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Luo J, Wang L, Cui C, Chen H, Zeng W, Li X. MicroRNA-19a-3p inhibits endothelial dysfunction in atherosclerosis by targeting JCAD. BMC Cardiovasc Disord 2024; 24:394. [PMID: 39080547 PMCID: PMC11287888 DOI: 10.1186/s12872-024-04063-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/19/2024] [Indexed: 08/03/2024] Open
Abstract
OBJECTIVE To examine the influences and mechanisms of MicroRNA-19a-3p (miR-19a-3p) on endothelial dysfunction in atherosclerosis. METHODS An analysis of miR-19a expression was carried out using the Gene Expression Omnibus (GEO) database. The effect of miR-19a-3p on endothelial function in HUVECs was evaluated by miR-19a-3p overexpression under TNF-α treatment. Luciferase assays were performed to explore the potential target genes. Overexpression of junctional protein associated with coronary artery disease (JCAD) was used to examine the effects of miR-19a-3p on cell adhesion, and proliferation. RESULTS MiR-19a-3p expression in endothelial cells decreased after exposure to TNF-α and/or oscillatory flow, consistent with the expression change of miR-19a-3p found in atherosclerotic plaques. Additionally, endothelial cell dysfunction and inflammation were significantly diminished by miR-19a-3p overexpression but markedly exacerbated by miR-19a-3p inhibition. MiR-19a-3p transfection significantly decreased the expression of JCAD by binding to the 3'-UTR of JCAD mRNA. Furthermore, the protective effect of miR-19a-3p against endothelial cell dysfunction and inflammation was achieved by regulating JCAD and was closely linked to the Hippo/YAP signaling pathway. CONCLUSION MiR-19a-3p expression is a crucial molecular switch in the onset of atherosclerosis and miR-19a-3p overexpression is a possible pharmacological therapeutic strategy for reversing the development of atherosclerosis.
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Affiliation(s)
- Jinque Luo
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
- College of Pharmacy, Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha, 410219, Hunan, China
| | - Ling Wang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
- College of Pharmacy, Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha, 410219, Hunan, China
| | - Chaoyue Cui
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
| | - Hongyu Chen
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
| | - Wanli Zeng
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
| | - Xin Li
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China.
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Baek KI, Ryu K. Role of Flow-Sensitive Endothelial Genes in Atherosclerosis and Antiatherogenic Therapeutics Development. J Cardiovasc Transl Res 2024; 17:609-623. [PMID: 38010480 DOI: 10.1007/s12265-023-10463-w] [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: 09/13/2023] [Accepted: 11/14/2023] [Indexed: 11/29/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease that is the underlying cause of cardiovascular disease which initiates from endothelial dysfunction from genetic and environmental risk factors, including biomechanical forces: blood flow. Endothelial cells (ECs) lining the inner arterial wall regions exposed to disturbed flow are prone to atherosclerosis development, whereas the straight regions exposed to stable flow are spared from the disease. These flow patterns induce genome- and epigenome-wide changes in gene expression in ECs. Through the sweeping changes in gene expression, disturbed flow reprograms ECs from athero-protected cell types under the stable flow condition to pro-atherogenic cell conditions. The pro-atherogenic changes induced by disturbed flow, in combination with additional risk factors such as hypercholesterolemia, lead to the progression of atherosclerosis. The flow-sensitive genes and proteins are critical in understanding the mechanisms and serve as novel targets for antiatherogenic therapeutics.
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Affiliation(s)
- Kyung In Baek
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Kitae Ryu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
- Department of Biotechnology, The University of Suwon, 17, Wauan-Gil, Bongdam-Eup, Hwaseong-Si, Gyeonggi-Do, 18323, Republic of Korea.
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Pinto TS, Feltran GDS, Fernandes CJDC, de Camargo Andrade AF, Coque ADC, Silva SL, Abuderman AA, Zambuzzi WF, Foganholi da Silva RA. Epigenetic changes in shear-stressed endothelial cells. Cell Biol Int 2024; 48:665-681. [PMID: 38420868 DOI: 10.1002/cbin.12138] [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: 03/19/2023] [Revised: 01/18/2024] [Accepted: 01/28/2024] [Indexed: 03/02/2024]
Abstract
Epigenetic changes, particularly histone compaction modifications, have emerged as critical regulators in the epigenetic pathway driving endothelial cell phenotype under constant exposure to laminar forces induced by blood flow. However, the underlying epigenetic mechanisms governing endothelial cell behavior in this context remain poorly understood. To address this knowledge gap, we conducted in vitro experiments using human umbilical vein endothelial cells subjected to various tensional forces simulating pathophysiological blood flow shear stress conditions, ranging from normotensive to hypertensive forces. Our study uncovers a noteworthy observation wherein endothelial cells exposed to high shear stress demonstrate a decrease in the epigenetic marks H3K4ac and H3K27ac, accompanied by significant alterations in the levels of HDAC (histone deacetylase) proteins. Moreover, we demonstrate a negative regulatory effect of increased shear stress on HOXA13 gene expression and a concomitant increase in the expression of the long noncoding RNA, HOTTIP, suggesting a direct association with the suppression of HOXA13. Collectively, these findings represent the first evidence of the role of histone-related epigenetic modifications in modulating chromatin compaction during mechanosignaling of endothelial cells in response to elevated shear stress forces. Additionally, our results highlight the importance of understanding the physiological role of HOXA13 in vascular biology and hypertensive patients, emphasizing the potential for developing small molecules to modulate its activity. These findings warrant further preclinical investigations and open new avenues for therapeutic interventions targeting epigenetic mechanisms in hypertensive conditions.
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Affiliation(s)
- Thaís Silva Pinto
- Lab. of Bioassays and Cellular Dynamics, Department of Chemical and Biological Sciences, Institute of Biosciences, Paulista State University-UNESP, Botucatu, São Paulo, Brazil
| | - Geórgia da Silva Feltran
- Lab. of Bioassays and Cellular Dynamics, Department of Chemical and Biological Sciences, Institute of Biosciences, Paulista State University-UNESP, Botucatu, São Paulo, Brazil
| | - Célio Júnior da C Fernandes
- Lab. of Bioassays and Cellular Dynamics, Department of Chemical and Biological Sciences, Institute of Biosciences, Paulista State University-UNESP, Botucatu, São Paulo, Brazil
| | - Amanda Fantini de Camargo Andrade
- Lab. of Bioassays and Cellular Dynamics, Department of Chemical and Biological Sciences, Institute of Biosciences, Paulista State University-UNESP, Botucatu, São Paulo, Brazil
| | - Alex de Camargo Coque
- Epigenetic Study Center and Gene Regulation-CEEpiRG, Program in Environmental and Experimental Pathology, Paulista University, São Paulo, São Paulo, Brazil
| | - Simone L Silva
- School of Dentistry, University of Taubaté, Taubaté, São Paulo, Brazil
| | - Abdulwahab A Abuderman
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, Riyadh, Saudi Arabia
| | - Willian F Zambuzzi
- Lab. of Bioassays and Cellular Dynamics, Department of Chemical and Biological Sciences, Institute of Biosciences, Paulista State University-UNESP, Botucatu, São Paulo, Brazil
| | - Rodrigo A Foganholi da Silva
- Epigenetic Study Center and Gene Regulation-CEEpiRG, Program in Environmental and Experimental Pathology, Paulista University, São Paulo, São Paulo, Brazil
- School of Dentistry, University of Taubaté, Taubaté, São Paulo, Brazil
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Shen MZ, Zhang Y, Wu F, Shen MZ, Liang JL, Zhang XL, Liu XJ, Li XS, Wang RS. MicroRNA-298 determines the radio-resistance of colorectal cancer cells by directly targeting human dual-specificity tyrosine(Y)-regulated kinase 1A. World J Gastrointest Oncol 2024; 16:1453-1464. [PMID: 38660649 PMCID: PMC11037043 DOI: 10.4251/wjgo.v16.i4.1453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/31/2023] [Accepted: 02/02/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer (CRC); yet, the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission. AIM To elucidate the role played by microRNA-298 (miR-298) in CRC radio-resistance. METHODS To establish a radio-resistant CRC cell line, HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period. The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR, and protein expression determination was realized through Western blotting. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay. Radio-induced apoptosis was discerned through flow cytometry analysis. RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells. MiR-298 emerged as a key determinant of cell survival following radiation exposure, as its overexpression led to a notable reduction in radiation-induced apoptosis. Intriguingly, miR-298 expression exhibited a strong correlation with CRC cell viability. Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A (DYRK1A) as miR-298's direct target. CONCLUSION Taken together, our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation, thereby positioning miR-298 as a promising candidate for mitigating radio-resistance in CRC.
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Affiliation(s)
- Mei-Zhu Shen
- Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yong Zhang
- Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fang Wu
- Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Mei-Zhen Shen
- Department of Radiotherapy, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jun-Lin Liang
- Department of Colorectal Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Long Zhang
- Department of Colorectal Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Jian Liu
- Department of Colorectal Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xin-Shu Li
- Department of Clinical Medicine, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ren-Sheng Wang
- Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Searles CD. MicroRNAs and Cardiovascular Disease Risk. Curr Cardiol Rep 2024; 26:51-60. [PMID: 38206553 PMCID: PMC10844442 DOI: 10.1007/s11886-023-02014-1] [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] [Accepted: 12/10/2023] [Indexed: 01/12/2024]
Abstract
PURPOSE OF REVIEW MicroRNAs (miRNAs)-short, non-coding RNAs-play important roles in almost all aspects of cardiovascular biology, and changes in intracellular miRNA expression are indicative of cardiovascular disease development and progression. Extracellular miRNAs, which are easily measured in blood and can be reflective of changes in intracellular miRNA levels, have emerged as potential non-invasive biomarkers for disease. This review summarizes current knowledge regarding miRNAs as biomarkers for assessing cardiovascular disease risk and prognosis. RECENT FINDINGS Numerous studies over the last 10-15 years have identified associations between extracellular miRNA profiles and cardiovascular disease, supporting the potential use of extracellular miRNAs as biomarkers for risk stratification. However, clinical application of extracellular miRNA profiles has been hampered by poor reproducibility and inter-study variability that is due largely to methodological differences between studies. While recent studies indicate that circulating extracellular miRNAs are promising biomarkers for cardiovascular disease, evidence for clinical implementation is lacking. This highlights the need for larger, well-designed studies that use standardized methods for sample preparation, miRNA isolation, quantification, and normalization.
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Affiliation(s)
- Charles D Searles
- Emory University School of Medicine and Atlanta VA Health Care System, 1670 Clairmont Road, Decatur, GA, 30033, USA.
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Shaheen N, Shaheen A, Diab RA, Desouki MT. MicroRNAs (miRNAs) role in hypertension: pathogenesis and promising therapeutics. Ann Med Surg (Lond) 2024; 86:319-328. [PMID: 38222760 PMCID: PMC10783350 DOI: 10.1097/ms9.0000000000001498] [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: 09/24/2023] [Accepted: 11/02/2023] [Indexed: 01/16/2024] Open
Abstract
Background MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating various cellular processes, including cell proliferation, differentiation, apoptosis, and disease development. Recent studies have highlighted the importance of miRNAs in the development and progression of essential hypertension, a common form of high blood pressure that affects millions of individuals worldwide. The molecular mechanisms by which miRNAs regulate hypertension are complex and multifaceted. MiRNAs target the 3' untranslated regions of mRNA molecules, thereby regulating the synthesis of specific proteins involved in cardiovascular function. For instance, miRNAs are known to regulate the expression of genes involved in blood vessel tone, cardiac function, and inflammation. The growing body of research on miRNAs in hypertension has highlighted their potential as therapeutic targets for managing this condition. Studies have shown that miRNA-based therapies can modulate the expression of key genes involved in hypertension, leading to improvements in blood pressure and cardiovascular function. However, more research is needed to fully understand the mechanisms of miRNA-mediated hypertension and to develop effective therapeutic strategies. Conclusions In summary, this review highlights the current understanding of the role of miRNAs in essential hypertension, including their molecular mechanisms and potential therapeutic applications. Further research is needed to fully understand the impact of miRNAs on hypertension and to develop new treatments for this common and debilitating condition.
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Affiliation(s)
- Nour Shaheen
- Faculty of Medicine, Alexandria University, Alexandria
| | - Ahmed Shaheen
- Faculty of Medicine, Alexandria University, Alexandria
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7
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Tamargo IA, Baek KI, Kim Y, Park C, Jo H. Flow-induced reprogramming of endothelial cells in atherosclerosis. Nat Rev Cardiol 2023; 20:738-753. [PMID: 37225873 PMCID: PMC10206587 DOI: 10.1038/s41569-023-00883-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/25/2023] [Indexed: 05/26/2023]
Abstract
Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the success of treatments with cholesterol-lowering drugs and drug-eluting stents, raising the need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude oscillatory shear stress. By contrast, straight arterial regions exposed to stable flow, which is associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial cell responses. Flow potently regulates structural, functional, transcriptomic, epigenomic and metabolic changes in endothelial cells through mechanosensors and mechanosignal transduction pathways. A study using single-cell RNA sequencing and chromatin accessibility analysis in a mouse model of flow-induced atherosclerosis demonstrated that disturbed flow reprogrammes arterial endothelial cells in situ from healthy phenotypes to diseased ones characterized by endothelial inflammation, endothelial-to-mesenchymal transition, endothelial-to-immune cell-like transition and metabolic changes. In this Review, we discuss this emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a potential pro-atherogenic mechanism. Defining the flow-induced mechanisms through which endothelial cells are reprogrammed to promote atherosclerosis is a crucial area of research that could lead to the identification of novel therapeutic targets to combat the high prevalence of atherosclerotic disease.
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Affiliation(s)
- Ian A Tamargo
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA
- Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA, USA
| | - Kyung In Baek
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA
| | - Yerin Kim
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA
| | - Christian Park
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA
| | - Hanjoong Jo
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
- Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA, USA.
- Department of Medicine, Emory University School, Atlanta, GA, USA.
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Xie B, Zhao L, Zhang Z, Zhou C, Tian Y, Kang Y, Chen J, Wei H, Li L. CADM1 impairs the effect of miR-1246 on promoting cell cycle progression in chemo-resistant leukemia cells. BMC Cancer 2023; 23:955. [PMID: 37814227 PMCID: PMC10561441 DOI: 10.1186/s12885-023-11458-1] [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: 03/15/2023] [Accepted: 09/28/2023] [Indexed: 10/11/2023] Open
Abstract
The interruption of normal cell cycle execution acts as an important part to the development of leukemia. It was reported that microRNAs (miRNAs) were closely related to tumorigenesis and progression, and their aberrant expression had been demonstrated to play a crucial role in numerous types of cancer. Our previous study showed that miR-1246 was preferentially overexpressed in chemo-resistant leukemia cell lines, and participated in process of cell cycle progression and multidrug resistant regulation. However, the underlying mechanism remains unclear. In present study, bioinformatics prediction and dual luciferase reporter assay indicated that CADM1 was a direct target of miR-1246. Evidently decreased expression of CADM1 was observed in relapsed primary leukemia patients and chemo-resistant cell lines. Our results furtherly proved that inhibition of miR-1246 could significantly enhance drug sensitivity to Adriamycin (ADM), induce cell cycle arrest at G0/G1 phase, promote cell apoptosis, and relieve its suppression on CADM1 in K562/ADM and HL-60/RS cells. Interference with CADM1 could reduce the increased drug sensitivity induced by miR-1246 inhibition, and notably restore drug resistance by promoting cell cycle progression and cell survival via regulating CDKs/Cyclins complexes in chemo-resistant leukemia cells. Above all, our results demonstrated that CADM1 attenuated the role of miR-1246 in promoting cell cycle progression and cell survival, thus influencing multidrug resistance within chemo-resistant leukemia cells via CDKs/Cyclins. Higher expression of miR-1246 and lower expression of CADM1 might be risk factors for leukemia.
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Affiliation(s)
- Bei Xie
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, No. 199 Donggang West Road, Lanzhou, 730000, Gansu, China.
| | - Lei Zhao
- Shaanxi Meili Omni-Honesty Animal Health Co., Ltd, Xi'an, 710000, Shaanxi, China
| | - Zhewen Zhang
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, No. 199 Donggang West Road, Lanzhou, 730000, Gansu, China
| | - Cunmin Zhou
- The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Ye Tian
- The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Yingying Kang
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, No. 199 Donggang West Road, Lanzhou, 730000, Gansu, China
| | - Jing Chen
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, No. 199 Donggang West Road, Lanzhou, 730000, Gansu, China
| | - Hulai Wei
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, No. 199 Donggang West Road, Lanzhou, 730000, Gansu, China.
| | - Linjing Li
- The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China.
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Sum H, Brewer AC. Epigenetic modifications as therapeutic targets in atherosclerosis: a focus on DNA methylation and non-coding RNAs. Front Cardiovasc Med 2023; 10:1183181. [PMID: 37304954 PMCID: PMC10248074 DOI: 10.3389/fcvm.2023.1183181] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/02/2023] [Indexed: 06/13/2023] Open
Abstract
Significant progress in the diagnosis and treatment of cardiovascular disease (CVD) has been made in the past decade, yet it remains a leading cause of morbidity and mortality globally, claiming an estimated 17.9 million deaths per year. Although encompassing any condition that affects the circulatory system, including thrombotic blockage, stenosis, aneurysms, blood clots and arteriosclerosis (general hardening of the arteries), the most prevalent underlying hallmark of CVD is atherosclerosis; the plaque-associated arterial thickening. Further, distinct CVD conditions have overlapping dysregulated molecular and cellular characteristics which underlie their development and progression, suggesting some common aetiology. The identification of heritable genetic mutations associated with the development of atherosclerotic vascular disease (AVD), in particular resulting from Genome Wide Association Studies (GWAS) studies has significantly improved the ability to identify individuals at risk. However, it is increasingly recognised that environmentally-acquired, epigenetic changes are key factors associated with atherosclerosis development. Increasing evidence suggests that these epigenetic changes, most notably DNA methylation and the misexpression of non-coding, microRNAs (miRNAs) are potentially both predictive and causal in AVD development. This, together with their reversible nature, makes them both useful biomarkers for disease and attractive therapeutic targets potentially to reverse AVD progression. We consider here the association of aberrant DNA methylation and dysregulated miRNA expression with the aetiology and progression of atherosclerosis, and the potential development of novel cell-based strategies to target these epigenetic changes therapeutically.
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Hu Q, Huang T. Regulation of the Cell Cycle by ncRNAs Affects the Efficiency of CDK4/6 Inhibition. Int J Mol Sci 2023; 24:ijms24108939. [PMID: 37240281 DOI: 10.3390/ijms24108939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Cyclin-dependent kinases (CDKs) regulate cell division at multiple levels. Aberrant proliferation induced by abnormal cell cycle is a hallmark of cancer. Over the past few decades, several drugs that inhibit CDK activity have been created to stop the development of cancer cells. The third generation of selective CDK4/6 inhibition has proceeded into clinical trials for a range of cancers and is quickly becoming the backbone of contemporary cancer therapy. Non-coding RNAs, or ncRNAs, do not encode proteins. Many studies have demonstrated the involvement of ncRNAs in the regulation of the cell cycle and their abnormal expression in cancer. By interacting with important cell cycle regulators, preclinical studies have demonstrated that ncRNAs may decrease or increase the treatment outcome of CDK4/6 inhibition. As a result, cell cycle-associated ncRNAs may act as predictors of CDK4/6 inhibition efficacy and perhaps present novel candidates for tumor therapy and diagnosis.
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Affiliation(s)
- Qingyi Hu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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11
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Davis MJ, Earley S, Li YS, Chien S. Vascular mechanotransduction. Physiol Rev 2023; 103:1247-1421. [PMID: 36603156 PMCID: PMC9942936 DOI: 10.1152/physrev.00053.2021] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 09/26/2022] [Accepted: 10/04/2022] [Indexed: 01/07/2023] Open
Abstract
This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Scott Earley
- Department of Pharmacology, University of Nevada, Reno, Nevada
| | - Yi-Shuan Li
- Department of Bioengineering, University of California, San Diego, California
- Institute of Engineering in Medicine, University of California, San Diego, California
| | - Shu Chien
- Department of Bioengineering, University of California, San Diego, California
- Institute of Engineering in Medicine, University of California, San Diego, California
- Department of Medicine, University of California, San Diego, California
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12
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Almaghrbi H, Giordo R, Pintus G, Zayed H. Non-coding RNAs as biomarkers of myocardial infarction. Clin Chim Acta 2023; 540:117222. [PMID: 36627010 DOI: 10.1016/j.cca.2023.117222] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/04/2023] [Accepted: 01/04/2023] [Indexed: 01/08/2023]
Abstract
Non-coding RNAs (ncRNAs) encompass a family of ubiquitous RNA molecules that lack protein-coding potential and have tissue-specific expression. A significant body of evidence indicates that ncRNA's aberrant expression plays a critical role in disease onset and development. NcRNAs' biochemical characteristics such as disease-associated concentration changes, structural stability, and high abundance in body fluids make them promising prognostic and diagnostic biomarkers. Myocardial infarction (MI) is a leading cause of mortality worldwide. Acute myocardial infarction (AMI), the term in use to describe MI's early phase, is generally diagnosed by physical examination, electrocardiogram (ECG), and the presence of specific biomarkers. In this regard, compared to standard MI biomarkers, such as the cardiac troponin isoforms (cTnT & cTnI) and the Creatinine Kinase (CK), ncRNAs appears to provide better sensitivity and specificity, ensuring a rapid and correct diagnosis, an earlier treatment, and consequently a good prognosis for the patients. This review aims to summarize and discuss the most promising and recent data on the potential clinical use of circulating ncRNAs as MI biomarkers. Specifically, we focused primarily on miRNAs and lncRNAs, highlighting their significant specificity and sensitivity, discussing their limitations, and suggesting possible overcoming approaches.
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Affiliation(s)
- Heba Almaghrbi
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Roberta Giordo
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, 505055 Dubai, United Arab Emirates
| | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, 07100 Sassari, Italy; Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research, University of Sharjah, University City Rd, Sharjah 27272, United Arab Emirates.
| | - Hatem Zayed
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
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13
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Königstein K, Meier J, Angst T, Maurer DJ, Kröpfl JM, Carrard J, Infanger D, Baumann S, Bischofsberger I, Harder M, Jäggi Y, Wettach S, Hanssen H, Schmidt-Trucksäss A. VascuFit: vascular effects of non-linear periodized exercise training in sedentary adults with elevated cardiovascular risk - protocol for a randomized controlled trial. BMC Cardiovasc Disord 2022; 22:449. [PMID: 36303113 PMCID: PMC9615395 DOI: 10.1186/s12872-022-02905-1] [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: 08/16/2022] [Accepted: 10/17/2022] [Indexed: 11/12/2022] Open
Abstract
Background Early vascular aging (EVA) is increasingly prevalent in the general population. Exercise is important for primary cardiovascular prevention, but often insufficient due to ineffective training methods and a lack of biomarkers suitable to monitor its vascular effects. VascuFit will assess the effectiveness of non-linear periodized aerobic exercise (NLPE) in a non-athletic sedentary population to improve both established and promising biomarkers of EVA. Methods Forty-three sedentary adults, aged 40–60 years, with elevated cardiovascular risk will either engage in 8 weeks of ergometer-based NLPE (n = 28) or receive standard exercise recommendations (n = 15). The primary outcome will be the change of brachial-arterial flow-mediated dilation (baFMD) after versus before the intervention. Secondary outcomes will be the change in static vessel analysis (SVA; clinical biomarker of microvascular endothelial function), endomiRs (microRNAs regulating key molecular pathways of endothelial cell homeostasis) and circulating cellular markers of endothelial function (mature endothelial cells, endothelial progenitor cells). Tertiary outcomes will be the change in sphingolipidome, maximum oxygen capacity, and traditional cardiovascular risk factors (blood pressure, triglycerides, cholesterol, fasting glucose, high-sensitivity C-reactive protein). Discussion We expect an improvement of baFMD of at least 2.6% and significant pre-post intervention differences of SVA and endomiRs as well as of the tertiary outcomes in the intervention group. VascuFit may demonstrate the effectiveness of NLPE to improve endothelial function, thus vascular health, in the general sedentary population. Furthermore, this project might demonstrate the potential of selected molecular and cellular biomarkers to monitor endothelial adaptations to aerobic exercise. Trial registration The trial was registered on www.clinicaltrials.gov (NCT05235958) in February 11th 2022.
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Affiliation(s)
- Karsten Königstein
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland. .,Clinic for Children and Adolescent Medicine, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
| | - Jennifer Meier
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Thomas Angst
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Debbie J Maurer
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland.,Swiss Research Institute for Sports Medicine (SRISM), Davos, Switzerland
| | - Julia M Kröpfl
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Justin Carrard
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Denis Infanger
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Sandra Baumann
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Imerio Bischofsberger
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Marc Harder
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Yves Jäggi
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Sabrina Wettach
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Henner Hanssen
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Arno Schmidt-Trucksäss
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
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14
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Jiang M, Ding H, Huang Y, Wang L. Shear Stress and Metabolic Disorders-Two Sides of the Same Plaque. Antioxid Redox Signal 2022; 37:820-841. [PMID: 34148374 DOI: 10.1089/ars.2021.0126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Significance: Shear stress and metabolic disorder are the two sides of the same atherosclerotic coin. Atherosclerotic lesions are prone to develop at branches and curvatures of arteries, which are exposed to oscillatory and low shear stress exerted by blood flow. Meanwhile, metabolic disorders are pivotal contributors to the formation and advancement of atherosclerotic plaques. Recent Advances: Accumulated evidence has provided insight into the impact and mechanisms of biomechanical forces and metabolic disorder on atherogenesis, in association with mechanotransduction, epigenetic regulation, and so on. Moreover, recent studies have shed light on the cross talk between the two drivers of atherosclerosis. Critical Issues: There are extensive cross talk and interactions between shear stress and metabolic disorder during the pathogenesis of atherosclerosis. The communications may amplify the proatherogenic effects through increasing oxidative stress and inflammation. Nonetheless, the precise mechanisms underlying such interactions remain to be fully elucidated as the cross talk network is considerably complex. Future Directions: A better understanding of the cross talk network may confer benefits for a more comprehensive clinical management of atherosclerosis. Critical mediators of the cross talk may serve as promising therapeutic targets for atherosclerotic vascular diseases, as they can inhibit effects from both sides of the plaque. Hence, further in-depth investigations with advanced omics approaches are required to develop novel and effective therapeutic strategies against atherosclerosis. Antioxid. Redox Signal. 37, 820-841.
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Affiliation(s)
- Minchun Jiang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Huanyu Ding
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yu Huang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Li Wang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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15
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Sufianov A, Begliarzade S, Kudriashov V, Nafikova R, Ilyasova T, Liang Y. Role of miRNAs in vascular development. Noncoding RNA Res 2022; 8:1-7. [PMID: 36262425 PMCID: PMC9552023 DOI: 10.1016/j.ncrna.2022.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/27/2022] Open
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16
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Chen X, Shi C, Wang Y, Yu H, Zhang Y, Zhang J, Li P, Gao J. The mechanisms of glycolipid metabolism disorder on vascular injury in type 2 diabetes. Front Physiol 2022; 13:952445. [PMID: 36117707 PMCID: PMC9473659 DOI: 10.3389/fphys.2022.952445] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Patients with diabetes have severe vascular complications, such as diabetic nephropathy, diabetic retinopathy, cardiovascular disease, and neuropathy. Devastating vascular complications lead to increased mortality, blindness, kidney failure, and decreased overall quality of life in people with type 2 diabetes (T2D). Glycolipid metabolism disorder plays a vital role in the vascular complications of T2D. However, the specific mechanism of action remains to be elucidated. In T2D patients, vascular damage begins to develop before insulin resistance and clinical diagnosis. Endothelial dysregulation is a significant cause of vascular complications and the early event of vascular injury. Hyperglycemia and hyperlipidemia can trigger inflammation and oxidative stress, which impair endothelial function. Furthermore, during the pathogenesis of T2D, epigenetic modifications are aberrant and activate various biological processes, resulting in endothelial dysregulation. In the present review, we provide an overview and discussion of the roles of hyperglycemia- and hyperlipidemia-induced endothelial dysfunction, inflammatory response, oxidative stress, and epigenetic modification in the pathogenesis of T2D. Understanding the connections of glucotoxicity and lipotoxicity with vascular injury may reveal a novel potential therapeutic target for diabetic vascular complications.
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Affiliation(s)
- Xiatian Chen
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | | | - Yin Wang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Hua Yu
- The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao, China
| | - Yu Zhang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jiaxuan Zhang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Peifeng Li
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- *Correspondence: Peifeng Li, ; Jinning Gao,
| | - Jinning Gao
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- *Correspondence: Peifeng Li, ; Jinning Gao,
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17
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Abstract
Mechanical variables such as stiffness, stress, strain, and fluid shear stress are central to tissue functions, thus, must be maintained within the proper range. Mechanics are especially important in the cardiovascular system and lung, the functions of which are essentially mechanical. Mechanical homeostasis is characterized by negative feedback in which deviations from the optimal value or set point activates mechanisms to return the system to the correct range. In chronic diseases, homeostatic mechanisms are generally overcome or replaced with positive feedback loops that promote disease progression. Recent work has shown that microRNAs (miRNAs) are essential to mechanical homeostasis in a number of biological systems and that perturbations to miRNA biogenesis play key roles in cardiovascular and pulmonary diseases. In this review, we integrate current knowledge of miRNAs in mechanical homeostasis and how these mechanisms are altered in disease.
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Affiliation(s)
- Jeremy A Herrera
- The Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Martin A Schwartz
- Yale Cardiovascular Research Center and Departments of Internal Medicine (Cardiology), Cell Biology, and Biomedical Engineering, Yale School of Medicine, New Haven 06511, Connecticut, USA
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18
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Chung J, Kim KH, Yu N, An SH, Lee S, Kwon K. Fluid Shear Stress Regulates the Landscape of microRNAs in Endothelial Cell-Derived Small Extracellular Vesicles and Modulates the Function of Endothelial Cells. Int J Mol Sci 2022; 23:ijms23031314. [PMID: 35163238 PMCID: PMC8836123 DOI: 10.3390/ijms23031314] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 12/10/2022] Open
Abstract
Blood fluid shear stress (FSS) modulates endothelial function and vascular pathophysiology. The small extracellular vesicles (sEVs) such as exosomes are potent mediators of intercellular communication, and their contents reflect cellular stress. Here, we explored the miRNA profiles in endothelial cells (EC)-derived sEVs (EC-sEVs) under atheroprotective laminar shear stress (LSS) and atheroprone low-oscillatory shear stress (OSS) and conducted a network analysis to identify the main biological processes modulated by sEVs’ miRNAs. The EC-sEVs were collected from culture media of human umbilical vein endothelial cells exposed to atheroprotective LSS (20 dyne/cm2) and atheroprone OSS (±5 dyne/cm2). We explored the miRNA profiles in FSS-induced EC-sEVs (LSS-sEVs and OSS-sEVs) and conducted a network analysis to identify the main biological processes modulated by sEVs’ miRNAs. In vivo studies were performed in a mouse model of partial carotid ligation. The sEVs’ miRNAs-targeted genes were enriched for endothelial activation such as angiogenesis, cell migration, and vascular inflammation. OSS-sEVs promoted tube formation, cell migration, monocyte adhesion, and apoptosis, and upregulated the expression of proteins that stimulate these biological processes. FSS-induced EC-sEVs had the same effects on endothelial mechanotransduction signaling as direct stimulation by FSS. In vivo studies showed that LSS-sEVs reduced the expression of pro-inflammatory genes, whereas OSS-sEVs had the opposite effect. Understanding the landscape of EC-exosomal miRNAs regulated by differential FSS patterns, this research establishes their biological functions on a system level and provides a platform for modulating the overall phenotypic effects of sEVs.
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Affiliation(s)
- Jihwa Chung
- Exollence Biotechnology Co., Ltd., Seoul 07985, Korea; (J.C.); (K.H.K.); (S.H.A.)
| | - Kyoung Hwa Kim
- Exollence Biotechnology Co., Ltd., Seoul 07985, Korea; (J.C.); (K.H.K.); (S.H.A.)
| | - Namhee Yu
- Research Institute, National Cancer Center, Goyangsi 10408, Korea;
| | - Shung Hyun An
- Exollence Biotechnology Co., Ltd., Seoul 07985, Korea; (J.C.); (K.H.K.); (S.H.A.)
| | - Sanghyuk Lee
- Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea;
| | - Kihwan Kwon
- Exollence Biotechnology Co., Ltd., Seoul 07985, Korea; (J.C.); (K.H.K.); (S.H.A.)
- Department of Internal Medicine, Cardiology Division, School of Medicine, Ewha Womans University, Seoul 07985, Korea
- Correspondence: ; Tel.: +82-2-2650-2640
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19
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De Rosa S, Iaconetti C, Eyileten C, Yasuda M, Albanese M, Polimeni A, Sabatino J, Sorrentino S, Postula M, Indolfi C. Flow-Responsive Noncoding RNAs in the Vascular System: Basic Mechanisms for the Clinician. J Clin Med 2022; 11:jcm11020459. [PMID: 35054151 PMCID: PMC8777617 DOI: 10.3390/jcm11020459] [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: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/10/2022] Open
Abstract
The vascular system is largely exposed to the effect of changing flow conditions. Vascular cells can sense flow and its changes. Flow sensing is of pivotal importance for vascular remodeling. In fact, it influences the development and progression of atherosclerosis, controls its location and has a major influx on the development of local complications. Despite its importance, the research community has traditionally paid scarce attention to studying the association between different flow conditions and vascular biology. More recently, a growing body of evidence has been accumulating, revealing that ncRNAs play a key role in the modulation of several biological processes linking flow-sensing to vascular pathophysiology. This review summarizes the most relevant evidence on ncRNAs that are directly or indirectly responsive to flow conditions to the benefit of the clinician, with a focus on the underpinning mechanisms and their potential application as disease biomarkers.
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Affiliation(s)
- Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
- Correspondence: (S.D.R.); (C.I.)
| | - Claudio Iaconetti
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 02-097 Warsaw, Poland; (C.E.); (M.P.)
| | - Masakazu Yasuda
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
| | - Michele Albanese
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
| | - Alberto Polimeni
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
| | - Jolanda Sabatino
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
| | - Sabato Sorrentino
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 02-097 Warsaw, Poland; (C.E.); (M.P.)
| | - Ciro Indolfi
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (C.I.); (M.Y.); (M.A.); (A.P.); (J.S.); (S.S.)
- Mediterranea Cardiocentro, 80122 Naples, Italy
- Correspondence: (S.D.R.); (C.I.)
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20
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Huang Y, Wang L, Chen Y, Han H, Li Q. Lipoic Acid-Modified Oligoethyleneimine-Mediated miR-34a Delivery to Achieve the Anti-Tumor Efficacy. Molecules 2021; 26:molecules26164827. [PMID: 34443415 PMCID: PMC8400101 DOI: 10.3390/molecules26164827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/03/2021] [Accepted: 08/09/2021] [Indexed: 11/16/2022] Open
Abstract
MiR-34a, an important tumor suppressor, has been demonstrated to possess great potential in tumor gene therapy. To achieve the upregulation of miR-34a expression level, an oligoethyleneimine (OEI) derivative was constructed and employed as the carrier through the modification with lipoic acid (LA), namely LA-OEI. In contrast to OEI, the derivative LA-OEI exhibited superior transfection efficiency measured by confocal laser scanning microscopy and flow cytometry, owing to rapid cargo release in the disulfide bond-based reduction sensitive pattern. The anti-proliferation and anti-migration effects were tested after the miR-34a transfection to evaluate the anti-tumor response, using human cervical carcinoma cell line HeLa as a model. The delivery of LA-OEI/miR-34a nanoparticles could achieve obvious anti-proliferative effect caused by the induction of cell apoptosis and cell cycle arrest at G1 phase. In addition, it could inhibit the migration of tumor cells via the downregulation of MMP-9 and Notch-1 level. Overall, the LA-OEI-mediated miR-34a delivery was potential to be used as an effective way in the tumor gene therapy.
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Affiliation(s)
| | | | | | - Haobo Han
- Correspondence: (H.H.); (Q.L.); Tel.: +86-431-85155201 (H.H.); +86-431-85155200 (Q.L.)
| | - Quanshun Li
- Correspondence: (H.H.); (Q.L.); Tel.: +86-431-85155201 (H.H.); +86-431-85155200 (Q.L.)
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21
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Van Guilder GP, Preston CC, Munce TA, Faustino RS. Impacts of circulating microRNAs in exercise-induced vascular remodeling. Am J Physiol Heart Circ Physiol 2021; 320:H2401-H2415. [PMID: 33989080 DOI: 10.1152/ajpheart.00894.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cardiovascular adaptation underlies all athletic training modalities, with a variety of factors contributing to overall response during exercise-induced stimulation. In this regard the role of circulating biomarkers is a well-established and invaluable tool for monitoring cardiovascular function. Specifically, novel biomarkers such as circulating cell free DNA and RNA are now becoming attractive tools for monitoring cardiovascular function with the advent of next generation technologies that can provide unprecedented precision and resolution of these molecular signatures, paving the way for novel diagnostic and prognostic avenues to better understand physiological remodeling that occurs in trained versus untrained states. In particular, microRNAs are a species of regulatory RNAs with pleiotropic effects on multiple pathways in tissue-specific manners. Furthermore, the identification of cell free microRNAs within peripheral circulation represents a distal signaling mechanism that is just beginning to be explored via a diversity of molecular and bioinformatic approaches. This article provides an overview of the emerging field of sports/performance genomics with a focus on the role of microRNAs as novel functional diagnostic and prognostic tools, and discusses present knowledge in the context of athletic vascular remodeling. This review concludes with current advantages and limitations, touching upon future directions and implications for applying contemporary systems biology knowledge of exercise-induced physiology to better understand how disruption can lead to pathology.
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Affiliation(s)
- Gary P Van Guilder
- Vascular Protection Research Laboratory, Exercise & Sport Science Department, Western Colorado University, Gunnison, Colorado
| | - Claudia C Preston
- Genetics and Genomics Group, Sanford Research, Sioux Falls, South Dakota
| | - Thayne A Munce
- Environmental Influences on Health & Disease Group, Sanford Research, Sioux Falls, South Dakota.,Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota
| | - Randolph S Faustino
- Genetics and Genomics Group, Sanford Research, Sioux Falls, South Dakota.,Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota
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22
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Oladejo AO, Li Y, Wu X, Imam BH, Shen W, Ding XZ, Wang S, Yan Z. MicroRNAome: Potential and Veritable Immunomolecular Therapeutic and Diagnostic Baseline for Lingering Bovine Endometritis. Front Vet Sci 2020; 7:614054. [PMID: 33426032 PMCID: PMC7785807 DOI: 10.3389/fvets.2020.614054] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 11/18/2020] [Indexed: 12/28/2022] Open
Abstract
The bovine endometrium is a natural pathogen invasion barrier of the uterine tissues' endometrial epithelial cells that can resist foreign pathogen invasion by controlling the inflammatory immune response. Some pathogens suppress the innate immune system of the endometrium, leading to prolonged systemic inflammatory response through the blood circulation or cellular degradation resulting in bovine endometritis by bacterial endotoxins. The microRNA (miRNA) typically involves gene expression in multicellular organisms in post-transcription regulation by affecting both the stability and the translation of messenger RNA. Accumulated evidence suggests that miRNAs are important regulators of genes in several cellular processes. They are a class of endogenous non-coding RNAs, which play pivotal roles in the inflammatory response of reproductive diseases. Studies confirmed that miRNAs play a key regulatory role in various inflammatory diseases by mediating the molecular mechanism of inflammatory cytokines via signal pathways. It implicates some miRNAs in the occurrence of bovine endometritis, resorting to regulating the activities of some inflammatory cytokines, chemokine, differentially expressed genes, and protein through modulating of specific cellular signal pathways functions. This review dwells on improving the knowledge of the role of miRNAs involvement in inflammatory response as to early diagnosis, control, and prevention of bovine endometritis and consequently enlighten on the molecular improvement of the genes coded by various differentially expressed miRNA through the need to adopt recent genetic technologies and the development of new pharmaceutical preparations.
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Affiliation(s)
- Ayodele Olaolu Oladejo
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China.,Department of Animal Health Technology, Oyo State College of Agriculture and Technology, Igbo-Ora, Nigeria
| | - Yajuan Li
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Xiaohu Wu
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Bereket Habte Imam
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Wenxiang Shen
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Xue Zhi Ding
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Shengyi Wang
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Zuoting Yan
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
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23
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Sonmez UM, Cheng YW, Watkins SC, Roman BL, Davidson LA. Endothelial cell polarization and orientation to flow in a novel microfluidic multimodal shear stress generator. LAB ON A CHIP 2020; 20:4373-4390. [PMID: 33099594 PMCID: PMC7686155 DOI: 10.1039/d0lc00738b] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Endothelial cells (EC) respond to shear stress to maintain vascular homeostasis, and a disrupted response is associated with cardiovascular diseases. To understand how different shear stress modalities affect EC morphology and behavior, we developed a microfluidic device that concurrently generates three different levels of uniform wall shear stress (WSS) and six different WSS gradients (WSSG). In this device, human umbilical vein endothelial cells (HUVECs) exhibited a rapid and robust response to WSS, with the relative positioning of the Golgi and nucleus transitioning from a non-polarized to polarized state in a WSS magnitude- and gradient-dependent manner. By contrast, polarized HUVECs oriented their Golgi and nucleus polarity to the flow vector in a WSS magnitude-dependent manner, with positive WSSG inhibiting and negative WSSG promoting upstream orientation. Having validated this device, this chip can now be used to dissect the mechanisms underlying EC responses to different WSS modalities, including shear stress gradients, and to investigate the influence of flow on a diverse range of cells during development, homeostasis and disease.
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Affiliation(s)
- Utku M. Sonmez
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ya-Wen Cheng
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Simon C. Watkins
- Department of Cellular Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Beth L. Roman
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Lance A. Davidson
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Developmental Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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24
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Stadnik PS, Gilbert SJ, Tarn J, Charlton S, Skelton AJ, Barter MJ, Duance VC, Young DA, Blain EJ. Regulation of microRNA-221, -222, -21 and -27 in articular cartilage subjected to abnormal compressive forces. J Physiol 2020; 599:143-155. [PMID: 33052608 PMCID: PMC8132181 DOI: 10.1113/jp279810] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 10/09/2020] [Indexed: 01/01/2023] Open
Abstract
Key points
microRNAs (miRs) are small non‐coding molecules that regulate post‐transcriptional target gene expression. miRs are involved in regulating cellular activities in response to mechanical loading in all physiological systems, although it is largely unknown whether this response differs with increasing magnitudes of load. miR‐221, miR‐222, miR‐21‐5p and miR‐27a‐5p were significantly increased in ex vivo cartilage explants subjected to increasing load magnitude and in in vivo joint cartilage exposed to abnormal loading. TIMP3 and CPEB3 are putative miR targets in chondrocytes Identification of mechanically regulated miRs that have potential to impact on tissue homeostasis provides a mechanism by which load‐induced tissue behaviour is regulated, in both health and pathology, in all physiological systems. Abstract MicroRNAs (miRs) are small non‐coding molecules that regulate post‐transcriptional target gene expression and are involved in mechano‐regulation of cellular activities in all physiological systems. It is unknown whether such epigenetic mechanisms are regulated in response to increasing magnitudes of load. The present study investigated mechano‐regulation of miRs in articular cartilage subjected to ‘physiological’ and ‘non‐physiological’ compressive loads in vitro as a model system and validated findings in an in vivo model of abnormal joint loading. Bovine full‐depth articular cartilage explants were loaded to 2.5 MPa (physiological) or 7 MPa (non‐physiological) (1 Hz, 15 min) and mechanically‐regulated miRs identified using next generation sequencing and verified using a quantitative PCR. Downstream targets were verified using miR‐specific mimics or inhibitors in conjunction with 3′‐UTR luciferase activity assays. A subset of miRs were mechanically‐regulated in ex vivo cartilage explants and in vivo joint cartilage. miR‐221, miR‐222, miR‐21‐5p and miR‐27a‐5p were increased and miR‐483 levels decreased with increasing load magnitude. Tissue inhibitor of metalloproteinase 3 (TIMP3) and cytoplasmic polyadenylation element binding protein 3 (CPEB3) were identified as putative downstream targets. Our data confirm miR‐221 and ‐222 mechano‐regulation and demonstrates novel mechano‐regulation of miR‐21‐5p and miR‐27a‐5p in ex vivo and in vivo cartilage loading models. TIMP3 and CPEB3 are putative miR targets in chondrocytes. Identification of specific miRs that are regulated by increasing load magnitude, as well as their potential to impact on tissue homeostasis, has direct relevance to other mechano‐sensitive physiological systems and provides a mechanism by which load‐induced tissue behaviour is regulated, in both health and pathology.
microRNAs (miRs) are small non‐coding molecules that regulate post‐transcriptional target gene expression. miRs are involved in regulating cellular activities in response to mechanical loading in all physiological systems, although it is largely unknown whether this response differs with increasing magnitudes of load. miR‐221, miR‐222, miR‐21‐5p and miR‐27a‐5p were significantly increased in ex vivo cartilage explants subjected to increasing load magnitude and in in vivo joint cartilage exposed to abnormal loading. TIMP3 and CPEB3 are putative miR targets in chondrocytes Identification of mechanically regulated miRs that have potential to impact on tissue homeostasis provides a mechanism by which load‐induced tissue behaviour is regulated, in both health and pathology, in all physiological systems.
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Affiliation(s)
- Paulina S Stadnik
- Biomechanics and Bioengineering Research Centre Versus Arthritis, Biomedicine Division, School of Biosciences, The Sir Martin Evans Building, Cardiff University, Cardiff, Wales, UK
| | - Sophie J Gilbert
- Biomechanics and Bioengineering Research Centre Versus Arthritis, Biomedicine Division, School of Biosciences, The Sir Martin Evans Building, Cardiff University, Cardiff, Wales, UK
| | - Jessica Tarn
- Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Sarah Charlton
- Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew J Skelton
- Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Matthew J Barter
- Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Victor C Duance
- Biomechanics and Bioengineering Research Centre Versus Arthritis, Biomedicine Division, School of Biosciences, The Sir Martin Evans Building, Cardiff University, Cardiff, Wales, UK
| | - David A Young
- Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Emma J Blain
- Biomechanics and Bioengineering Research Centre Versus Arthritis, Biomedicine Division, School of Biosciences, The Sir Martin Evans Building, Cardiff University, Cardiff, Wales, UK
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25
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Morris G, Puri BK, Olive L, Carvalho A, Berk M, Walder K, Gustad LT, Maes M. Endothelial dysfunction in neuroprogressive disorders-causes and suggested treatments. BMC Med 2020; 18:305. [PMID: 33070778 PMCID: PMC7570030 DOI: 10.1186/s12916-020-01749-w] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. MAIN TEXT Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. CONCLUSIONS Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.
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Affiliation(s)
- Gerwyn Morris
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
| | | | - Lisa Olive
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
- School of Psychology, Faculty of Health, Deakin University, Geelong, Australia
| | - Andre Carvalho
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - Michael Berk
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia.
- Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
| | - Ken Walder
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
| | - Lise Tuset Gustad
- Department of Circulation and medical imaging, Norwegian University of Technology and Science (NTNU), Trondheim, Norway
- Nord-Trøndelag Hospital Trust, Levanger Hospital, Levanger, Norway
| | - Michael Maes
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
- Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
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26
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Differential expression, function and prognostic value of miR-17-92 cluster in ER-positive and triple-negative breast cancer. Cancer Treat Res Commun 2020; 25:100224. [PMID: 33096318 DOI: 10.1016/j.ctarc.2020.100224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/02/2020] [Accepted: 10/11/2020] [Indexed: 12/19/2022]
Abstract
Recent evidence has shown that the miR-17-92 cluster can function either as oncogene or tumor suppressor in human cancers. The function of miR-17-92 in subtypes of breast cancer remains largely unknown. The expression of miR-17-92 is elevated in triple negative breast cancer (TNBC) but reduced in estrogen receptor (ER)-positive breast cancer (ERPBC). We show that increased expression of miRNAs belonging to the miR-17-92 cluster is associated with poor outcome in TNBC, whereas the expression of miR-17-92 miRNAs is with good outcome in ERPBC. We show that ectopic expression of miR-17-92 inhibited cell growth and invasion of ER-positive and HER2-enriched cells. On the contrary, miR-17-92 expression enhanced cell growth and invasion of TNBC cells. Further, we found that miR-17-92 expression sensitized MCF7 cells to chemotherapeutic compounds, whereas it rendered SKBR3 cells resistant to them. We found that expression of ADORA1 was reduced by miR-17-92-expressing breast cancer cells, specifically in ERPBC. We observed an inverse correlation between the expression of ADORA1 and miR-17-92 in human breast cancer. Treatment with DPCPX, a selective ADORA1 antagonist, abolished the difference in the growth of control and miR-17-92 overexpressing MCF7 cells and identified ADORA1 as a key functional target of miR-17-92 in ERPBC. Furthermore, increased expression of ADORA1 in ERPBC is associated with a poor outcome. Our observations underscore the context-dependent role of miR-17-92 in breast cancer subtypes and suggest that miR-17-92 could serve as novel prognostic markers in breast cancer.
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27
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Karthika CL, Ahalya S, Radhakrishnan N, Kartha CC, Sumi S. Hemodynamics mediated epigenetic regulators in the pathogenesis of vascular diseases. Mol Cell Biochem 2020; 476:125-143. [PMID: 32844345 DOI: 10.1007/s11010-020-03890-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/14/2020] [Indexed: 12/19/2022]
Abstract
Endothelium of blood vessels is continuously exposed to various hemodynamic forces. Flow-mediated epigenetic plasticity regulates vascular endothelial function. Recent studies have highlighted the significant role of mechanosensing-related epigenetics in localized endothelial dysfunction and the regional susceptibility for lesions in vascular diseases. In this article, we review the epigenetic mechanisms such as DNA de/methylation, histone modifications, as well as non-coding RNAs in promoting endothelial dysfunction in major arterial and venous diseases, consequent to hemodynamic alterations. We also discuss the current challenges and future prospects for the use of mechanoepigenetic mediators as biomarkers of early stages of vascular diseases and dysregulated mechanosensing-related epigenetic regulators as therapeutic targets in various vascular diseases.
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Affiliation(s)
- C L Karthika
- Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - S Ahalya
- Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - N Radhakrishnan
- St.Thomas Institute of Research on Venous Diseases, Changanassery, Kerala, India
| | - C C Kartha
- Society for Continuing Medical Education & Research (SOCOMER), Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala, India
| | - S Sumi
- Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India.
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28
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Xue Y, Zhu X, Meehan B, Venneti S, Martinez D, Morin G, Maïga RI, Chen H, Papadakis AI, Johnson RM, O'Sullivan MJ, Erdreich-Epstein A, Gotlieb WH, Park M, Judkins AR, Pelletier J, Foulkes WD, Rak J, Huang S. SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors. J Pathol 2020; 252:77-87. [PMID: 32558936 DOI: 10.1002/path.5493] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/27/2020] [Accepted: 06/10/2020] [Indexed: 01/04/2023]
Abstract
Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to the rhabdoid tumor family and is usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodeling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA-approved CDK4/6 inhibitors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Yibo Xue
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Xianbing Zhu
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Brian Meehan
- Department of Pediatrics, McGill University, and Research Institute of McGill University Health Centre, Montreal Children's Hospital, Montreal, Canada
| | - Sriram Venneti
- Pathology and Neuropathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Daniel Martinez
- Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
| | - Geneviève Morin
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Rayelle I Maïga
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Hongbo Chen
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, PR China
| | - Andreas I Papadakis
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Radia M Johnson
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Maureen J O'Sullivan
- School of Medicine, University of Dublin, Trinity College, Dublin, Ireland.,Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Anat Erdreich-Epstein
- Departments of Pediatrics and Pathology, The Saban Research Institute at Children's Hospital Los Angeles and the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Walter H Gotlieb
- Division of Gynecologic Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada
| | - Morag Park
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - Alexander R Judkins
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Jerry Pelletier
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
| | - William D Foulkes
- Department of Human Genetics, McGill University, Montreal, Canada.,Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada.,Department of Medical Genetics and Cancer Research Program, McGill University Health Centre, Montreal, Canada
| | - Janusz Rak
- Department of Pediatrics, McGill University, and Research Institute of McGill University Health Centre, Montreal Children's Hospital, Montreal, Canada
| | - Sidong Huang
- Department of Biochemistry, McGill University, Montreal, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, Canada
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29
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Modulatory Effect of Indoles on the Expression of miRNAs Regulating G1/S Cell Cycle Phase in Breast Cancer Cells. Appl Biochem Biotechnol 2020; 192:1208-1223. [PMID: 32710170 DOI: 10.1007/s12010-020-03378-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/23/2020] [Indexed: 12/13/2022]
Abstract
Indole-3-carbinol (I3C) is a naturally occurring glucosinolate found in Brassica vegetables that is usually converted in gastric acidic environment to the efficient metabolite 3,3'-diindolylmethane (DIM). Both indoles (I3C and DIM) are known chemopreventive agents for various cancers including breast cancer. This study aimed to investigate the influence of both indoles on the tumor suppressor miRNAs (let-7a-e, miR-15a, miR-16, miR-17-5p, miR-19a, and miR-20a) and oncomiRs (miR-181a, miR-181b, miR-210, miR-221, and miR-106a), which are controlling the cell cycle key regulators: cyclin-dependent kinases (CDKs), CDK inhibitor p27Kip1, and cyclin D1. Our results indicated that both indoles generally elevated the expression of the tumor suppressor miRNAs let-7a-e, miR-19a, miR-17-5p, and miR-20a and decreased the expression of the oncomiR list. Both indoles were able to significantly suppress the expression of CDK4 and CDK6 as well as the apoptotic markers Bcl-2 and survivin. Both indoles decreased cyclin-D1 protein, where I3C decreased cytoplasmic and nuclear cyclin-D1 significantly. Cytoplasmic and nuclear P27Kip1 showed overexpression following treatment with I3C higher than that detected following DIM treatment. This study provides a mechanistic elucidation of the previously reported cell cycle arrest by I3C and DIM in breast cancer cells suggesting that this effect could be through modulation of miRNAs expression that, in turn, regulates the genetic network controlling the G1/S phase in cell cycle progression.
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30
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MicroRNAs as sentinels and protagonists of carotid artery thromboembolism. Clin Sci (Lond) 2020; 134:169-192. [PMID: 31971230 DOI: 10.1042/cs20190651] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/12/2019] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
Abstract
Stroke is the leading cause of serious disability in the world and a large number of ischemic strokes are due to thromboembolism from unstable carotid artery atherosclerotic plaque. As it is difficult to predict plaque rupture and surgical treatment of asymptomatic disease carries a risk of stroke, carotid disease continues to present major challenges with regard to clinical decision-making and revascularization. There is therefore an imminent need to better understand the molecular mechanisms governing plaque instability and rupture, as this would allow for the development of biomarkers to identify at-risk asymptomatic carotid plaque prior to disease progression and stroke. Further, it would aid in creation of therapeutics to stabilize carotid plaque. MicroRNAs (miRNAs) have been implicated as key protagonists in various stages of atherosclerotic plaque initiation, development and rupture. Notably, they appear to play a crucial role in carotid artery thromboembolism. As the molecular pathways governing the role of miRNAs are being uncovered, we are learning that their involvement is complex, tissue- and stage-specific, and highly selective. Notably, miRNAs can be packaged and secreted in extracellular vesicles (EVs), where they participate in cell-cell communication. The measurement of EV-encapsulated miRNAs in the circulation may inform disease mechanisms occurring in the plaque itself, and therefore may serve as sentinels of unstable plaque as well as therapeutic targets.
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31
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Fasolo F, Di Gregoli K, Maegdefessel L, Johnson JL. Non-coding RNAs in cardiovascular cell biology and atherosclerosis. Cardiovasc Res 2020; 115:1732-1756. [PMID: 31389987 DOI: 10.1093/cvr/cvz203] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/14/2019] [Accepted: 08/05/2019] [Indexed: 02/07/2023] Open
Abstract
Atherosclerosis underlies the predominant number of cardiovascular diseases and remains a leading cause of morbidity and mortality worldwide. The development, progression and formation of clinically relevant atherosclerotic plaques involves the interaction of distinct and over-lapping mechanisms which dictate the roles and actions of multiple resident and recruited cell types including endothelial cells, vascular smooth muscle cells, and monocyte/macrophages. The discovery of non-coding RNAs (ncRNAs) including microRNAs, long non-coding RNAs, and circular RNAs, and their identification as key mechanistic regulators of mRNA and protein expression has piqued interest in their potential contribution to atherosclerosis. Accruing evidence has revealed ncRNAs regulate pivotal cellular and molecular processes during all stages of atherosclerosis including cell invasion, growth, and survival; cellular uptake and efflux of lipids, expression and release of pro- and anti-inflammatory intermediaries, and proteolytic balance. The expression profile of ncRNAs within atherosclerotic lesions and the circulation have been determined with the aim of identifying individual or clusters of ncRNAs which may be viable therapeutic targets alongside deployment as biomarkers of atherosclerotic plaque progression. Consequently, numerous in vivo studies have been convened to determine the effects of moderating the function or expression of select ncRNAs in well-characterized animal models of atherosclerosis. Together, clinicopathological findings and studies in animal models have elucidated the multifaceted and frequently divergent effects ncRNAs impose both directly and indirectly on the formation and progression of atherosclerosis. From these findings' potential novel therapeutic targets and strategies have been discovered which may pave the way for further translational studies and possibly taken forward for clinical application.
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Affiliation(s)
- Francesca Fasolo
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar-Technical University Munich, Biedersteiner Strasse 29, Munich, Germany
| | - Karina Di Gregoli
- Laboratory of Cardiovascular Pathology, Bristol Medical School, University of Bristol, Bristol, UK
| | - Lars Maegdefessel
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar-Technical University Munich, Biedersteiner Strasse 29, Munich, Germany.,Molecular Vascular Medicine, Karolinska Institute, Center for Molecular Medicine L8:03, 17176 Stockholm, Sweden.,German Center for Cardiovascular Research (DZHK), Partner Site Munich (Munich Heart Alliance), Munich, Germany
| | - Jason L Johnson
- Laboratory of Cardiovascular Pathology, Bristol Medical School, University of Bristol, Bristol, UK
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32
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An Overview of Non-coding RNAs and Cardiovascular System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:3-45. [PMID: 32285403 DOI: 10.1007/978-981-15-1671-9_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease management and timely diagnosis remain a major dilemma. Delineating molecular mechanisms of cardiovascular diseases is opening horizon in the field of molecular medicines and in the development of early diagnostic markers. Non-coding RNAs are the highly functional and vibrant nucleic acids and are known to be involved in the regulation of endothelial cells, vascular and smooth muscles cells, cardiac metabolism, ischemia, inflammation and many processes in cardiovascular system. This chapter is comprehensively focusing on the overview of the non-coding RNAs including their discovery, generation, classification and functional regulation. In addition, overview regarding different non-coding RNAs as long non-coding, siRNAs and miRNAs involvement in the cardiovascular diseases is also addressed. Detailed functional analysis of this vast group of highly regulatory molecules will be promising for shaping future drug discoveries.
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33
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Henning RJ. Cardiovascular Exosomes and MicroRNAs in Cardiovascular Physiology and Pathophysiology. J Cardiovasc Transl Res 2020; 14:195-212. [PMID: 32588374 DOI: 10.1007/s12265-020-10040-5] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 05/26/2020] [Indexed: 12/16/2022]
Abstract
Cardiac exosomes mediate cell-to-cell communication, stimulate or inhibit the activities of target cells, and affect myocardial hypertrophy, injury and infarction, ventricular remodeling, angiogenesis, and atherosclerosis. The exosomes that are released in the heart from cardiomyocytes, vascular cells, fibroblasts, and resident stem cells are hypoimmunogenic, are physiologically more stable than cardiac cells, can circulate in the body, and are able to cross the blood-brain barrier. Exosomes utilize three mechanisms for cellular communication: (1) internalization by cells, (2) direct fusion to the cell membrane, and (3) receptor-ligand interactions. Cardiac exosomes transmit proteins, mRNA, and microRNAs to other cells during both physiological and pathological process. Cardiac-specific exosome miRNAs can regulate the expression of sarcomeric genes, ion channel genes, autophagy, anti-apoptotic and anti-fibrotic activity, and angiogenesis. This review discusses the role of exosomes and microRNAs in normal myocardium, myocardial injury and infarction, atherosclerosis, and the importance of circulating microRNAs as biomarkers of cardiac disease. Graphical Abstract.
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Affiliation(s)
- Robert J Henning
- University of South Florida, 13201 Bruce B. Downs Blvd., Tampa, FL, 33612-3805, USA.
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34
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Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets. J Clin Med 2020; 9:jcm9061995. [PMID: 32630452 PMCID: PMC7355625 DOI: 10.3390/jcm9061995] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/15/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular diseases (CVD), including heart and pathological circulatory conditions, are the world's leading cause of mortality and morbidity. Endothelial dysfunction involved in CVD pathogenesis is a trigger, or consequence, of oxidative stress and inflammation. Endothelial dysfunction is defined as a diminished production/availability of nitric oxide, with or without an imbalance between endothelium-derived contracting, and relaxing factors associated with a pro-inflammatory and prothrombotic status. Endothelial dysfunction-induced phenotypic changes include up-regulated expression of adhesion molecules and increased chemokine secretion, leukocyte adherence, cell permeability, low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. Inflammation-induced oxidative stress results in an increased accumulation of reactive oxygen species (ROS), mainly derived from mitochondria. Excessive ROS production causes oxidation of macromolecules inducing cell apoptosis mediated by cytochrome-c release. Oxidation of mitochondrial cardiolipin loosens cytochrome-c binding, thus, favoring its cytosolic release and activation of the apoptotic cascade. Oxidative stress increases vascular permeability, promotes leukocyte adhesion, and induces alterations in endothelial signal transduction and redox-regulated transcription factors. Identification of new endothelial dysfunction-related oxidative stress markers represents a research goal for better prevention and therapy of CVD. New-generation therapeutic approaches based on carriers, gene therapy, cardiolipin stabilizer, and enzyme inhibitors have proved useful in clinical practice to counteract endothelial dysfunction. Experimental studies are in continuous development to discover new personalized treatments. Gene regulatory mechanisms, implicated in endothelial dysfunction, represent potential new targets for developing drugs able to prevent and counteract CVD-related endothelial dysfunction. Nevertheless, many challenges remain to overcome before these technologies and personalized therapeutic strategies can be used in CVD management.
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Guarner-Lans V, Ramírez-Higuera A, Rubio-Ruiz ME, Castrejón-Téllez V, Soto ME, Pérez-Torres I. Early Programming of Adult Systemic Essential Hypertension. Int J Mol Sci 2020; 21:E1203. [PMID: 32054074 PMCID: PMC7072742 DOI: 10.3390/ijms21041203] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/27/2020] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular diseases are being included in the study of developmental origins of health and disease (DOHaD) and essential systemic hypertension has also been added to this field. Epigenetic modifications are one of the main mechanisms leading to early programming of disease. Different environmental factors occurring during critical windows in the early stages of life may leave epigenetic cues, which may be involved in the programming of hypertension when individuals reach adulthood. Such environmental factors include pre-term birth, low weight at birth, altered programming of different organs such as the blood vessels and the kidney, and living in disadvantageous conditions in the programming of hypertension. Mechanisms behind these factors that impact on the programming include undernutrition, oxidative stress, inflammation, emotional stress, and changes in the microbiota. These factors and their underlying causes acting at the vascular level will be discussed in this paper. We also explore the establishment of epigenetic cues that may lead to hypertension at the vascular level such as DNA methylation, histone modifications (methylation and acetylation), and the role of microRNAs in the endothelial cells and blood vessel smooth muscle which participate in hypertension. Since epigenetic changes are reversible, the knowledge of this type of markers could be useful in the field of prevention, diagnosis or epigenetic drugs as a therapeutic approach to hypertension.
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Affiliation(s)
- Verónica Guarner-Lans
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.E.R.-R.); (V.C.-T.)
| | - Abril Ramírez-Higuera
- Nutrition Biochemistry Laboratory, Research and Food Development Unit. Veracruz Technological Institute, National Technological of Mexico, Veracruz 91897, Mexico;
| | - María Esther Rubio-Ruiz
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.E.R.-R.); (V.C.-T.)
| | - Vicente Castrejón-Téllez
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.E.R.-R.); (V.C.-T.)
| | - María Elena Soto
- Department of Immunology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico 14080, Mexico;
| | - Israel Pérez-Torres
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico 14080, Mexico;
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Peng Z, Shu B, Zhang Y, Wang M. Endothelial Response to Pathophysiological Stress. Arterioscler Thromb Vasc Biol 2019; 39:e233-e243. [PMID: 31644356 DOI: 10.1161/atvbaha.119.312580] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Located in the innermost layer of the vasculature and directly interacting with blood flow, endothelium integrates various biochemical and biomechanical signals to maintain barrier function with selective permeability, vascular tone, blood fluidity, and vascular formation. Endothelial cells respond to laminar and disturbed flow by structural and functional adaption, which involves reprogramming gene expression, cell proliferation and migration, senescence, autophagy and cell death, as well as synthesizing signal molecules (nitric oxide and prostanoids, etc) that act in manners of autocrine, paracrine, or juxtacrine. Inflammation occurs after infection or tissue injury. Dysregulated inflammatory response participates in pathogenesis of many diseases. Endothelial cells exposed to inflammatory stimuli from the circulation or the microenvironment exhibit impaired vascular tone, increased permeability, elevated procoagulant activity, and dysregulated vascular formation, collectively contributing to the development of vascular diseases. Understanding the endothelial response to pathophysiological stress of hemodynamics and inflammation provides mechanistic insights into cardiovascular diseases, as well as therapeutic opportunities.
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Affiliation(s)
- Zekun Peng
- From the State Key Laboratory of Cardiovascular Disease (Z.P., B.S., Y.Z., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bingyan Shu
- From the State Key Laboratory of Cardiovascular Disease (Z.P., B.S., Y.Z., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yurong Zhang
- From the State Key Laboratory of Cardiovascular Disease (Z.P., B.S., Y.Z., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Miao Wang
- From the State Key Laboratory of Cardiovascular Disease (Z.P., B.S., Y.Z., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Zemskov EA, Lu Q, Ornatowski W, Klinger CN, Desai AA, Maltepe E, Yuan JXJ, Wang T, Fineman JR, Black SM. Biomechanical Forces and Oxidative Stress: Implications for Pulmonary Vascular Disease. Antioxid Redox Signal 2019; 31:819-842. [PMID: 30623676 PMCID: PMC6751394 DOI: 10.1089/ars.2018.7720] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Oxidative stress in the cell is characterized by excessive generation of reactive oxygen species (ROS). Superoxide (O2-) and hydrogen peroxide (H2O2) are the main ROS involved in the regulation of cellular metabolism. As our fundamental understanding of the underlying causes of lung disease has increased it has become evident that oxidative stress plays a critical role. Recent Advances: A number of cells in the lung both produce, and respond to, ROS. These include vascular endothelial and smooth muscle cells, fibroblasts, and epithelial cells as well as the cells involved in the inflammatory response, including macrophages, neutrophils, eosinophils. The redox system is involved in multiple aspects of cell metabolism and cell homeostasis. Critical Issues: Dysregulation of the cellular redox system has consequential effects on cell signaling pathways that are intimately involved in disease progression. The lung is exposed to biomechanical forces (fluid shear stress, cyclic stretch, and pressure) due to the passage of blood through the pulmonary vessels and the distension of the lungs during the breathing cycle. Cells within the lung respond to these forces by activating signal transduction pathways that alter their redox state with both physiologic and pathologic consequences. Future Directions: Here, we will discuss the intimate relationship between biomechanical forces and redox signaling and its role in the development of pulmonary disease. An understanding of the molecular mechanisms induced by biomechanical forces in the pulmonary vasculature is necessary for the development of new therapeutic strategies.
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Affiliation(s)
- Evgeny A Zemskov
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Qing Lu
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Wojciech Ornatowski
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Christina N Klinger
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Ankit A Desai
- Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Emin Maltepe
- Department of Pediatrics, University of California, San Francisco, San Francisco, California
| | - Jason X-J Yuan
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Ting Wang
- Department of Internal Medicine, The University of Arizona Health Sciences, Phoenix, Arizona
| | - Jeffrey R Fineman
- Department of Pediatrics, University of California, San Francisco, San Francisco, California
| | - Stephen M Black
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
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Lee DY, Chiu JJ. Atherosclerosis and flow: roles of epigenetic modulation in vascular endothelium. J Biomed Sci 2019; 26:56. [PMID: 31387590 PMCID: PMC6685237 DOI: 10.1186/s12929-019-0551-8] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/29/2019] [Indexed: 12/18/2022] Open
Abstract
Background Endothelial cell (EC) dysfunctions, including turnover enrichment, gap junction disruption, inflammation, and oxidation, play vital roles in the initiation of vascular disorders and atherosclerosis. Hemodynamic forces, i.e., atherprotective pulsatile (PS) and pro-atherogenic oscillatory shear stress (OS), can activate mechanotransduction to modulate EC function and dysfunction. This review summarizes current studies aiming to elucidate the roles of epigenetic factors, i.e., histone deacetylases (HDACs), non-coding RNAs, and DNA methyltransferases (DNMTs), in mechanotransduction to modulate hemodynamics-regulated EC function and dysfunction. Main body of the abstract OS enhances the expression and nuclear accumulation of class I and class II HDACs to induce EC dysfunction, i.e., proliferation, oxidation, and inflammation, whereas PS induces phosphorylation-dependent nuclear export of class II HDACs to inhibit EC dysfunction. PS induces overexpression of the class III HDAC Sirt1 to enhance nitric oxide (NO) production and prevent EC dysfunction. In addition, hemodynamic forces modulate the expression and acetylation of transcription factors, i.e., retinoic acid receptor α and krüppel-like factor-2, to transcriptionally regulate the expression of microRNAs (miRs). OS-modulated miRs, which stimulate proliferative, pro-inflammatory, and oxidative signaling, promote EC dysfunction, whereas PS-regulated miRs, which induce anti-proliferative, anti-inflammatory, and anti-oxidative signaling, inhibit EC dysfunction. PS also modulates the expression of long non-coding RNAs to influence EC function. i.e., turnover, aligmant, and migration. On the other hand, OS enhances the expression of DNMT-1 and -3a to induce EC dysfunction, i.e., proliferation, inflammation, and NO repression. Conclusion Overall, epigenetic factors play vital roles in modulating hemodynamic-directed EC dysfunction and vascular disorders, i.e., atherosclerosis. Understanding the detailed mechanisms through which epigenetic factors regulate hemodynamics-directed EC dysfunction and vascular disorders can help us to elucidate the pathogenic mechanisms of atherosclerosis and develop potential therapeutic strategies for atherosclerosis treatment.
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Affiliation(s)
- Ding-Yu Lee
- Department of Biological Science and Technology, China University of Science and Technology, Taipei, 115, Taiwan
| | - Jeng-Jiann Chiu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, 350, Taiwan. .,Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 300, Taiwan. .,Collage of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan. .,Institute of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan. .,Institute of Polymer Science and Engineering, National Taiwan University, Taipei, 106, Taiwan.
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Yang X, Li X, Lin Q, Xu Q. Up-regulation of microRNA-203 inhibits myocardial fibrosis and oxidative stress in mice with diabetic cardiomyopathy through the inhibition of PI3K/Akt signaling pathway via PIK3CA. Gene 2019; 715:143995. [PMID: 31336140 DOI: 10.1016/j.gene.2019.143995] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 07/19/2019] [Accepted: 07/19/2019] [Indexed: 12/18/2022]
Abstract
Diabetic cardiomyopathy (DCM) refers to the myocardial dysfunction in the absence of coronary artery disease and hypertension. Recently, the role of microRNAs (miRs) in gene expression regulation has attracted much more attention. Studies have shown that the PI3K/Akt signaling pathway is involved in the growth, metabolism and apoptosis of myocardial cells. Therefore, this study aimed to explore the regulatory role of miR-203 in myocardial fibrosis in mice with DCM via involvement of the PI3K/Akt signaling pathway. Firstly, mouse model of diabetes mellitus (DM) was established and injected with agomir, antagomir or IGF-1 (PI3K/Akt signaling pathway activator) for investigating the role of miR-203 in PIK3CA and the PI3K/Akt signaling pathway. PIK3CA was identified as a target gene of miR-203, and overexpressed miR-203 inhibited the activation of PI3K/Akt signaling pathway. The obtained results indicated that up-regulation of miR-203 reduced myocardial hypertrophy, myocardial fibrosis, myocardial apoptosis, and levels of PIK3CA, PI3K, Akt, CoI I, CoI III, ANP, MDA and ROS in the myocardial tissues, by which DM-induced cardiac dysfunction and pathological changes could be ameliorated. Collectively, our present study highlighted that overexpression of miR-203 may function as a cardioprotective regulator in DCM by targeting PIK3CA via inactivation of PI3K/Akt signaling pathway.
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Affiliation(s)
- Xubin Yang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China.
| | - Xiaoshan Li
- Department of Ultrasonography, Guangzhou YueXiu District Hospital of Traditional Chinese Medicine, Guangzhou 510030, PR China
| | - Qiongyan Lin
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
| | - Quanfu Xu
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China
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Gongol B, Marin T, Zhang J, Wang SC, Sun W, He M, Chen S, Chen L, Li J, Liu JH, Martin M, Han Y, Kang J, Johnson DA, Lytle C, Li YS, Huang PH, Chien S, Shyy JYJ. Shear stress regulation of miR-93 and miR-484 maturation through nucleolin. Proc Natl Acad Sci U S A 2019; 116:12974-12979. [PMID: 31182601 PMCID: PMC6600934 DOI: 10.1073/pnas.1902844116] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease.
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Affiliation(s)
- Brendan Gongol
- Department of Medicine, University of California, San Diego, CA 92093
| | - Traci Marin
- Department of Health Sciences, Victor Valley College, Victorville, CA 92395
| | - Jiao Zhang
- Department of Medicine, University of California, San Diego, CA 92093
| | - Shen-Chih Wang
- Department of Anesthesiology, Taipei Veterans General Hospital, 115 Taipei, Taiwan
| | - Wei Sun
- Division of Biomedical Sciences, University of California, Riverside, CA 92521
| | - Ming He
- Department of Medicine, University of California, San Diego, CA 92093
| | - Shanshan Chen
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China Xi'an, 710029 Xi'an, China
| | - Lili Chen
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China Xi'an, 710029 Xi'an, China
| | - Jie Li
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China Xi'an, 710029 Xi'an, China
| | - Jun-Hui Liu
- Department of Clinical Laboratory, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, 710029 Xi'an, China
| | - Marcy Martin
- Department of Medicine, University of California, San Diego, CA 92093
| | - Yue Han
- Institute of Mechanobiology and Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 200240 Shanghai, China
| | - Jian Kang
- Department of Medicine, University of California, San Diego, CA 92093
| | - David A Johnson
- Division of Biomedical Sciences, University of California, Riverside, CA 92521
| | - Christian Lytle
- Division of Biomedical Sciences, University of California, Riverside, CA 92521
| | - Yi-Shuan Li
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Po-Hsun Huang
- Cardiovascular Research Center, National Yang-Ming University, 112 Taipei, Taiwan
- Department of Critical Care Medicine, Taipei Veterans General Hospital, 115 Taipei, Taiwan
| | - Shu Chien
- Department of Medicine, University of California, San Diego, CA 92093;
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093
| | - John Y-J Shyy
- Department of Medicine, University of California, San Diego, CA 92093;
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China Xi'an, 710029 Xi'an, China
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A three-step approach identifies novel shear stress-sensitive endothelial microRNAs involved in vasculoprotective effects of high-intensity interval training (HIIT). Oncotarget 2019. [DOI: 10.18632/oncotarget.26944] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Schmitz B, Breulmann FL, Jubran B, Rolfes F, Thorwesten L, Krüger M, Klose A, Schnittler HJ, Brand SM. A three-step approach identifies novel shear stress-sensitive endothelial microRNAs involved in vasculoprotective effects of high-intensity interval training (HIIT). Oncotarget 2019; 10:3625-3640. [PMID: 31217898 PMCID: PMC6557206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 04/03/2019] [Indexed: 11/22/2022] Open
Abstract
Circulatory microRNAs (c-miRNAs) are regulated in response to physical activity and may exert anti-atherosclerotic effects. Since the vascular endothelium is an abundant source of c-miRNAs, we aimed to identify novel vasculoprotective exercise-induced c-miRNAs by the combined analysis of published endothelial miRNA array data followed by in vivo and in vitro validation. We identified 8 different array-based publications reporting 185 endothelial shear stress-regulated miRNAs of which 13 were identified in ≥3 independent reports. Nine miRNAs had already been associated with physical activity. Of the remaining novel miRNAs, miR-98-3p and miR-125-5p were selected for further analysis due to reported vasculoprotective effects. Analysis in two different 4-week high-intensity interval training (HIIT) groups (group 1 [n=27]: 4x30 s, group 2 [n=25]: 8x15 s; all-out running) suggested significantly elevated miR-98 and miR-125a-5p levels in response to acute exercise at baseline and at follow-up. Endothelial in vitro shear stress experiments revealed increased miR-125a-5p and miR-98-3p levels in medium of human umbilical vein endothelial cells at 30 dyn/cm2 after 20 and 60 min, respectively. Our results suggest that miR-98-3p and miR-125a-5p can be rapidly secreted by endothelial cells, which might be the source of increased c-miR-98-3p and -125a-5p levels in response to HIIT. Both miRNAs attenuate endothelial inflammation and may mediate vasculoprotective effects of physical exercise including HIIT.
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Affiliation(s)
- Boris Schmitz
- 1 Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany
| | - Franziska L. Breulmann
- 1 Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany
| | - Bothaynah Jubran
- 2 Institute of Anatomy and Vascular Biology, University of Muenster, Muenster, Germany
| | - Florian Rolfes
- 1 Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany
| | - Lothar Thorwesten
- 1 Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany
| | - Michael Krüger
- 3 Department of Physical Education and Sports History, University of Muenster, Muenster, Germany
| | - Andreas Klose
- 3 Department of Physical Education and Sports History, University of Muenster, Muenster, Germany
| | | | - Stefan-Martin Brand
- 1 Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany
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Cerebral Thromboembolism after Lobectomy for Lung Cancer: Pathological Diagnosis and Mechanism of Thrombus Formation. Cancers (Basel) 2019; 11:cancers11040488. [PMID: 30959839 PMCID: PMC6521235 DOI: 10.3390/cancers11040488] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 12/15/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Although molecular therapies have emerged as efficacious strategies for the treatment of lung cancer, surgical resection is still recommended as a radical therapeutic option. Currently, lobectomy is regarded as the most reliable radical treatment of primary lung cancer. Among the various complications after lobectomy, cerebral thromboembolism requires attention as a life-threatening complication during the early postoperative period. It occurs in 0.2–1.2% of surgical cases of lung cancer and typically develops following left upper lobectomy with a long pulmonary vein stump (PVS). PVS-associated thrombosis is known to cause cerebral thromboembolism after such procedures; however, distinguishing this specific complication from that caused by postoperative atrial fibrillation is challenging. We summarize herein the diagnostic pathology of thrombus formation in accordance with its thrombogenic mechanism. We focus on the potential utility of the pathological assessment of thrombectomy specimens. The morphological information obtained from these specimens enables the presumption of thrombogenic etiology and provides useful clues to both select an appropriate pharmacotherapy and determine a follow-up treatment for cerebral thromboembolism.
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Li XF, Zhao GQ, Li LY. Ginsenoside impedes proliferation and induces apoptosis of human osteosarcoma cells by down-regulating β-catenin. Cancer Biomark 2019; 24:395-404. [PMID: 30909183 DOI: 10.3233/cbm-182046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Osteosarcoma (OS) is the most commonly occurred primary bone malignancy with high incident rates among children and adolescents. In pharmacologic treatment, the drug ginsenoside has been shown to exert anticancer effects on several malignant diseases. The purpose of this research was to investigate the effect of ginsenoside on the apoptosis and proliferation of human OS MG-63 and Saos-2 cells by regulating the expression of β-catenin. METHODS Human OS MG-63 and Saos-2 cells were assigned into control group, and four groups with treatment by varying concentrations (12.5 μg/mL, 25 μg/mL, 50 μg/mL and 100 μg/mL) of ginsenoside, respectively. Cell growth after treatment was observed through cell slides. The proliferation rate of MG-63 and Saos-2 cells in each group was detected by CCK-8. After cell transfection at 48 h, cell cycle and cell apoptosis were detected by FITC-Annexin V staining and flow cytometry. The protein and mRNA expressions of β-catenin, Cyclin D1, Bcl-2, Bax and cleaved caspase-3 were detected by RT-qPCR and western blot analysis. RESULTS With increased exposure and concentration of ginsenoside, the cell density, total cell numbers and the absorbance of MG-63 and Saos-2 cells gradually decreased. FITC-Annexin V and FITC-Annexin V/PI staining demonstrated that the cell proportion at S phase decreased, whereas the total apoptotic rate of MG-63 and Saos-2 cells was increased. Furthermore, RT-qPCR and western blot analysis highlighted a gradual decrease in protein and mRNA expressions of β-catenin, Bcl-2 and Cyclin D1, while an elevation in those of Bax and cleaved caspase-3. CONCLUSION The results of this study demonstrate that ginsenoside inhibits proliferation and promotes apoptosis of human OS MG-63 and Saos-2 cells by reducing the expressions of β-catenin, Bcl-2 and Cyclin D1 and increasing the expression of Bax and cleaved caspase-3.
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Fang Y, Wu D, Birukov KG. Mechanosensing and Mechanoregulation of Endothelial Cell Functions. Compr Physiol 2019; 9:873-904. [PMID: 30873580 PMCID: PMC6697421 DOI: 10.1002/cphy.c180020] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Vascular endothelial cells (ECs) form a semiselective barrier for macromolecules and cell elements regulated by dynamic interactions between cytoskeletal elements and cell adhesion complexes. ECs also participate in many other vital processes including innate immune reactions, vascular repair, secretion, and metabolism of bioactive molecules. Moreover, vascular ECs represent a unique cell type exposed to continuous, time-dependent mechanical forces: different patterns of shear stress imposed by blood flow in macrovasculature and by rolling blood cells in the microvasculature; circumferential cyclic stretch experienced by the arterial vascular bed caused by heart propulsions; mechanical stretch of lung microvascular endothelium at different magnitudes due to spontaneous respiration or mechanical ventilation in critically ill patients. Accumulating evidence suggests that vascular ECs contain mechanosensory complexes, which rapidly react to changes in mechanical loading, process the signal, and develop context-specific adaptive responses to rebalance the cell homeostatic state. The significance of the interactions between specific mechanical forces in the EC microenvironment together with circulating bioactive molecules in the progression and resolution of vascular pathologies including vascular injury, atherosclerosis, pulmonary edema, and acute respiratory distress syndrome has been only recently recognized. This review will summarize the current understanding of EC mechanosensory mechanisms, modulation of EC responses to humoral factors by surrounding mechanical forces (particularly the cyclic stretch), and discuss recent findings of magnitude-specific regulation of EC functions by transcriptional, posttranscriptional and epigenetic mechanisms using -omics approaches. We also discuss ongoing challenges and future opportunities in developing new therapies targeting dysregulated mechanosensing mechanisms to treat vascular diseases. © 2019 American Physiological Society. Compr Physiol 9:873-904, 2019.
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Affiliation(s)
- Yun Fang
- Department of Medicine, University of Chicago, Chicago, Illinois, USA,Correspondence to
| | - David Wu
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Konstantin G. Birukov
- Department of Anesthesiology, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA
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Kumar S, Williams D, Sur S, Wang JY, Jo H. Role of flow-sensitive microRNAs and long noncoding RNAs in vascular dysfunction and atherosclerosis. Vascul Pharmacol 2019; 114:76-92. [PMID: 30300747 PMCID: PMC6905428 DOI: 10.1016/j.vph.2018.10.001] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/19/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is the primary underlying cause of myocardial infarction, ischemic stroke, and peripheral artery disease. The disease preferentially occurs in arterial regions exposed to disturbed blood flow, in part, by altering expression of flow-sensitive coding- and non-coding genes. In this review, we summarize the role of noncoding RNAs, [microRNAs (miRNAs) and long noncoding RNAs(lncRNAs)], as regulators of gene expression and outline their relationship to the pathogenesis of atherosclerosis. While miRNAs are small noncoding genes that post-transcriptionally regulate gene expression by targeting mRNA transcripts, the lncRNAs regulate gene expression by diverse mechanisms, which are still emerging and incompletely understood. We focused on multiple flow-sensitive miRNAs such as, miR-10a, -19a, -23b, -17~92, -21, -663, -92a, -143/145, -101, -126, -712, -205, and -155 that play a critical role in endothelial function and atherosclerosis by targeting inflammation, cell cycle, proliferation, migration, apoptosis, and nitric oxide signaling. Flow-dependent regulation of lncRNAs is just emerging, and their role in vascular dysfunction and atherosclerosis is unknown. Here, we discuss the flow-sensitive lncRNA STEEL along with other lncRNAs studied in the context of vascular pathophysiology and atherosclerosis such as MALAT1, MIAT1, ANRIL, MYOSLID, MEG3, SENCR, SMILR, LISPR1, and H19. Also discussed is the use of these noncoding RNAs as potential biomarkers and therapeutics to reduce and regress atherosclerosis.
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Affiliation(s)
- Sandeep Kumar
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Darian Williams
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Sanjoli Sur
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Jun-Yao Wang
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
| | - Hanjoong Jo
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA; Division of Cardiology, Emory University, Atlanta, USA.
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Yi J, Gao ZF. MicroRNA-9-5p promotes angiogenesis but inhibits apoptosis and inflammation of high glucose-induced injury in human umbilical vascular endothelial cells by targeting CXCR4. Int J Biol Macromol 2019; 130:1-9. [PMID: 30716366 DOI: 10.1016/j.ijbiomac.2019.02.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 02/08/2023]
Abstract
High glucose (HG) has the potential to cause vascular endothelial cell injury, while microRNAs (miRNAs) play a key role in treating endothelial cell injury. CXC chemokine receptor-4 (CXCR4) is reported to be expressed in vascular endothelial cells. Hence, this study investigated role of miR-9-5p in the angiogenesis and apoptosis of HG-induced human umbilical vascular endothelial cells (HUVECs) injury. Dual luciferase reporter gene assay verified that miR-9-5p targeted CXCR4. RT-qPCR and western blot analysis revealed that miR-9-5p was down-regulated, meanwhile CXCR4 was up-regulated in the HG-induced HUVECs. HUVECs were cultured in 30 mmol/L HG in vitro, and then transfected with miR-9-5p mimic or CXCR4 siRNA to identify the effect of miR-9-5p on cell activity, angiogenesis, apoptosis, and inflammation of HG-induced HUVECs. The results suggested that overexpression of miR-9-5p or silencing of CXCR4 in HG-induced HUVECs increased cell proliferation and tubule length, while decreasing the apoptosis rate and the expression of inflammatory factors. Furthermore, miR-9-5p inhibited the phosphorylation of extracellular regulated protein kinases (ERK), protein kinase B (AKT), and Mammalian Target of Rapamycin (mTOR) proteins via downregulation of CXCR4. Therefore, overexpression of miR-9-5p suppressed the mitogen-activated protein kinase (MAPK)/ERK and the PI3K/AKT/mTOR pathway by inhibiting CXCR4, thereby reducing HG-induced injury in HUVECs.
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Affiliation(s)
- Jun Yi
- Department of Anesthesiology, Beijing Jishuitan Hospital, Beijing 100035, PR China
| | - Zhi-Feng Gao
- Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, PR China.
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Charbonier FW, Zamani M, Huang NF. Endothelial Cell Mechanotransduction in the Dynamic Vascular Environment. ADVANCED BIOSYSTEMS 2019; 3:e1800252. [PMID: 31328152 PMCID: PMC6640152 DOI: 10.1002/adbi.201800252] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Indexed: 12/11/2022]
Abstract
The vascular endothelial cells (ECs) that line the inner layer of blood vessels are responsible for maintaining vascular homeostasis under physiological conditions. In the presence of disease or injury, ECs can become dysfunctional and contribute to a progressive decline in vascular health. ECs are constantly exposed to a variety of dynamic mechanical stimuli, including hemodynamic shear stress, pulsatile stretch, and passive signaling cues derived from the extracellular matrix. This review describes the molecular mechanisms by which ECs perceive and interpret these mechanical signals. The translational applications of mechanosensing are then discussed in the context of endothelial-to-mesenchymal transition and engineering of vascular grafts.
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Affiliation(s)
- Frank W. Charbonier
- Department of Mechanical Engineering, Stanford University, Stanford, CA, 94305
| | - Maedeh Zamani
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, 94305
| | - Ngan F. Huang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, 94305
- Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304
- The Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305
- Stanford University, 300 Pasteur Drive, MC 5407, Stanford, CA 94305-5407, USA
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Fernández-Hernando C, Suárez Y. MicroRNAs in endothelial cell homeostasis and vascular disease. Curr Opin Hematol 2019; 25:227-236. [PMID: 29547400 DOI: 10.1097/moh.0000000000000424] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Since the first discovery of microRNAs (miRNAs) in 1993, the involvement of miRNAs in different aspects of vascular disease has emerged as an important research field. In this review, we summarize the fundamental roles of miRNAs in controlling endothelial cell functions and their implication with several aspects of vascular dysfunction. RECENT FINDINGS MiRNAs have been found to be critical modulators of endothelial homeostasis. The dysregulation of miRNAs has been linked to endothelial dysfunction and the development and progression of vascular disease which and open new opportunities of using miRNAs as potential therapeutic targets for vascular disease. SUMMARY Further determination of miRNA regulatory circuits and defining miRNAs-specific target genes remains key to future miRNA-based therapeutic applications toward vascular disease prevention. Many new and unanticipated roles of miRNAs in the control of endothelial functions will assist clinicians and researchers in developing potential therapeutic applications.
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Affiliation(s)
- Carlos Fernández-Hernando
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Department of Pathology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
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ZBTB46 is a shear-sensitive transcription factor inhibiting endothelial cell proliferation via gene expression regulation of cell cycle proteins. J Transl Med 2019; 99:305-318. [PMID: 29884909 PMCID: PMC6286701 DOI: 10.1038/s41374-018-0060-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 02/08/2018] [Accepted: 02/20/2018] [Indexed: 11/24/2022] Open
Abstract
ZBTB46 is a transcription factor identified in classical dendritic cells and keeps dendritic cells in a quiescent state. Chromatin immunoprecipitation sequencing in dendritic cells has identified over 1300 potential gene targets of ZBTB46, affecting many processes including cell cycle. Endothelial cells (ECs) also express ZBTB46 and are mostly in a quiescent non-proliferative state. While EC proliferation is a critical process in development, dysregulation of EC proliferation as seen in areas of disturbed flow play an important role in many disease processes such as atherosclerosis, pulmonary hypertension, transplant vasculopathy, neointimal hyperplasia, and in-stent restenosis. We studied the role of ZBTB46 in ECs, hypothesizing that it inhibits EC proliferation. Using a model of disturbed flow in mice, we found that ZBTB46 is expressed in murine arterial ECs in vivo, and is downregulated by disturbed flow. In vitro results using HAECs showed that cell confluence and laminar shear stress, both known physiological conditions promoting EC quiescence, led to upregulation of ZBTB46 expression. Adenoviral-mediated overexpression of ZBTB46 in vitro caused reduced EC proliferation, and increased number of cells in the G0/G1 phase of cell cycle, without affecting apoptosis or senescence, while siRNA knockdown of ZBTB46 negated the known inhibitory role of unidirectional laminar shear stress on EC proliferation. ZBTB46 overexpression also led to a broad suppression of genes involved in cell cycle progression including multiple cyclins and cyclin-dependent kinases, but an increase in the CDK inhibitor CDKN1A. Phosphorylation of the retinoblastoma protein was also decreased as assessed by Western blot. Tube formation on Matrigel was reduced, suggesting an inhibitory role for ZBTB46 in angiogenesis. Further research is required to investigate the potential role of ZBTB46 in specific pathologic conditions and whether it can be targeted in a therapeutic manner.
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