases, Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
| | - Danijel Petrovič
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia;
- Laboratory for Histology and Genetics of Atherosclerosis and Microvascular Diseases, Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
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He J, Wang Y, Zhan J, Li S, Ni Y, Huang W, Long L, Tan P, Wang Y, Liu Y. Icariin attenuates the calcification of vascular smooth muscle cells through ERα - p38MAPK pathway. Aging Med (Milton) 2023; 6:379-385. [PMID: 38239714 PMCID: PMC10792338 DOI: 10.1002/agm2.12267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 08/09/2023] [Accepted: 08/14/2023] [Indexed: 01/22/2024] Open
Abstract
Objective To investigate the relationship between icariin and the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) and the signal pathway involved. Methods We applied a universally accepted calcification model of VSMCs induced by β glycerophosphate. Then the VSMCs calcification was observed by treatment with icariin and/or inhibitors of estrogen receptors (ERs) and p38-mitogen-activated protein kinase (MAPK) signaling. Results Icariin inhibited osteoblastic differentiation and mineralization of VSMCs due to decreased ALP activity and Runx2 expression. Further study demonstrated that icariin exerted this suppression effect through activating p38-MAPK but not extracellular-regulated kinase, JNK or Akt. An inhibitor of p38-MAPK partially reversed the inhibitory effects of icariin on osteoblastic differentiation. Interestingly, treatment of VSMCs with an ER antagonist ICI182780 and a selective ERα receptor antagonist PPT attenuated icariin-mediated inhibition effect of VSMCs calcification, associated with suppression of p38-MAPK phosphorylation. Conclusions Icariin inhibited the osteoblastic differentiation of VSMCs, and that the inhibitory effects were mediated by p38-MAPK pathways through ERα.
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Affiliation(s)
- Jieyu He
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Yanjiao Wang
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Junkun Zhan
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Shuang Li
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Yuqing Ni
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Wu Huang
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Limin Long
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Pan Tan
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Yi Wang
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Youshuo Liu
- Department of Geriatrics, The Second Xiangya HospitalCentral South UniversityChangshaChina
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Michalak-Stoma A, Walczak K, Adamczyk M, Kowal M, Krasowska D. Selected miRNA and Psoriasis-Cardiovascular Disease (CVD)-Overweight/Obesity Network-A Pilot Study. Int J Mol Sci 2023; 24:13916. [PMID: 37762217 PMCID: PMC10530775 DOI: 10.3390/ijms241813916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Psoriasis is nowadays recognized as a multifactorial systemic disease with complex and not fully understood pathogenesis. In psoriatic patients, the increased cardiovascular disease (CVD) risk and frequent comorbidities like obesity are observed. The aim of this study was to investigate differences in miRNA (miR-22-3p, miR-133a-3p, miR-146a-5p, miR-369-3p, and Let-7b-5p) involved in CVD risk among psoriatic patients with overweight/obesity and with normal weight. The study comprised 28 male psoriatic patients and 16 male healthy controls. miRNA isolated from peripheral blood mononuclear cells was reverse-transcribed and RT-qPCR was performed. We have found decreased levels of miR-22, miR-133a, miR-146a, and miR-369 among the psoriatic patients. There was a statistically significant difference in miR-22 and miR-146a levels between psoriatic patients with overweight/obesity and with normal weight. There were positive correlations between miR-22 and miR-146a levels and psoriatic arthritis (PsA) in psoriatic patients with normal weight and between the miR-133a level and PsA in the overweight/obese patients. The decreased levels of selected miRNA are consistent with the levels observed in CVD indicating their impact on the CVD risk in psoriatic patients. miR-22 and miR-146 may be recognized as one of the contributing factors in the obesity-CVD-psoriasis network.
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Affiliation(s)
- Anna Michalak-Stoma
- Chair and Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, ul. Staszica 16, 20-081 Lublin, Poland; (K.W.); (M.A.); (M.K.); (D.K.)
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Paneru BD, Hill DA. The role of extracellular vesicle-derived miRNAs in adipose tissue function and metabolic health. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00027. [PMID: 37501663 PMCID: PMC10371064 DOI: 10.1097/in9.0000000000000027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/23/2023] [Indexed: 07/29/2023]
Abstract
Extracellular vesicles (EVs) are nanometer size lipid particles that are released from virtually every cell type. Recent studies have shown that miRNAs carried by EVs play important roles in intercellular and interorgan communication. In the context of obesity and insulin resistance, EV-derived miRNAs functionally bridge major metabolic organs, including the adipose tissue, skeletal muscle, liver, and pancreas, to regulate insulin secretion and signaling. As a result, many of these EV-derived miRNAs have been proposed as potential disease biomarkers and/or therapeutic agents. However, the field's knowledge of EV miRNA-mediated regulation of mammalian metabolism is still in its infancy. Here, we review the evidence indicating that EV-derived miRNAs provide cell-to-cell and organ-to-organ communication to support metabolic health, highlight the potential medical relevance of these discoveries, and discuss the most important knowledge gaps and future directions for this field.
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Affiliation(s)
- Bam D. Paneru
- Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - David A. Hill
- Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Institute for Immunology, and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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11
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Ding N, Lv Y, Su H, Wang Z, Kong X, Zhen J, Lv Z, Wang R. Vascular calcification in CKD: New insights into its mechanisms. J Cell Physiol 2023; 238:1160-1182. [PMID: 37269534 DOI: 10.1002/jcp.31021] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/28/2023] [Indexed: 06/05/2023]
Abstract
Vascular calcification (VC) is a common complication of chronic kidney disease (CKD) and contributes to an increased risk of cardiovascular morbidity and mortality. However, effective therapies are still unavailable at present. It has been well established that VC associated with CKD is not a passive process of calcium phosphate deposition, but an actively regulated and cell-mediated process that shares many similarities with bone formation. Additionally, numerous studies have suggested that CKD patients have specific risk factors and contributors to the development of VC, such as hyperphosphatemia, uremic toxins, oxidative stress and inflammation. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in CKD-related VC, many questions remain unanswered. Moreover, studies from the past decade have demonstrated that epigenetic modifications abnormalities, such as DNA methylation, histone modifications and noncoding RNAs, play an important role in the regulation of VC. This review seeks to provide an overview of the pathophysiological and molecular mechanisms of VC associated with CKD, mainly focusing on the involvement of epigenetic modifications in the initiation and progression of uremic VC, with the aim to develop promising therapies for CKD-related cardiovascular events in the future.
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Affiliation(s)
- Nannan Ding
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yaodong Lv
- Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Hong Su
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ziyang Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xianglei Kong
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Junhui Zhen
- Department of Pathology, Shandong University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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12
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Wang G, Luo Y, Gao X, Liang Y, Yang F, Wu J, Fang D, Luo M. MicroRNA regulation of phenotypic transformations in vascular smooth muscle: relevance to vascular remodeling. Cell Mol Life Sci 2023; 80:144. [PMID: 37165163 PMCID: PMC11071847 DOI: 10.1007/s00018-023-04793-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/10/2023] [Accepted: 04/27/2023] [Indexed: 05/12/2023]
Abstract
Alterations in the vascular smooth muscle cells (VSMC) phenotype play a critical role in the pathogenesis of several cardiovascular diseases, including hypertension, atherosclerosis, and restenosis after angioplasty. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs (approximately 19-25 nucleotides in length) that function as regulators in various physiological and pathophysiological events. Recent studies have suggested that aberrant miRNAs' expression might underlie VSMC phenotypic transformation, appearing to regulate the phenotypic transformations of VSMCs by targeting specific genes that either participate in the maintenance of the contractile phenotype or contribute to the transformation to alternate phenotypes, and affecting atherosclerosis, hypertension, and coronary artery disease by altering VSMC proliferation, migration, differentiation, inflammation, calcification, oxidative stress, and apoptosis, suggesting an important regulatory role in vascular remodeling for maintaining vascular homeostasis. This review outlines recent progress in the discovery of miRNAs and elucidation of their mechanisms of action and functions in VSMC phenotypic regulation. Importantly, as the literature supports roles for miRNAs in modulating vascular remodeling and for maintaining vascular homeostasis, this area of research will likely provide new insights into clinical diagnosis and prognosis and ultimately facilitate the identification of novel therapeutic targets.
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Affiliation(s)
- Gang Wang
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Longmatan District, No. 1, Section 1, Xianglin Road, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Yulin Luo
- GCP Center, Affiliated Hospital (Traditional Chinese Medicine) of Southwest Medical University, Luzhou, China
| | - Xiaojun Gao
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Longmatan District, No. 1, Section 1, Xianglin Road, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Yu Liang
- Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Feifei Yang
- School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Jianbo Wu
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Longmatan District, No. 1, Section 1, Xianglin Road, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Dan Fang
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Longmatan District, No. 1, Section 1, Xianglin Road, Luzhou, Sichuan, China.
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
| | - Mao Luo
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Longmatan District, No. 1, Section 1, Xianglin Road, Luzhou, Sichuan, China.
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
- Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, Luzhou, Sichuan, China.
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13
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Peniche Silva CJ, De La Vega RE, Panos J, Joris V, Evans CH, Balmayor ER, van Griensven M. MiRNAs as Potential Regulators of Enthesis Healing: Findings in a Rodent Injury Model. Int J Mol Sci 2023; 24:8556. [PMID: 37239902 PMCID: PMC10218430 DOI: 10.3390/ijms24108556] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNA sequences with the ability to inhibit the expression of a target mRNA at the post-transcriptional level, acting as modulators of both the degenerative and regenerative processes. Therefore, these molecules constitute a potential source of novel therapeutic tools. In this study, we investigated the miRNA expression profile that presented in enthesis tissue upon injury. For this, a rodent enthesis injury model was developed by creating a defect at a rat's patellar enthesis. Following injury, explants were collected on days 1 (n = 10) and 10 (n = 10). Contra lateral samples (n = 10) were harvested to be used for normalization. The expression of miRNAs was investigated using a "Fibrosis" pathway-focused miScript qPCR array. Later, target prediction for the aberrantly expressed miRNAs was performed by means of the Ingenuity Pathway Analysis, and the expression of mRNA targets relevant for enthesis healing was confirmed using qPCRs. Additionally, the protein expression levels of collagens I, II, III, and X were investigated using Western blotting. The mRNA expression pattern of EGR1, COL2A1, RUNX2, SMAD1, and SMAD3 in the injured samples indicated their possible regulation by their respective targeting miRNA, which included miR-16, -17, -100, -124, -133a, -155 and -182. Furthermore, the protein levels of collagens I and II were reduced directly after the injury (i.e., day 1) and increased 10 days post-injury, while collagens III and X showed the opposite pattern of expression.
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Affiliation(s)
- Carlos Julio Peniche Silva
- Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands; (C.J.P.S.); (R.E.D.L.V.); (V.J.)
| | - Rodolfo E. De La Vega
- Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands; (C.J.P.S.); (R.E.D.L.V.); (V.J.)
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; (J.P.); (C.H.E.); (E.R.B.)
| | - Joseph Panos
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; (J.P.); (C.H.E.); (E.R.B.)
| | - Virginie Joris
- Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands; (C.J.P.S.); (R.E.D.L.V.); (V.J.)
| | - Christopher H. Evans
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; (J.P.); (C.H.E.); (E.R.B.)
| | - Elizabeth R. Balmayor
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; (J.P.); (C.H.E.); (E.R.B.)
- Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Martijn van Griensven
- Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands; (C.J.P.S.); (R.E.D.L.V.); (V.J.)
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; (J.P.); (C.H.E.); (E.R.B.)
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14
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Singh D, Rai V, Agrawal DK. Non-Coding RNAs in Regulating Plaque Progression and Remodeling of Extracellular Matrix in Atherosclerosis. Int J Mol Sci 2022; 23:13731. [PMID: 36430208 PMCID: PMC9692922 DOI: 10.3390/ijms232213731] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/31/2022] [Accepted: 11/05/2022] [Indexed: 11/09/2022] Open
Abstract
Non-coding RNAs (ncRNAs) regulate cell proliferation, migration, differentiation, inflammation, metabolism of clinically important biomolecules, and other cellular processes. They do not encode proteins but are involved in the regulatory network of various proteins that are directly related to the pathogenesis of diseases. Little is known about the ncRNA-associated mechanisms of atherosclerosis and related cardiovascular disorders. Remodeling of the extracellular matrix (ECM) is critical in the pathogenesis of atherosclerosis and related disorders; however, its regulatory proteins are the potential subjects to explore with special emphasis on epigenetic regulatory components. The activity of regulatory proteins involved in ECM remodeling is regulated by various ncRNA molecules, as evident from recent research. Thus, it is important to critically evaluate the existing literature to enhance the understanding of nc-RNAs-regulated molecular mechanisms regulating ECM components, remodeling, and progression of atherosclerosis. This is crucial since deregulated ECM remodeling contributes to atherosclerosis. Thus, an in-depth understanding of ncRNA-associated ECM remodeling may identify novel targets for the treatment of atherosclerosis and other cardiovascular diseases.
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Affiliation(s)
| | | | - Devendra K. Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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15
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Yao J, Cai L, Chen Y, Zhang J, Zhuang W, Liang J, Li H. Exosomes: mediators regulating the phenotypic transition of vascular smooth muscle cells in atherosclerosis. Cell Commun Signal 2022; 20:153. [PMID: 36221105 PMCID: PMC9555104 DOI: 10.1186/s12964-022-00949-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/31/2022] [Indexed: 11/10/2022] Open
Abstract
Cardiovascular disease is one of the leading causes of human mortality worldwide, mainly due to atherosclerosis (AS), and the phenotypic transition of vascular smooth muscle cells (VSMCs) is a key event in the development of AS. Exosomes contain a variety of specific nucleic acids and proteins that mediate intercellular communication. The role of exosomes in AS has attracted attention. This review uses the VSMC phenotypic transition in AS as the entry point, introduces the effect of exosomes on AS from different perspectives, and discusses the status quo, deficiencies, and potential future directions in this field to provide new ideas for clinical research and treatment of AS. Video Abstract.
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Affiliation(s)
- Jiali Yao
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Linqian Cai
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yingrui Chen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jie Zhang
- Department of Neurology, Afliated Hospital of Yangzhou University, Yangzhou, 225001, China
| | - Wenwen Zhuang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jingyan Liang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China.,Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Hongliang Li
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .,Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
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16
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Shi L, Li Y, Shi M, Li X, Li G, Cen J, Liu D, Wei C, Lin Y. Hsa_circRNA_0008028 Deficiency Ameliorates High Glucose-Induced Proliferation, Calcification, and Autophagy of Vascular Smooth Muscle Cells via miR-182-5p/TRIB3 Axis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5142381. [PMID: 36062192 PMCID: PMC9433223 DOI: 10.1155/2022/5142381] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/17/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022]
Abstract
Background It is well-known that dysfunctions of vascular smooth muscle cells (VSMCs) act an essential part in vascular complications of diabetes. Studies have shown that circular RNAs (circRNAs) and microRNAs (miRNAs) play a crucial role in regulating cell functions. However, their influence on the proliferation, calcification, and autophagy of VSMCs remains to be further explored. Therefore, this study elucidates the role and mechanism of hsa_circRNA_0008028 in high glucose- (HG-, 30 mM) treated VSMCs in vitro. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was chosen to detect the levels of hsa_circRNA_0008028, miR-182-5p, and tribble 3 (TRIB3). Then, dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to predict and verify the binding relationship between miR-182-5p and hsa_circRNA_0008028 or TRIB3. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, corresponding commercial kits, and western blotting were used to measure indexes reflecting cell viability, proliferation, calcification, and autophagy of VSMCs, respectively. Results In HG-induced VSMCs, hsa_circRNA_0008028 and TRIB3 were highly expressed, whereas miR-182-5p decreased. Meanwhile, cell proliferation, calcification, and autophagy could be repressed by silencing of hsa_circRNA_0008028. However, these effects can be eliminated by miR-182-5p inhibition. Furthermore, it was demonstrated that hsa_circRNA_0008028 could promote the expression of TRIB3, a target of miR-182-5p, by directly sponging miR-182-5p. The expression of TRIB3 was suppressed by hsa_circRNA_0008028 knockout, which was rescued by miR-182-5p inhibition. Conclusion This study reveals that hsa_circRNA_0008028 can act as a sponge of miR-182-5p and promote HG-induced proliferation, calcification, and autophagy of VSMCs partly by regulating TRIB3.
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Affiliation(s)
- Lili Shi
- Department of Cadre Ward, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Yuliang Li
- Department of Anesthesiology, The Fifth Hospital of Harbin, Harbin 150081, China
| | - Meixin Shi
- Department of Pathophysiology, Harbin Medical University, Harbin 150086, China
| | - Xiaoxue Li
- Department of Pathophysiology, Harbin Medical University, Harbin 150086, China
| | - Guopeng Li
- Department of Pathophysiology, Harbin Medical University, Harbin 150086, China
| | - Jie Cen
- Department of Pathophysiology, Harbin Medical University, Harbin 150086, China
| | - Dan Liu
- Department of Cadre Ward, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Can Wei
- Department of Pathophysiology, Harbin Medical University, Harbin 150086, China
| | - Yan Lin
- Department of Pathophysiology, Qiqihar Medical University, Qiqihar 161006, China
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Xu F, Zhong JY, Guo B, Lin X, Wu F, Li FXZ, Shan SK, Zheng MH, Wang Y, Xu QS, Lei LM, Tan CM, Liao XB, Yuan LQ. H19 Promotes Osteoblastic Transition by Acting as ceRNA of miR-140-5p in Vascular Smooth Muscle Cells. Front Cell Dev Biol 2022; 10:774363. [PMID: 35198556 PMCID: PMC8859097 DOI: 10.3389/fcell.2022.774363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/07/2022] [Indexed: 11/27/2022] Open
Abstract
Arterial medial calcification is a common disease in patients with type 2 diabetes, end-stage renal disease and hypertension, resulting in high incidence and mortality of cardiovascular event. H19 has been demonstrated to be involved in cardiovascular diseases like aortic valve diseases. However, role of H19 in arterial medial calcification remains largely unknown. We identified that H19 was upregulated in ß-glycerophosphate (β-GP) induced vascular smooth muscle cells (VSMCs), a cellular calcification model in vitro. Overexpression of H19 potentiated while knockdown of H19 inhibited osteogenic differentiation of VSMCs, as demonstrated by changes of osteogenic genes Runx2 and ALP as well as ALP activity. Notably, H19 interacted with miR-140-5p directly, as demonstrated by luciferase report system and RIP analysis. Mechanistically, miR-140-5p attenuated osteoblastic differentiation of VSMCs by targeting Satb2 and overexpression of miR-140-5p blocked H19 induced elevation of Satb2 as well as the promotion of osteoblastic differentiation of VSMCs. Interestingly, over-expression of Satb2 induced phosphorylation of ERK1/2 and p38MAPK. In conclusion, H19 promotes VSMC calcification by acting as competing endogenous RNA of miR-140-5p and at least partially by activating Satb2-induced ERK1/2 and p38MAPK signaling.
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Affiliation(s)
- Feng Xu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jia-Yu Zhong
- Department of Nuclear Medicine, Xiangya Hospital of Central South University, Changsha, China
| | - Bei Guo
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Feng Wu
- Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fu-Xing-Zi Li
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Su-Kang Shan
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ming-Hui Zheng
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yi Wang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qiu-Shuang Xu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Li-Min Lei
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chang-Ming Tan
- Department of Cardiothoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiao-Bo Liao
- Department of Cardiothoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan, ; Xiao-Bo Liao,
| | - Ling-Qing Yuan
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan, ; Xiao-Bo Liao,
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18
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Chum PP, Hakim MA, Behringer EJ. Cerebrovascular microRNA Expression Profile During Early Development of Alzheimer's Disease in a Mouse Model. J Alzheimers Dis 2021; 85:91-113. [PMID: 34776451 DOI: 10.3233/jad-215223] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Emerging evidence demonstrates association of Alzheimer's disease (AD) with impaired delivery of blood oxygen and nutrients to and throughout the brain. The cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition entailing moment-to-moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment to prevent or delay the progression of AD, cerebrovascular microRNA (miRNA) markers corresponding to post-transcriptional regulation may distinguish phases of AD. OBJECTIVE We tested the hypothesis that cerebrovascular miRNA expression profiles indicate developmental stages of AD pathology. METHODS Total RNA was isolated from total brain vessel segments of male and female 3xTg-AD mice [young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques+neurofibrillary tangles (AβT), 12-15 mo]. NanoString technology nCounter miRNA Expression panel for mouse was used to screen for 599 miRNAs. RESULTS Significant (p < 0.05) downregulation of various miRNAs indicated transitions from young to CI (e.g., let-7g & miR-1944, males; miR-133a & miR-2140, females) and CI to Aβ (e.g., miR-99a, males) but not from Aβ to AβT. In addition, altered expression of select miRNAs from overall Pre-AD (young + CI) versus AD (Aβ+ AβT) were detected in both males (let-7d, let-7i, miR-23a, miR-34b-3p, miR-99a, miR-126-3p, miR-132, miR-150, miR-151-5p, miR-181a) and females (miR-150, miR-539). Altogether, at least 20 cerebrovascular miRNAs effectively delineate AD versus Pre-AD pathology. CONCLUSION Using the 3xTg-AD mouse model, these data demonstrate that cerebrovascular miRNAs pertaining to endothelial function, vascular permeability, angiogenesis, inflammation, and Aβ/tau metabolism can track early development of AD.
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Affiliation(s)
- Phoebe P Chum
- Basic Sciences, Loma Linda University, Loma Linda, CA, USA
| | - Md A Hakim
- Basic Sciences, Loma Linda University, Loma Linda, CA, USA
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19
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Nappi F, Iervolino A, Avtaar Singh SS, Chello M. MicroRNAs in Valvular Heart Diseases: Biological Regulators, Prognostic Markers and Therapeutical Targets. Int J Mol Sci 2021; 22:12132. [PMID: 34830016 PMCID: PMC8618095 DOI: 10.3390/ijms222212132] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022] Open
Abstract
miRNAs have recently attracted investigators' interest as regulators of valvular diseases pathogenesis, diagnostic biomarkers, and therapeutical targets. Evidence from in-vivo and in-vitro studies demonstrated stimulatory or inhibitory roles in mitral valve prolapse development, aortic leaflet fusion, and calcification pathways, specifically osteoblastic differentiation and transcription factors modulation. Tissue expression assessment and comparison between physiological and pathological phenotypes of different disease entities, including mitral valve prolapse and mitral chordae tendineae rupture, emerged as the best strategies to address miRNAs over or under-representation and thus, their impact on pathogeneses. In this review, we discuss the fundamental intra- and intercellular signals regulated by miRNAs leading to defects in mitral and aortic valves, congenital heart diseases, and the possible therapeutic strategies targeting them. These miRNAs inhibitors are comprised of antisense oligonucleotides and sponge vectors. The miRNA mimics, miRNA expression vectors, and small molecules are instead possible practical strategies to increase specific miRNA activity. Advantages and technical limitations of these new drugs, including instability and complex pharmacokinetics, are also presented. Novel delivery strategies, such as nanoparticles and liposomes, are described to improve knowledge on future personalized treatment directions.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord de Saint-Denis, 93200 Paris, France
| | - Adelaide Iervolino
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy;
| | | | - Massimo Chello
- Cardiovascular Surgery, University Campus Bio-Medico di Roma, 00128 Rome, Italy;
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Díez-Ricote L, Ruiz-Valderrey P, Micó V, Blanco-Rojo R, Tomé-Carneiro J, Dávalos A, Ordovás JM, Daimiel L. Trimethylamine n-Oxide (TMAO) Modulates the Expression of Cardiovascular Disease-Related microRNAs and Their Targets. Int J Mol Sci 2021; 22:ijms222011145. [PMID: 34681805 PMCID: PMC8539082 DOI: 10.3390/ijms222011145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 12/20/2022] Open
Abstract
Diet is a well-known risk factor of cardiovascular diseases (CVDs). Some microRNAs (miRNAs) have been described to regulate molecular pathways related to CVDs. Diet can modulate miRNAs and their target genes. Choline, betaine, and l-carnitine, nutrients found in animal products, are metabolized into trimethylamine n-oxide (TMAO), which has been associated with CVD risk. The aim of this study was to investigate TMAO regulation of CVD-related miRNAs and their target genes in cellular models of liver and macrophages. We treated HEPG-2, THP-1, mouse liver organoids, and primary human macrophages with 6 µM TMAO at different timepoints (4, 8, and 24 h for HEPG-2 and mouse liver organoids, 12 and 24 h for THP-1, and 12 h for primary human macrophages) and analyzed the expression of a selected panel of CVD-related miRNAs and their target genes and proteins by real-time PCR and Western blot, respectively. HEPG-2 cells were transfected with anti-miR-30c and syn-miR-30c. TMAO increased the expression of miR-21-5p and miR-30c-5p. PER2, a target gene of both, decreased its expression with TMAO in HEPG-2 and mice liver organoids but increased its mRNA expression with syn-miR-30c. We concluded that TMAO modulates the expression of miRNAs related to CVDs, and that such modulation affects their target genes.
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Affiliation(s)
- Laura Díez-Ricote
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain; (L.D.-R.); (P.R.-V.); (V.M.); (R.B.-R.); (J.M.O.)
| | - Paloma Ruiz-Valderrey
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain; (L.D.-R.); (P.R.-V.); (V.M.); (R.B.-R.); (J.M.O.)
| | - Víctor Micó
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain; (L.D.-R.); (P.R.-V.); (V.M.); (R.B.-R.); (J.M.O.)
| | - Ruth Blanco-Rojo
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain; (L.D.-R.); (P.R.-V.); (V.M.); (R.B.-R.); (J.M.O.)
- Research and Development Department, Biosearch Life, 18004 Granada, Spain
| | - João Tomé-Carneiro
- Bioactive Food Ingredients Group, Precision Nutrition and Cardiometabolic Health Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain;
| | - Alberto Dávalos
- Epigenetics of Lipid Metabolism Group, Precision Nutrition and Cardiometabolic Health Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain;
| | - José M. Ordovás
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain; (L.D.-R.); (P.R.-V.); (V.M.); (R.B.-R.); (J.M.O.)
- Nutrition and Genomics Laboratory, JM_USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
| | - Lidia Daimiel
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain; (L.D.-R.); (P.R.-V.); (V.M.); (R.B.-R.); (J.M.O.)
- Correspondence: ; Tel.: +34-(91)-7278100 (ext. 309)
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21
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Banitalebi E, Ghahfarrokhi MM, Dehghan M. Effect of 12-weeks elastic band resistance training on MyomiRs and osteoporosis markers in elderly women with Osteosarcopenic obesity: a randomized controlled trial. BMC Geriatr 2021; 21:433. [PMID: 34284726 PMCID: PMC8290586 DOI: 10.1186/s12877-021-02374-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/02/2021] [Indexed: 12/21/2022] Open
Abstract
Background Interorgan communication networks established during exercise in several different tissues can be mediated by several exercise-induced factors. Therefore, the present study aimed to investigate the effects of resistance-type training using elastic band-induced changes of myomiRs (i.e., miR-206 and miR-133), vitamin D, CTX-I, ALP, and FRAX® score in elderly women with osteosarcopenic obesity (OSO). Methods In this randomized controlled trial, 63 women (aged 65–80 years) with Osteosarcopenic Obesity were recruited and assessed, using a dual-energy X-ray absorptiometry instrument. The resistance-type training via elastic bands was further designed three times per week for 12-weeks. The main outcomes were Fracture Risk Assessment Tool score, bone mineral content, bone mineral density, vitamin D, alkaline phosphatase, C-terminal telopeptides of type I collagen, expression of miR-206 and miR-133. Results There was no significant difference between the study groups in terms of the Fracture Risk Assessment Tool score (p = 0.067), vitamin D (p = 0.566), alkaline phosphatase (p = 0.334), C-terminal telopeptides of type I collagen (p = 0.067), microR-133 (p = 0.093) and miR-206 (p = 0.723). Conclusion Overall, the results of this study illustrated 12-weeks of elastic band resistance training causes a slight and insignificant improvement in osteoporosis markers in women affected with Osteosarcopenic Obesity. Trial registration Randomized controlled trial (RCT) (Iranian Registry of Clinical Trials, trial registration number: IRCT20180627040260N1. Date of registration: 27/11/2018. Supplementary Information The online version contains supplementary material available at 10.1186/s12877-021-02374-9.
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Affiliation(s)
| | | | - Mortaza Dehghan
- Clinical Research Development Unit, Kashani Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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22
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Laird NZ, Acri TM, Tingle K, Salem AK. Gene- and RNAi-activated scaffolds for bone tissue engineering: Current progress and future directions. Adv Drug Deliv Rev 2021; 174:613-627. [PMID: 34015421 PMCID: PMC8217358 DOI: 10.1016/j.addr.2021.05.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/30/2021] [Accepted: 05/11/2021] [Indexed: 01/02/2023]
Abstract
Large bone defects are usually managed by replacing lost bone with non-biological prostheses or with bone grafts that come from the patient or a donor. Bone tissue engineering, as a field, offers the potential to regenerate bone within these large defects without the need for grafts or prosthetics. Such therapies could provide improved long- and short-term outcomes in patients with critical-sized bone defects. Bone tissue engineering has long relied on the administration of growth factors in protein form to stimulate bone regeneration, though clinical applications have shown that using such proteins as therapeutics can lead to concerning off-target effects due to the large amounts required for prolonged therapeutic action. Gene-based therapies offer an alternative to protein-based therapeutics where the genetic material encoding the desired protein is used and thus loading large doses of protein into the scaffolds is avoided. Gene- and RNAi-activated scaffolds are tissue engineering devices loaded with nucleic acids aimed at promoting local tissue repair. A variety of different approaches to formulating gene- and RNAi-activated scaffolds for bone tissue engineering have been explored, and include the activation of scaffolds with plasmid DNA, viruses, RNA transcripts, or interfering RNAs. This review will discuss recent progress in the field of bone tissue engineering, with specific focus on the different approaches employed by researchers to implement gene-activated scaffolds as a means of facilitating bone tissue repair.
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Affiliation(s)
- Noah Z Laird
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Timothy M Acri
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Kelsie Tingle
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Aliasger K Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
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23
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Li S, Zhi F, Hu M, Xue X, Mo Y. MiR-133a is a potential target for arterial calcification in patients with end-stage renal disease. Int Urol Nephrol 2021; 54:217-224. [PMID: 34115259 DOI: 10.1007/s11255-021-02906-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 05/30/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Arterial calcification is an important risk factor for patients with end-stage renal disease. Despite substantial research efforts, the detailed mechanisms of the process of arterial calcification in end-stage renal disease remain unclear. METHODS miR-133a expression in radial artery samples was detected by FISH and Alizarin Red Staining. The expressions of miR-133a and RUNX2 in A7r5 cells with BMP2 induction were detected by qRT-PCR. In addition, qRT-PCR, Western blot, and ELISA assay were performed to detect changes in miR-133a levels in A7R5 cells after different treatments. RESULTS Alizarin Red staining showed that red crystal deposition occurred in the tunica media. FISH analysis indicated that miR-133a was upregulated in the tunica media of the radial artery samples without calcification when compared with those with calcification. We also found that expression of RUNX2 in A7r5 cells increased at day 7 and day 14 after BMP2 induction and decreased miR-133a expression decreased at day 14. In addition, RUNX2 protein and OCN expression were upregulated in A7r5 cells during BMP2-induced calcification. When miR-133a expression was suppressed, cell calcification aggravated, which led to upregulation of RUNX2 and OCN. When miR-133a was overexpressed, calcification of cells was inhibited, resulting in downregulation of RUNX2 and OCN. CONCLUSION The present study reveals that miR-133a could indirectly regulate cell calcification through the RUNX2 gene expression. Our findings provide insight into the potential use of miR-133a as a molecular target for diagnosing vascular calcification in end-stage renal disease.
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Affiliation(s)
- Sha Li
- Nephrology Department, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital), Jinglongjianshe Road, Longhua District, Shenzhen, 518109, China
| | - Fan Zhi
- Urology Department, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital), Shenzhen, 518109, China
| | - Mingliang Hu
- Nephrology Department, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital), Jinglongjianshe Road, Longhua District, Shenzhen, 518109, China.
| | - Xingkui Xue
- Central Laboratory, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital), Shenzhen, 518109, China
| | - Yihao Mo
- Nephrology Department, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital), Jinglongjianshe Road, Longhua District, Shenzhen, 518109, China
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24
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Sileno S, Beji S, D'Agostino M, Carassiti A, Melillo G, Magenta A. microRNAs involved in psoriasis and cardiovascular diseases. VASCULAR BIOLOGY 2021; 3:R49-R68. [PMID: 34291190 PMCID: PMC8284950 DOI: 10.1530/vb-21-0007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022]
Abstract
Psoriasis is a chronic inflammatory disease involving the skin. Both genetic and environmental factors play a pathogenic role in psoriasis and contribute to the severity of the disease. Psoriasis, in fact, has been associated with different comorbidities such as diabetes, metabolic syndrome, gastrointestinal or kidney diseases, cardiovascular disease (CVD), and cerebrovascular diseases (CeVD). Indeed, life expectancy in severe psoriasis is reduced by up to 5 years due to CVD and CeVD. Moreover, patients with severe psoriasis have a higher prevalence of traditional cardiovascular (CV) risk factors, including dyslipidemia, diabetes, smoking, and hypertension. Further, systemic inflammation is associated with oxidative stress increase and induces endothelial damage and atherosclerosis progression. Different miRNA have been already described in psoriasis, both in the skin tissues and in the blood flow, to play a role in the progression of disease. In this review, we will summarize and discuss the most important miRNAs that play a role in psoriasis and are also linked to CVD.
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Affiliation(s)
- Sara Sileno
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Sara Beji
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Marco D'Agostino
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Alessandra Carassiti
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Guido Melillo
- Unit of Cardiology, IDI-IRCCS, Via Monti di Creta, Rome, Italy
| | - Alessandra Magenta
- Institute of Translational Pharmacology (IFT), National Research Council of Italy (CNR), Via Fosso del Cavaliere, Rome, Italy
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Zhou Y, Chen X, Zhu Z, Bi D, Ma S. MiR-133a delivery to osteoblasts ameliorates mechanical unloading-triggered osteopenia progression in vitro and in vivo. Int Immunopharmacol 2021; 97:107613. [PMID: 33962226 DOI: 10.1016/j.intimp.2021.107613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/08/2021] [Accepted: 03/22/2021] [Indexed: 01/19/2023]
Abstract
Mechanical unloading-induced bone loss is a clinical challenge, and deep understanding for this disease is necessary for developing novel and effective therapies. MicroRNAs (miRNAs) are small non-coding RNAs, and involved in bone remodeling. In the study, we attempted to explore the potential of miR-133a in regulating osteoblast activation and its anti-osteopenia function both in vitro and in vivo. Our in vitro studies at first showed that miR-133a could significantly promote the expression of osteocalcin (OCN), Collagen I, alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and osterix (Osx), promoting the activation and mineralization of osteoblasts. Then, hindlimb unloading (HU)-challenged mice were established with or without intravenous injection of agomir-miR-133a using an osteoblast-targeting delivery system. We found that miR-133a in osteoblasts significantly alleviated the bone loss, microstructural, and biomechanical property in mice with mechanical unloading, contributing to osteopenia alleviation. Furthermore, both in vitro and in vivo experiments showed that miR-133a could restrain osteoclastogenesis via tartrate-resistant acid phosphatase (TRAP) staining. In conclusion, our results suggested that miR-133a may be a promising factor in mediating the occurrence and progression of osteopenia caused by mechanical unloading, and thus targeting miR-133a could be considered as an effective therapeutic strategy for the suppression of pathological osteopenia.
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Affiliation(s)
- Youlong Zhou
- Department of Orthopaedics, Changxing People's Hospital, Huzhou, Zhejiang 313100, China.
| | - Xing Chen
- Department of Orthopaedics, Changxing People's Hospital, Huzhou, Zhejiang 313100, China
| | - Zemin Zhu
- Department of Orthopaedics, Changxing People's Hospital, Huzhou, Zhejiang 313100, China
| | - Daochi Bi
- Department of Orthopaedics, Changxing People's Hospital, Huzhou, Zhejiang 313100, China
| | - Shuyun Ma
- Department of Orthopaedics, Changxing People's Hospital, Huzhou, Zhejiang 313100, China
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Bano S, Tandon S, Tandon C. Emerging role of exosomes in arterial and renal calcification. Hum Exp Toxicol 2021; 40:1385-1402. [PMID: 33739177 DOI: 10.1177/09603271211001122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Exosomes are small, cell-derived vesicles of 30-100 nm that participate in cell-to-cell communication. They are released by many cells, such as dendritic cells (DC), lymphocytes, platelets, epithelial cells, endothelial cells (EC), and are found in most body fluids, including blood, saliva, urine, and breast milk. The exosomes released from cells within the cardiovascular system may contain either inhibitors of calcification in normal physiological conditions or promoters in the pathological environment [atherosclerosis (AS), and Chronic Kidney Disease (CKD)]. The exosomes of the vascular smooth muscle cells (VSMCs) are novel players in vascular repair processes and calcification. Several studies have shown that the cytoplasmic contents of exosomes are rich in a variety of proteins, nucleic acids, and lipids. Currently, exosomal micro RNAs and proteins are increasingly being recognized as biomarkers for the diagnosis of several diseases, including those of kidney and liver, as well as different types of cancer. In this review, we summarize recent advances in the role of exosomes in vascular calcification and their potential applications as diagnostic markers as well as a brief overview of the role of stem cell-derived exosomes in cardiovascular diseases.
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Affiliation(s)
- Shumaila Bano
- 531065Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, 77282Amity University, Noida, Uttar Pradesh, India
| | - Chanderdeep Tandon
- 531065Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
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27
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Düsing P, Zietzer A, Goody PR, Hosen MR, Kurts C, Nickenig G, Jansen F. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. J Mol Med (Berl) 2021; 99:335-348. [PMID: 33481059 PMCID: PMC7900031 DOI: 10.1007/s00109-021-02037-7] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 12/14/2020] [Accepted: 01/05/2021] [Indexed: 12/13/2022]
Abstract
Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.
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Affiliation(s)
- Philip Düsing
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Andreas Zietzer
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Philip Roger Goody
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Mohammed Rabiul Hosen
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Christian Kurts
- Institute of Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany
| | - Georg Nickenig
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Felix Jansen
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
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28
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Zhao J, Liu Z, Chang Z. Osteogenic differentiation and calcification of human aortic smooth muscle cells is induced by the RCN2/STAT3/miR-155-5p feedback loop. Vascul Pharmacol 2021; 136:106821. [PMID: 33221530 DOI: 10.1016/j.vph.2020.106821] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/15/2020] [Accepted: 11/18/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Vascular calcification (VC) is associated with the high morbidity and mortality of cardiovascular diseases in dialysis patients and is a process in which vascular smooth muscle cells (VSMCs) actively differentiate into osteoblast-like cells. Reticulocalbin-2 (RCN2) is involved in the process of osteogenic differentiation under diabetic conditions, but its regulatory role under hyperphosphatemic conditions and the related mechanisms remain unclear. In this study, the importance of the interactions among RCN2, STAT3 and miR-155-5p during the osteogenic differentiation and calcification of human aortic VSMCs (HASMCs) were investigated. METHODS RCN2 was measured in femoropopliteal artery plaque specimens from 6 peripheral arterial disease (PAD) patients with chronic kidney disease (CKD) and 6 PAD patients without CKD. RCN2 protein and mRNA expression were assessed in the high phosphate-induced aortic rings culture ex vivo model. In vitro calcification assays and molecular mechanism studies were performed in HASMCs. RESULTS Immunohistochemical staining results revealed increased RCN2 expression in the calcified plaques of femoral arteries of patients with CKD and in a high phosphate-induced aortic culture ex vivo model. RCN2 promoted HASMCs osteogenic differentiation and calcification by inducing STAT3 phosphorylation. Furthermore, inhibition of STAT3 activation by cryptotanshinone (CT) promoted miR-155-5p expression in HASMCs. In turn, miR-155-5p inhibited RCN2 mRNA expression, while RCN2 overexpression partially offset the miR-155-5p-mediated inhibition of HASMC calcification, acting as a positive feedback loop. CONCLUSION These results demonstrate that RCN2 is a crucial regulator of VC under hyperphosphatemic conditions. RCN2/STAT3/miR-155-5p feedback loop is important in VC and targeting each member of this feedback loop could potentially reverse high phosphate-induced VC.
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Affiliation(s)
- Jian Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Zhaoyu Liu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Zhihui Chang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
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Li FXZ, Lin X, Xu F, Shan SK, Guo B, Lei LM, Zheng MH, Wang Y, Xu QS, Yuan LQ. The Role of Mesenchymal Stromal Cells-Derived Small Extracellular Vesicles in Diabetes and Its Chronic Complications. Front Endocrinol (Lausanne) 2021; 12:780974. [PMID: 34987478 PMCID: PMC8721875 DOI: 10.3389/fendo.2021.780974] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/29/2021] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are applied in regenerative medicine of several tissues and organs nowadays by virtue of their self-renewal capabilities, multiple differentiation capacity, potent immunomodulatory properties, and their ability to be favourably cultured and manipulated. With the continuous development of "cell-free therapy" research, MSC-derived small extracellular vesicles (MSC-sEVs) have increasingly become a research hotspot in the treatment of various diseases. Small extracellular vesicles (SEVs) are membrane vesicles with diameters of 30 to 150 nm that mediate signal transduction between adjacent or distal cells or organs by delivering non-coding RNA, protein, and DNA. The contents and effects of sEVs vary depending on the properties of the originating cell. In recent years, MSC-sEVs have been found to play an important role in the occurrence and development of diabetes mellitus as a new way of communication between cells. Diabetes mellitus is a common metabolic disease in clinic. Its complications of the heart, brain, kidney, eyes, and peripheral nerves are a serious threat to human health and has been a hot issue for clinicians. MSC-sEVs could be applied to repair or prevent damage from the complications of diabetes mellitus through anti-inflammatory effects, reduction of endoplasmic reticulum-related protein stress, polarization of M2 macrophages, and increasing autophagy. Therefore, we highly recommend that MSC-sEVs-based therapies to treat diabetes mellitus and its chronic complication be further explored. The analysis of the role and molecular mechanisms of MSC-sEVs in diabetes and its related complications will provide new idea and insights for the prevention and treatment of diabetes.
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Affiliation(s)
- Fu-Xing-Zi Li
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Wang
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan,
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Culibrk RA, Hahn MS. The Role of Chronic Inflammatory Bone and Joint Disorders in the Pathogenesis and Progression of Alzheimer's Disease. Front Aging Neurosci 2020; 12:583884. [PMID: 33364931 PMCID: PMC7750365 DOI: 10.3389/fnagi.2020.583884] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Late-onset Alzheimer's Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic Aβ plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies ultimately incite the propagation of a disease-associated subset of microglia-the principle immune cells of the brain-characterized by preferentially pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been identified as one of the cardinal pathophysiological driving features of AD; however, despite a number of works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis and relation to the inception of cognitive impairment remain obscure. Moreover, the limited clinical success of treatments targeting specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative, more holistic approaches for ameliorating AD outcomes. Accumulating evidence suggests significant interplay between peripheral immune activity and blood-brain barrier permeability, microglial activation and proliferation, and AD-related cognitive decline. In this work, we review a narrow but significant subset of chronic peripheral inflammatory conditions, describe how these pathologies are associated with the preponderance of neuroinflammation, and posit that we may exploit peripheral immune processes to design interventional, preventative therapies for LOAD. We then provide a comprehensive overview of notable treatment paradigms that have demonstrated considerable merit toward treating these disorders.
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Affiliation(s)
| | - Mariah S. Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
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Li Y, Sun W, Saaoud F, Wang Y, Wang Q, Hodge J, Hui Y, Yin S, Lessner SM, Kong X, Fan D. MiR155 modulates vascular calcification by regulating Akt-FOXO3a signalling and apoptosis in vascular smooth muscle cells. J Cell Mol Med 2020; 25:535-548. [PMID: 33210462 PMCID: PMC7810936 DOI: 10.1111/jcmm.16107] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/13/2020] [Accepted: 11/01/2020] [Indexed: 12/17/2022] Open
Abstract
microRNA‐155 (miR155) is pro‐atherogenic; however, its role in vascular calcification is unknown. In this study, we aim to examine whether miR155 regulates vascular calcification and to understand the underlying mechanism. Quantitative real‐time PCR showed that miR155 is highly expressed in human calcific carotid tissue and positively correlated with the expression of osteogenic genes. Wound‐healing assay and TUNEL staining showed deletion of miR155 inhibited vascular smooth muscle cell (VSMC) migration and apoptosis. miR155 deficiency attenuated calcification of cultured mouse VSMCs and aortic rings induced by calcification medium, whereas miR155 overexpression promoted VSMC calcification. Compared with wild‐type mice, miR155−/− mice showed significant resistance to vitamin D3 induced vascular calcification. Protein analysis showed that miR155 deficiency alleviated the reduction of Rictor, increased phosphorylation of Akt at S473 and accelerated phosphorylation and degradation of FOXO3a in cultured VSMCs and in the aortas of vitamin D3‐treated mice. A PI3K inhibitor that suppresses Akt phosphorylation increased, whereas a pan‐caspase inhibitor that suppresses apoptosis reduced VSMC calcification; and both inhibitors diminished the protective effects of miR155 deficiency on VSMC calcification. In conclusion, miR155 deficiency attenuates vascular calcification by increasing Akt phosphorylation and FOXO3a degradation, and thus reducing VSMC apoptosis induced by calcification medium.
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Affiliation(s)
- Yong Li
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Wei Sun
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA.,Department of Cardiology and Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fatma Saaoud
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Yuzhen Wang
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Quanyi Wang
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Johnie Hodge
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Yvonne Hui
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Sophia Yin
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Susan M Lessner
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Xiangqing Kong
- Department of Cardiology and Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
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32
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Hao S, Salzo J, Zhao H, Hao M, Darzynkiewicz Z, Ferreri NR. MicroRNA-133a-Dependent Inhibition of Proximal Tubule Angiotensinogen by Renal TNF (Tumor Necrosis Factor). Hypertension 2020; 76:1744-1752. [PMID: 33131307 DOI: 10.1161/hypertensionaha.120.15435] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We showed that intrarenal suppression of TNF (tumor necrosis factor) production under low salt (LS) conditions increases renal cortical AGT (angiotensinogen) mRNA and protein expression. Intrarenal injection of murine recombinant TNF attenuated increases of AGT in mice ingesting LS. Moreover, AGT mRNA and protein expression increased ≈6-fold and 2-fold, respectively, in mice ingesting LS that also received an intrarenal injection of a lentivirus construct that specifically silenced TNF in the kidney (U6-TNF-ex4). Silencing of TNF under normal salt and high salt (HS) conditions also resulted in increased AGT expression. Since renal TNF production decreases in response to LS and increases in response to HS, the data suggest that alterations in TNF production under these conditions modulate the degree of AGT expression. We also tested the hypothesis that TNF inhibits intrarenal AGT expression by a mechanism involving miR-133a. Expression of miR-133a decreased in mice given LS and increased in response to HS for 7 days. Intrarenal silencing of TNF reversed the effects of HS on miR-133a-dependent AGT expression. In contrast, intrarenal TNF administration increased miR-133a expression in the kidney. Collectively, the data suggest that miR-133a is a salt-sensitive microRNA that inhibits AGT in the kidney and is increased by TNF. The HS-induced increase in blood pressure observed following silencing of TNF was markedly reduced upon intrarenal administration of miR-133a suggesting that intrinsic effects of TNF in the kidney to limit the blood pressure response to HS include an increase in miR-133a, which suppresses AGT expression.
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Affiliation(s)
- Shoujin Hao
- From the Department of Pharmacology, New York Medical College, Valhalla
| | - Joseph Salzo
- From the Department of Pharmacology, New York Medical College, Valhalla
| | - Hong Zhao
- From the Department of Pharmacology, New York Medical College, Valhalla
| | - Mary Hao
- From the Department of Pharmacology, New York Medical College, Valhalla
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33
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Wang SS, Wang C, Chen H. MicroRNAs are critical in regulating smooth muscle cell mineralization and apoptosis during vascular calcification. J Cell Mol Med 2020; 24:13564-13572. [PMID: 33089928 PMCID: PMC7754013 DOI: 10.1111/jcmm.16005] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 09/27/2020] [Accepted: 10/01/2020] [Indexed: 02/01/2023] Open
Abstract
Vascular calcification refers to the pathological deposition of calcium and phosphate minerals into the vasculature. It is prevalent in atherosclerosis, ageing, type 2 diabetes mellitus and chronic kidney disease, thus, increasing morbidity and mortality from these conditions. Vascular calcification shares similar mechanisms with bone mineralization, with smooth muscle cells playing a critical role in both processes. In the last decade, a variety of microRNAs have been identified as key regulators for the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition in vascular smooth muscle cells during vascular calcification. Therefore, this review mainly discusses the roles of microRNAs in the pathophysiological mechanisms of vascular calcification in smooth muscle cells and describes several interventions against vascular calcification by regulating microRNAs. As the exact mechanisms of calcification remain not fully elucidated, having a better understanding of microRNA involvement in vascular calcification may give impetus to development of novel therapeutics for the control and treatment of vascular calcification.
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Affiliation(s)
- Shan-Shan Wang
- Department of Cardiology, Zhejiang Provincial Key Lab of Cardiovascular Disease Diagnosis and Treatment, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chen Wang
- Department of Cardiology, Zhejiang Provincial Key Lab of Cardiovascular Disease Diagnosis and Treatment, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Han Chen
- Department of Cardiology, Zhejiang Provincial Key Lab of Cardiovascular Disease Diagnosis and Treatment, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Duan M, Zhao WL, Zhou L, Novák P, Zhu X, Yin K. Omics research in vascular calcification. Clin Chim Acta 2020; 511:319-328. [PMID: 33096035 DOI: 10.1016/j.cca.2020.10.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/15/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023]
Abstract
Vascular calcification (VC), the pathological process of hydroxyapatite mineral deposition in the vascular system, is closely associated with aging, atherosclerotic plaque formation, cardiovascular disease (CVD) and diabetes mellitus (DM). Studies have shown that VC is related to cellular phenotypic changes, extracellular vesicles, disordered calcium and phosphate homeostasis, and an imbalance between inducers and inhibitors of VC. Unfortunately, there is currently no effective preventive or targeted treatment for pathologic condition. The rapid evolution of omics technology (genomics, epigenomics, transcriptomics, proteomics and metabolomics) has provided a novel approach for elucidation of pathophysiologic mechanisms in general and those associated with VC specifically. Here, we review articles published over the last twenty years and focus on the current state, challenges, limitations and future of omics in VC research and clinical practice. Highlighting potential targets based on omics technology will improve our understanding of this pathologic condition and assist in the development of potential treatment options for VC related disease.
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Affiliation(s)
- Meng Duan
- Research Lab of Translational Medicine, Hengyang Medical School, University of South China, Hengyang 421001, China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Wen-Li Zhao
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Le Zhou
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Petr Novák
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Xiao Zhu
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China.
| | - Kai Yin
- The Second Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China.
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35
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Duan M, Zhao WL, Zhou L, Novák P, Zhu X, Yin K. Omics research in vascular calcification. Clin Chim Acta 2020; 511:198-207. [PMID: 33096032 DOI: 10.1016/j.cca.2020.10.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023]
Abstract
Vascular calcification (VC), the pathological process of hydroxyapatite mineral deposition in the vascular system, is closely associated with aging, atherosclerotic plaque formation, cardiovascular disease (CVD) and diabetes mellitus (DM). Studies have shown that VC is related to cellular phenotypic changes, extracellular vesicles, disordered calcium phosphate homeostasis and an imbalance between inducers and inhibitors of VC. Unfortunately, there is currently no effective preventive or targeted treatment for this disorder. Recently, the evolution of omics technology (genomics, epigenomics, transcriptomics, proteomics and metabolomics) has paved the way for elucidation of complex biochemical processes and, as such, may provide new insight on VC. Accordingly, we conducted a review of articles published over the last twenty years and herein focus on current and future potential of omics technology in clarifying mechanisms of this disease process. Identification of new biomarkers will provide additional tools in characterizing this pathology and will further assist in the development of potential therapeutic targets.
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Affiliation(s)
- Meng Duan
- Research Lab of Translational Medicine, Hengyang Medical School, University of South China, Hengyang 421001, China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Wen-Li Zhao
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Le Zhou
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Petr Novák
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Xiao Zhu
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China.
| | - Kai Yin
- The Second Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China.
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Ryu J, Ahn Y, Kook H, Kim YK. The roles of non-coding RNAs in vascular calcification and opportunities as therapeutic targets. Pharmacol Ther 2020; 218:107675. [PMID: 32910935 DOI: 10.1016/j.pharmthera.2020.107675] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023]
Abstract
Vascular calcification (VC) is characterized by an accumulation of calcium phosphate crystals inside the vessel wall. VC is often associated with diabetes, chronic kidney disease (CKD), atherosclerosis, and cardiovascular disease (CVD). Even though the number of patients with VC remains prevalent, there are still no approved therapies for the treatment of VC. Since the pathogenesis of VC is diverse and involves multiple factors and mechanisms, it is critical to reveal the novel mechanisms involved in VC. Although protein-coding RNAs involved in VC have been extensively studied, the roles of non-coding RNAs (ncRNAs) are not yet fully understood. The field of ncRNAs has recently received attention, and accumulating evidence from studies in VC suggests that ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in the regulation of VC. NcRNAs can modulate VC by acting as promoters or inhibitors and may be useful in the clinical diagnosis and treatment of VC. In this article, we review and discuss ncRNAs that regulate VC and present the therapeutic implications of these ncRNAs.
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Affiliation(s)
- Juhee Ryu
- Basic Research Laboratory for Vascular Remodeling, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University, Jeollanam-do, Republic of Korea; Department of Biochemistry, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; Department of Pharmacology, Chonnam National University Medical School, Jeollanam-do, Republic of Korea
| | - Youngkeun Ahn
- Basic Research Laboratory for Vascular Remodeling, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; Department of Cardiology, Cardiovascular Center, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Hyun Kook
- Basic Research Laboratory for Vascular Remodeling, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University, Jeollanam-do, Republic of Korea; Department of Pharmacology, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.
| | - Young-Kook Kim
- Basic Research Laboratory for Vascular Remodeling, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University, Jeollanam-do, Republic of Korea; Department of Biochemistry, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.
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37
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Choe N, Shin S, Joung H, Ryu J, Kim Y, Ahn Y, Kook H, Kwon D. The microRNA miR-134-5p induces calcium deposition by inhibiting histone deacetylase 5 in vascular smooth muscle cells. J Cell Mol Med 2020; 24:10542-10550. [PMID: 32783377 PMCID: PMC7521311 DOI: 10.1111/jcmm.15670] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 06/30/2020] [Accepted: 07/03/2020] [Indexed: 12/30/2022] Open
Abstract
Calcium deposition in vascular smooth muscle cells (VSMCs) is a form of ectopic ossification in blood vessels. It can result in rigidity of the vasculature and an increase in cardiac events. Here, we report that the microRNA miR-134-5p potentiates inorganic phosphate (Pi)-induced calcium deposition in VSMCs by inhibiting histone deacetylase 5 (HDAC5). Using miRNA microarray analysis of Pi-treated rat VSMCs, we first selected miR-134-5p for further evaluation. Quantitative RT-PCR confirmed that miR-134-5p was increased in Pi-treated A10 cells, a rat VSMC line. Transfection of miR-134-5p mimic potentiated the Pi-induced increase in calcium contents. miR-134-5p increased the amounts of bone runt-related transcription factor 2 (RUNX2) protein and bone morphogenic protein 2 (BMP2) mRNA in the presence of Pi but decreased the expression of osteoprotegerin (OPG). Bioinformatic analysis showed that the HDAC5 3'untranslated region (3'UTR) was one of the targets of miR-134-5p. The luciferase construct containing the 3'UTR of HDAC5 was down-regulated by miR-134-5p mimic in a dose-dependent manner in VSMCs. Overexpression of HDAC5 mitigated the calcium deposition induced by miR-134-5p. Our results suggest that a Pi-induced increase of miR-134-5p may cause vascular calcification through repression of HDAC5.
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Affiliation(s)
- Nakwon Choe
- Department of PharmacologyChonnam National University Medical SchoolHwasunRepublic of Korea
| | - Sera Shin
- Department of PharmacologyChonnam National University Medical SchoolHwasunRepublic of Korea
| | - Hosouk Joung
- Department of PharmacologyChonnam National University Medical SchoolHwasunRepublic of Korea
| | - Juhee Ryu
- Department of PharmacologyChonnam National University Medical SchoolHwasunRepublic of Korea
| | - Young‐Kook Kim
- Department of BiochemistryChonnam National University Medical SchoolHwasunRepublic of Korea
| | - Youngkeun Ahn
- Department of CardiologyChonnam National University HospitalGwangjuRepublic of Korea
| | - Hyun Kook
- Department of PharmacologyChonnam National University Medical SchoolHwasunRepublic of Korea
| | - Duk‐Hwa Kwon
- Department of PharmacologyChonnam National University Medical SchoolHwasunRepublic of Korea
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Industry compensation and self-reported financial conflicts of interest among authors of highly cited peripheral artery disease studies. J Vasc Surg 2020; 72:673-684. [DOI: 10.1016/j.jvs.2019.09.053] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 09/07/2019] [Indexed: 12/20/2022]
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Lin X, Li F, Xu F, Cui RR, Xiong D, Zhong JY, Zhu T, Shan SK, Wu F, Xie XB, Liao XB, Yuan LQ. Aberration methylation of miR-34b was involved in regulating vascular calcification by targeting Notch1. Aging (Albany NY) 2020; 11:3182-3197. [PMID: 31129659 PMCID: PMC6555467 DOI: 10.18632/aging.101973] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/12/2019] [Indexed: 12/21/2022]
Abstract
Vascular calcification is one of the most important factors for cardiovascular and all-cause mortality in patients with end-stage renal diseases (ESRD). The current study was aimed to investigate the function and mechanisms of miR-34b on the calcification of vascular smooth muscle cells (VSMCs) both in vitro and in vivo. We found that the expression of miR-34b was significantly suppressed in VSMCs with high inorganic phosphate (Pi) treatment, as well as mouse arteries derived from 5/6 nephrectomy with a high-phosphate diet (0.9% Pi, 5/6 NTP) and human renal arteries from uraemia patients. Overexpression of miR-34b alleviated calcification of VSMCs, while VSMCs calcification was enhanced by inhibiting the expression of miR-34b. Bisulphite sequencing PCR (BSP) uncovered that CpG sites upstream of miR-34b DNA were hypermethylated in calcified VSMCs and calcified arteries due to 5/6 NTP, as well as calcified renal arterial tissues from uraemia patients. Meantime, increased DNA methyltransferase 3a (DNMT3a) resulted in the hypermethylation of miR-34b in VSMCs, while 5-aza-2′-deoxycytidine (5-aza) reduced the methylation rate of miR-34b and restored the expression of miR-34b in VSMCs. When DNMT3a was knocked down using DNMT3a siRNA, the effect of 3.5 mM of Pi on calcification of VSMCs was abrogated. In addition, Notch1 was validated as the functional target of miR-34b and involved in the process of calcification of VSMCs. Taken together, our data showed a specific role for miR-34b in regulating calcification of VSMCs both in vitro and in vivo, which was regulated by upstream DNA methylation of miR-34b and modulated by the downstream target gene expression, Notch1. These results suggested that modulation of miR-34b may offer new insight into a novel therapeutic approach for vascular calcification.
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Affiliation(s)
- Xiao Lin
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.,Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Fuxingzi Li
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Feng Xu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Rong-Rong Cui
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Dan Xiong
- Department of Endocrinology, Central Hospital of Yiyang, Yiyang, Hunan, People's Republic of China
| | - Jia-Yu Zhong
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.,Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ting Zhu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.,Department of Endocrinology, Central Hospital of Yiyang, Yiyang, Hunan, People's Republic of China
| | - Su-Kang Shan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Feng Wu
- Department of Pathology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xu-Biao Xie
- Center of Organ Transplantation, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiao-Bo Liao
- Department of Cardiovascular Surgery, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ling-Qing Yuan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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Castaño IM, Raftery RM, Chen G, Cavanagh B, Quinn B, Duffy GP, O'Brien FJ, Curtin CM. Rapid bone repair with the recruitment of CD206 +M2-like macrophages using non-viral scaffold-mediated miR-133a inhibition of host cells. Acta Biomater 2020; 109:267-279. [PMID: 32251781 DOI: 10.1016/j.actbio.2020.03.042] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/10/2020] [Accepted: 03/27/2020] [Indexed: 01/01/2023]
Abstract
microRNAs offer vast therapeutic potential for multiple disciplines. From a bone perspective, inhibition of miR-133a may offer potential to enhance Runx2 activity and increase bone repair. This study aims to assess the therapeutic capability of antagomiR-133a delivery from collagen-nanohydroxyapatite (coll-nHA) scaffolds following cell-free implantation in rat calvarial defects (7 mm diameter). This is, to the best of our knowledge, the first report of successful in vivo antagomiR uptake in host cells of fully immunocompetent animals without distribution to other off-target tissues. Our results demonstrate the localized release of antagomiR-133a to the implant site at 1 week post-implantation with increased calcium deposits already evident in the antagomiR-133a loaded scaffolds at this early timepoint. This was followed by an approximate 2-fold increase in bone volume versus antagomiR-free scaffolds and a significant 10-fold increase over the empty defect controls, after just 4 weeks. An increase in host CD206+ cells suggests an accelerated pro-remodeling response by M2-like macrophages accompanying bone repair with this treatment. Overall, this non-viral scaffold-mediated antagomiR-133a delivery platform demonstrates capability to accelerate bone repair in vivo - without the addition of exogenous cells - and underlines the role of M2 macrophage-like cells in directing accelerated bone repair. Expanding the repertoire of this platform to deliver alternative miRNAs offers exciting possibilities for a variety of therapeutic indications. STATEMENT OF SIGNIFICANCE: microRNAs, small non-coding RNA molecules involved in gene regulation, may have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. We developed a collagen-nanohydroxyapatite-microRNA scaffold system to investigate whether miR133a inhibition can enhance osteogenesis in rat MSCs and ultimately accelerate endogenous bone repair by host cells in vivo without pre-seeding cells prior to implantation. Overall, this off-the-shelf, non-viral scaffold-mediated antagomiR-133a delivery platform demonstrates capability to accelerate bone repair in vivo - without the requirement of exogenous cells - and highlights the role of CD206+M2 macrophage-like cells in guiding accelerated bone repair. Translating the repertoire of this platform to deliver alternative miRNAs offers exciting possibilities for a vast myriad of therapeutic indications.
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Zhong JY, Cui XJ, Zhan JK, Wang YJ, Li S, Lin X, Xiang QY, Ni YQ, Liu L, Liu YS. LncRNA-ES3 inhibition by Bhlhe40 is involved in high glucose-induced calcification/senescence of vascular smooth muscle cells. Ann N Y Acad Sci 2020; 1474:61-72. [PMID: 32483833 DOI: 10.1111/nyas.14381] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/28/2020] [Accepted: 05/08/2020] [Indexed: 12/29/2022]
Abstract
Long noncoding RNAs (lncRNAs) have been investigated as novel regulatory molecules involved in diverse biological processes. Our previous study demonstrated that lncRNA-ES3 is associated with the high glucose-induced calcification/senescence of human aortic vascular smooth muscle cells (HA-VSMCs). However, the mechanism of lncRNA-ES3 in vascular calcification/aging remained largely unknown. Here, we report that the expression of basic helix-loop-helix family member e40 (Bhlhe40) was decreased significantly in HA-VSMCs treated with high glucose, whereas the expression of basic leucine zipper transcription factor (BATF) was increased. Overexpression of Bhlhe40 and inhibition of BATF alleviated calcification/senescence of HA-VSMCs, as confirmed by Alizarin Red S staining and the presence of senescence-associated β-galactosidase-positive cells. Moreover, we identified that Bhlhe40 regulates lncRNA-ES3 in HA-VSMCs by binding to the promoter region of the lncRNA-ES3 gene (LINC00458). Upregulation or inhibition of lncRNA-ES3 expression significantly promoted or reduced calcification/senescence of HA-VSMCs, respectively. Additionally, we identified that lncRNA-ES3 functions in this process by suppressing the expression of miR-95-5p, miR-6776-5p, miR-3620-5p, and miR-4747-5p. The results demonstrate that lncRNA-ES3 triggers gene silencing of multiple miRNAs by binding to Bhlhe40, leading to calcification/senescence of VSMCs. Our findings suggest that pharmacological interventions targeting lncRNA-ES3 may be therapeutically beneficial in ameliorating vascular calcification/aging.
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Affiliation(s)
- Jia-Yu Zhong
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Xing-Jun Cui
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Jun-Kun Zhan
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Yan-Jiao Wang
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Shuang Li
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiao Lin
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Qun-Yan Xiang
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Yu-Qing Ni
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - Le Liu
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
| | - You-Shuo Liu
- Department of Geriatrics, The Second Xiangya Hospital, Institute of Aging and Age-Related Disease Research, Central South University, Changsha, Hunan, People's Republic of China
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Duale N, Eide DM, Amberger ML, Graupner A, Brede DA, Olsen AK. Using prediction models to identify miRNA-based markers of low dose rate chronic stress. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 717:137068. [PMID: 32062256 DOI: 10.1016/j.scitotenv.2020.137068] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/13/2020] [Accepted: 01/31/2020] [Indexed: 06/10/2023]
Abstract
Robust biomarkers of exposure to chronic low dose stressors such as ionizing radiation, particularly following chronic low doses and dose-rates, are urgently needed. MicroRNAs (miRNA) have emerged as promising markers of exposure to high dose and dose-rate. Here, we evaluated the feasibility of classifying γ-radiation exposure at different dose rates based on miRNA expression levels. Our objective was to identify miRNA-signatures discriminating between exposure to γ-radiation or not, including exposure to chronic low dose rates. We exposed male CBA/CaOlaHsd and C57BL/6NHsd wild-type mice to 0, 2.5, 10 and 100 mGy/h γ-irradiation (3 Gy total-dose). From an initial screening of 576 miRNAs, a set of 21 signature-miRNAs was identified based on differential expression (>± 2-fold or p < 0.05). This 21-signature miRNA panel was investigated in 39 samples from 4/5 livers/group/mouse strain. A set of significantly differentially expressed miRNAs was identified in all γ-irradiated samples. Most miRNAs were upregulated in all γ-irradiated groups compared to control, and functional analysis of these miRNAs revealed involvement in several cancer-related signaling pathways. To identify miRNAs that distinguished exposed mice from controls, nine prediction methods; i.e., six variants of generalized regression models, random-forest, boosted-tree and nearest-shrunken-centroid (PAM) were used. The generalized regression methods seem to outperform the other prediction methods for classification of irradiated and control samples. Using the 21-miRNA panel in the prediction models, we identified sets of candidate miRNA-markers that predict exposure to γ-radiation. Among the top10 miRNA predictors, contributing most in each of the three γ-irradiated groups, three miRNA predictors (miR-140-3p, miR-133a-5p and miR-145a-5p) were common. Three miRNAs, miR-188-3p/26a-5p/26b-5p, were specific for lower dose-rate γ-radiation. Similarly, exposure to the high dose-rates was also correctly predicted, including mice exposed to X-rays. Our approach identifying miRNA-based signature panels may be extended to classify exposure to environmental, nutritional and life-style-related stressors, including chronic low-stress scenarios.
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Affiliation(s)
- Nur Duale
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; Centre of Excellence "Centre for Environmental Radiation" (CERAD), Norway.
| | - Dag M Eide
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; Centre of Excellence "Centre for Environmental Radiation" (CERAD), Norway
| | - Maria L Amberger
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; Centre of Excellence "Centre for Environmental Radiation" (CERAD), Norway
| | - Anne Graupner
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; Centre of Excellence "Centre for Environmental Radiation" (CERAD), Norway
| | - Dag A Brede
- Centre of Excellence "Centre for Environmental Radiation" (CERAD), Norway; Faculty of Environmental Sciences and Natural Resource Management (MINA), Norwegian University of Life Sciences (NMBU), Ås, Norway
| | - Ann K Olsen
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; Centre of Excellence "Centre for Environmental Radiation" (CERAD), Norway
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Chen YL, Sheu JJ, Sun CK, Huang TH, Lin YP, Yip HK. MicroRNA-214 modulates the senescence of vascular smooth muscle cells in carotid artery stenosis. Mol Med 2020; 26:46. [PMID: 32410577 PMCID: PMC7227274 DOI: 10.1186/s10020-020-00167-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 04/16/2020] [Indexed: 11/12/2022] Open
Abstract
Background MicroRNAs control gene expression by post-transcriptional inhibition. Dysregulation of the expressions of miR-199a/214 cluster has been linked to cardiovascular diseases. This study aimed at identifying potential microRNAs related to vascular senescence. Methods Seven candidate microRNAs (miR-19a, −20a, −26b, −106b, − 126, − 214, and − 374) related to cell proliferation were tested for their expressions under CoCl2-induced hypoxia in vascular smooth muscle cells (VSMCs). After identification of miR-214 as the candidate microRNA, telomere integrity impairment and cell cycle arrest were examined in VSMCs by using miR-214 mimic, AntagomiR, and negative controls. To investigate the clinical significance of miR-214 in vascular diseases, its plasma level from patients with carotid artery stenosis (CAS) was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Results CoCl2 treatment for 48 h suppressed cell proliferation and angiogenesis as well as enhanced cell senescence in VSMCs. Besides, miR-214 level was elevated in both intracellular and exosome samples of VSMCs after CoCl2 treatment. Manipulating miR-214 in VSMCs demonstrated that miR-214 not only inhibited angiogenic and proliferative capacities but also promoted senescence through the suppression of quaking. Additionally, circulating miR-214 level was upregulated in CAS patients with high low-density lipoprotein cholesterol (LDL-C) value. Conclusion Our findings suggested that miR-214 plays a role in the modulation of VSMC angiogenesis, proliferation, and senescence with its plasma level being increased in CAS patients with elevated LDL-C value, implying that it may be a vascular senescence marker and a potential therapeutic target for vascular diseases.
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Affiliation(s)
- Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan
| | - Jiunn-Jye Sheu
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan.,Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan
| | - Cheuk-Kwan Sun
- Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, 82445, Taiwan
| | - Tien-Hung Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan
| | - Yuan-Ping Lin
- Department of health and Beauty, Shu-Zen Junior College of Medicine and Management, Kaohsiung, 82144, Taiwan.
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan. .,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan. .,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan. .,Department of Nursing, Asia University, Taichung, 41354, Taiwan. .,Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, 361028, Fujian, China.
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Abstract
Over the last decades, the association between vascular calcification (VC) and all-cause/cardiovascular mortality, especially in patients with high atherogenic status, such as those with diabetes and/or chronic kidney disease, has been repeatedly highlighted. For over a century, VC has been noted as a passive, degenerative, aging process without any treatment options. However, during the past decades, studies confirmed that mineralization of the arteries is an active, complex process, similar to bone genesis and formation. The main purpose of this review is to provide an update of the existing biomarkers of VC in serum and develop the various pathogenetic mechanisms underlying the calcification process, including the pivotal roles of matrix Gla protein, osteoprotegerin, bone morphogenetic proteins, fetuin-a, fibroblast growth-factor-23, osteocalcin, osteopontin, osteonectin, sclerostin, pyrophosphate, Smads, fibrillin-1 and carbonic anhydrase II.
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Xu F, Zhong J, Lin X, Shan S, Guo B, Zheng M, Wang Y, Li F, Cui R, Wu F, Zhou E, Liao X, Liu Y, Yuan L. Melatonin alleviates vascular calcification and ageing through exosomal miR-204/miR-211 cluster in a paracrine manner. J Pineal Res 2020; 68:e12631. [PMID: 31943334 PMCID: PMC7154654 DOI: 10.1111/jpi.12631] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 12/08/2019] [Accepted: 01/06/2020] [Indexed: 12/24/2022]
Abstract
In the elderly with atherosclerosis, hypertension and diabetes, vascular calcification and ageing are ubiquitous. Melatonin (MT) has been demonstrated to impact the cardiovascular system. In this study, we have shown that MT alleviates vascular calcification and ageing, and the underlying mechanism involved. We found that both osteogenic differentiation and senescence of vascular smooth muscle cells (VSMCs) were attenuated by MT in a MT membrane receptor-dependent manner. Moreover, exosomes isolated from VSMCs or calcifying vascular smooth muscle cells (CVSMCs) treated with MT could be uptaken by VSMCs and attenuated the osteogenic differentiation and senescence of VSMCs or CVSMCs, respectively. Moreover, we used conditional medium from MT-treated VSMCs and Transwell assay to confirm exosomes secreted by MT-treated VSMCs attenuated the osteogenic differentiation and senescence of VSMCs through paracrine mechanism. We also found exosomal miR-204/miR-211 mediated the paracrine effect of exosomes secreted by VSMCs. A potential target of these two miRs was revealed to be BMP2. Furthermore, treatment of MT alleviated vascular calcification and ageing in 5/6-nephrectomy plus high-phosphate diet-treated (5/6 NTP) mice, while these effects were partially reversed by GW4869. Exosomes derived from MT-treated VSMCs were internalised into mouse artery detected by in vivo fluorescence image, and these exosomes reduced vascular calcification and ageing of 5/6 NTP mice, but both effects were largely abolished by inhibition of exosomal miR-204 or miR-211. In summary, our present study revealed that exosomes from MT-treated VSMCs could attenuate vascular calcification and ageing in a paracrine manner through an exosomal miR-204/miR-211.
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Affiliation(s)
- Feng Xu
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Jia‐Yu Zhong
- Department of GeriatricsInstitute of Aging and Age‐related Disease ResearchThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Xiao Lin
- Department of RadiologyThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Su‐Kang Shan
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Bei Guo
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Ming‐Hui Zheng
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Yi Wang
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Fuxingzi Li
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Rong‐Rong Cui
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Feng Wu
- Department of PathologyThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - En Zhou
- Department of Otorhinolaryngology Head and Neck SurgeryHunan Provincial People's HospitalChangshaChina
| | - Xiao‐Bo Liao
- Department of Cardiovascular SurgeryThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - You‐Shuo Liu
- Department of GeriatricsInstitute of Aging and Age‐related Disease ResearchThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
| | - Ling‐Qing Yuan
- Department of Metabolism and EndocrinologyNational Clinical Research Center for Metabolic DiseasesHunan Provincial Key Laboratory of Metabolic Bone DiseasesThe Second Xiang‐Ya HospitalCentral South UniversityChangshaChina
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Ni YQ, Lin X, Zhan JK, Liu YS. Roles and Functions of Exosomal Non-coding RNAs in Vascular Aging. Aging Dis 2020; 11:164-178. [PMID: 32010490 PMCID: PMC6961769 DOI: 10.14336/ad.2019.0402] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/02/2019] [Indexed: 12/13/2022] Open
Abstract
Aging is a progressive loss of physiological integrity and functionality process which increases susceptibility and mortality to diseases. Vascular aging is a specific type of organic aging. The structure and function changes of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are the main cause of vascular aging, which could influence the threshold, process, and severity of vascular related diseases. Accumulating evidences demonstrate that exosomes serve as novel intercellular information communicator between cell to cell by delivering variety biologically active cargos, especially exosomal non-coding RNAs (ncRNAs), which are associated with most of aging-related biological and functional disorders. In this review, we will summerize the emerging roles and mechanisms of exosomal ncRNAs in vascular aging and vascular aging related diseases, focusing on the role of exosomal miRNAs and lncRNAs in regulating the functions of ECs and VSMCs. Moreover, the relationship between the ECs and VSMCs linked by exosomes, the potential diagnostic and therapeutic application of exosomes in vascular aging and the clinical evaluation and treatment of vascular aging and vascular aging related diseases will also be discussed.
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Affiliation(s)
| | | | - Jun-Kun Zhan
- Department of Geriatrics, Institute of Aging and Geriatrics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - You-Shuo Liu
- Department of Geriatrics, Institute of Aging and Geriatrics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
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The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective. Int J Mol Sci 2020; 21:ijms21030980. [PMID: 32024140 PMCID: PMC7037112 DOI: 10.3390/ijms21030980] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/14/2020] [Accepted: 01/15/2020] [Indexed: 12/26/2022] Open
Abstract
Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk.
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Huang M, Zheng L, Xu H, Tang D, Lin L, Zhang J, Li C, Wang W, Yuan Q, Tao L, Ye Z. Oxidative stress contributes to vascular calcification in patients with chronic kidney disease. J Mol Cell Cardiol 2019; 138:256-268. [PMID: 31866376 DOI: 10.1016/j.yjmcc.2019.12.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 12/08/2019] [Accepted: 12/10/2019] [Indexed: 01/02/2023]
Abstract
Vascular calcification (VC) is a major cause of mortality in patients with chronic kidney disease (CKD). While elevations in serum phosphorus contribute to VC, we provide evidence here for a major role of oxidative stress (OS) in VC pathogenesis without an apparent increase in serum phosphorus in early CKD. In a rat model for stage 5 CKD (CKD5), we observed 1) robust increases of VC and OS, 2) significant reductions of smooth muscle 22 alpha (SM22α) and calponin, and 3) upregulations in Runt-related transcription factor 2 (RUNX2) and collagen I in vascular smooth muscle cells (VSMCs). Inhibition of OS using MnTMPyP dramatically reduced these events without normalization of hyperphosphatemia. In CKD5 patients with VC (n = 11) but not in those without VC (n = 13), OS was significantly elevated. While the serum levels of calcium and phosphate were not altered in the animal model for early stage CKD (ECKD), OS, VC, SM22α, calponin, RUNX2, collagen I and NADPH oxidase 1 (NOX1) in VSMCs were all significantly changed. More importantly, serum (5%) derived from patients with ECKD (n = 30) or CKD5 (n = 30) induced SM22α and calponin downregulation, and RUNX2, collagen I, NOX1 upregulation along with a robust elevation of OS and calcium deposition in primary rat VSMCs. These alterations were all reduced by MnTMPyP, ML171 (a NOX1 inhibitor), and U0126 (an inhibitor of Erk signaling). Collectively, we provide a comprehensive set of evidence supporting an important role of OS in promoting VC development in CKD patients (particularly in those with ECKD); this was at least in part through induction of osteoblastic transition in VSMCs which may involve the Erk singling. Our research thus suggests that reductions in OS may prevent VC in CKD patients.
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Affiliation(s)
- Mei Huang
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Li Zheng
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China; Division of Nephrology, The Third Xiangya Hospital of the Central South University, Changsha, Hunan 410013, China
| | - Hui Xu
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Damu Tang
- Department of Medicine, McMaster University, Hamilton, ON, Canada; The Hamilton Center for Kidney Research, Hamilton, ON, Canada; Urologic Cancer Center for Research and Innovation (UCCRI), Hamilton, ON, Canada
| | - Lizhen Lin
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China
| | - Jin Zhang
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, China
| | - Cuifang Li
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China
| | - Wei Wang
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China
| | - Qiongjing Yuan
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China
| | - Lijian Tao
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China; State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410008, China
| | - Zunlong Ye
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, Hunan 410008, China; 1717 class, Chang Jun High School of Changsha, Changsha, Hunan 410002, China
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Pan W, Liang J, Tang H, Fang X, Wang F, Ding Y, Huang H, Zhang H. Differentially expressed microRNA profiles in exosomes from vascular smooth muscle cells associated with coronary artery calcification. Int J Biochem Cell Biol 2019; 118:105645. [PMID: 31733402 DOI: 10.1016/j.biocel.2019.105645] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/30/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The pathogenesis of coronary artery calcification (CAC) in coronary heart disease (CHD) is mediated by exosomes derived from vascular smooth muscle cells (VSMCs). However, little is known about their underlying mechanism. In this study, we aimed to investigate the differentially expressed miRNAs in VSMCs undergoing induced calcification. METHODS A cellular calcification model was established using the mouse VSMC line MOVAS-1. Calcium deposition was evaluated by Alizarin Red staining. Exosome sizes were determined by Nanoparticle Tracking Analysis (NTA), and exosome morphology was examined by transmission electron microscopy (TEM). The expression of exosome and calcification biomarkers was analyzed by quantitative real-time PCR (qPCR) and western blotting. Differential miRNA profiles were determined by deep sequencing and bioinformatics. Protein levels in VSMCs experiencing interference by a miR-324-3p inhibitor were detected by western blotting. RESULTS The MOVAS-1 calcification model was confirmed by Alizarin Red staining and expressional alteration of α-SMA, BMP-2, OPN, and MGP. Exosomes from the calcification model showed expression of exosomal biomarkers and regular exosome diameters, which caused significant calcification in MOVAS-1 cells. In total, 987 and 92 miRNAs were significantly upregulated and downregulated in exosomes from the cellular calcification model as compared with those from MOVAS-1 cells, respectively. Target genes of differential miRNAs were involved in various biological processes such as development, metabolism, and cellular component organization and biogenesis as well as multiple signaling pathways such as protein kinase B (AKT) signaling. The most differentially expressed miRNAs were validated by qPCR, which showed that mmu-let-7e-5p was downregulated and mmu-miR-324-3p was upregulated in exosomes from the MOVAS-1 cellular calcification model. The expression of IGF1R was increased, and the expressions of PIK3CA and MAP2K1 were reduced in MOVAS-1 transfected with a miR-324-3p inhibitor. CONCLUSION microRNA profiles were significantly altered in exosomes from VSMCs undergoing calcification.
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Affiliation(s)
- Wei Pan
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Jianwen Liang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Huili Tang
- Pediatric Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Xingrui Fang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Feng Wang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Yan Ding
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Hui Huang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China.
| | - Huanji Zhang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China.
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Disthabanchong S, Srisuwarn P. Mechanisms of Vascular Calcification in Kidney Disease. Adv Chronic Kidney Dis 2019; 26:417-426. [PMID: 31831120 DOI: 10.1053/j.ackd.2019.08.014] [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: 03/21/2019] [Revised: 08/18/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023]
Abstract
The increase in prevalence and severity of vascular calcification in chronic kidney disease is a result of complex interactions between changes in the vascular bed, mineral metabolites, and other uremic factors. Vascular calcification can occur in the intima and the media of arterial wall. Under permissive conditions, vascular smooth muscle cells (VSMCs) can transform to osteoblast-like phenotype. The membrane-bound vesicles released from transformed VSMCs and the apoptotic bodies derived from dying VSMCs serve as nucleating structures for calcium crystal formation. Alterations in the quality and the quantity of endogenous calcification inhibitors also give rise to an environment that potentiates calcification.
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Affiliation(s)
- Sinee Disthabanchong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
| | - Praopilad Srisuwarn
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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