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Zhang X, Qi M, Fu Q. Molecular genetics of congenital heart disease. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2861-9. [PMID: 40163266 DOI: 10.1007/s11427-024-2861-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 02/08/2025] [Indexed: 04/02/2025]
Abstract
Congenital heart disease (CHD) is the most prevalent human birth defect and remains a leading cause of mortality in childhood. Although advancements in surgical and medical interventions have significantly reduced mortality rates among infants with critical CHDs, many survivors experience substantial cardiac and extracardiac comorbidities that affect their quality of life. The etiology of CHD is multifactorial, involving both genetic and environmental factors, yet a definitive cause remains unidentified in many cases. Recent advancements in genetic testing technologies have improved our ability to identify the genetic causes of CHD. This review presents an updated summary of the established genetic contributions to CHD, including chromosomal aberrations and mutations in genes associated with transcription factors, cardiac structural proteins, chromatin modifiers, cilia-related proteins, and cell signaling pathways. Furthermore, we discuss recent findings that support the roles of non-coding mutations and complex inheritance in the etiology of CHD.
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Affiliation(s)
- Xiaoqing Zhang
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Key Laboratory of Molecular Diagnosis for Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Ming Qi
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Key Laboratory of Molecular Diagnosis for Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Qihua Fu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Key Laboratory of Molecular Diagnosis for Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences, Chengdu, 610072, China.
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2
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Zhang H, Lu W, Tang H, Chen A, Gao X, Zhu C, Zhang J. Novel Insight of N6-Methyladenosine in Cardiovascular System. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:222. [PMID: 40005339 PMCID: PMC11857502 DOI: 10.3390/medicina61020222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/19/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
N6-methyladenosine (m6A) is the most common and abundant internal co-transcriptional modification in eukaryotic RNAs. This modification is catalyzed by m6A methyltransferases, known as "writers", including METTL3/14 and WTAP, and removed by demethylases, or "erasers", such as FTO and ALKBH5. It is recognized by m6A-binding proteins, or "readers", such as YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPA2B1. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Recent studies indicate that m6A RNA modification plays a critical role in both the physiological and pathological processes involved in the initiation and progression of CVDs. In this review, we will explore how m6A RNA methylation impacts both the normal and disease states of the cardiovascular system. Our focus will be on recent advancements in understanding the biological functions, molecular mechanisms, and regulatory factors of m6A RNA methylation, along with its downstream target genes in various CVDs, such as atherosclerosis, ischemic diseases, metabolic disorders, and heart failure. We propose that the m6A RNA methylation pathway holds promise as a potential therapeutic target in cardiovascular disease.
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Affiliation(s)
- Huan Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Wei Lu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Haoyue Tang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Aiqun Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Xiaofei Gao
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Congfei Zhu
- Department of Cardiology, Lianshui County People’s Hospital, Affiliated Hospital of Kangda College, Nanjing Medical University, Huaian 223400, China
| | - Junjie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
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3
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Wang T, Zhou D, Hong Z. Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2025; 6:e70030. [PMID: 39764565 PMCID: PMC11702502 DOI: 10.1002/mco2.70030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 03/17/2025] Open
Abstract
Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.
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Affiliation(s)
- Tiantian Wang
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
| | - Dong Zhou
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
| | - Zhen Hong
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
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4
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Bibi A, Bartekova M, Gandhi S, Greco S, Madè A, Sarkar M, Stopa V, Tastsoglou S, de Gonzalo-Calvo D, Devaux Y, Emanueli C, Hatzigeorgiou AG, Nossent AY, Zhou Z, Martelli F. Circular RNA regulatory role in pathological cardiac remodelling. Br J Pharmacol 2025; 182:316-339. [PMID: 38830749 DOI: 10.1111/bph.16434] [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: 10/30/2023] [Revised: 03/14/2024] [Accepted: 04/12/2024] [Indexed: 06/05/2024] Open
Abstract
Cardiac remodelling involves structural, cellular and molecular alterations in the heart after injury, resulting in progressive loss of heart function and ultimately leading to heart failure. Circular RNAs (circRNAs) are a recently rediscovered class of non-coding RNAs that play regulatory roles in the pathogenesis of cardiovascular diseases, including heart failure. Thus, a more comprehensive understanding of the role of circRNAs in the processes governing cardiac remodelling may set the ground for the development of circRNA-based diagnostic and therapeutic strategies. In this review, the current knowledge about circRNA origin, conservation, characteristics and function is summarized. Bioinformatics and wet-lab methods used in circRNA research are discussed. The regulatory function of circRNAs in cardiac remodelling mechanisms such as cell death, cardiomyocyte hypertrophy, inflammation, fibrosis and metabolism is highlighted. Finally, key challenges and opportunities in circRNA research are discussed, and orientations for future work to address the pharmacological potential of circRNAs in heart failure are proposed. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Affiliation(s)
- Alessia Bibi
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
- Department of Biosciences, University of Milan, Milan, Italy
| | - Monika Bartekova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Comenius University in Bratislava, Bratislava, Slovakia
| | - Shrey Gandhi
- Institute of Immunology, University of Münster, Münster, Germany
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
| | - Simona Greco
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Alisia Madè
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Moumita Sarkar
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Victoria Stopa
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Spyros Tastsoglou
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | - David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Yvan Devaux
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Costanza Emanueli
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Artemis G Hatzigeorgiou
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | - A Yaël Nossent
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Zhichao Zhou
- Division of Cardiology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
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Li Y, Du J, Deng S, Liu B, Jing X, Yan Y, Liu Y, Wang J, Zhou X, She Q. The molecular mechanisms of cardiac development and related diseases. Signal Transduct Target Ther 2024; 9:368. [PMID: 39715759 DOI: 10.1038/s41392-024-02069-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/28/2024] [Accepted: 11/04/2024] [Indexed: 12/25/2024] Open
Abstract
Cardiac development is a complex and intricate process involving numerous molecular signals and pathways. Researchers have explored cardiac development through a long journey, starting with early studies observing morphological changes and progressing to the exploration of molecular mechanisms using various molecular biology methods. Currently, advancements in stem cell technology and sequencing technology, such as the generation of human pluripotent stem cells and cardiac organoids, multi-omics sequencing, and artificial intelligence (AI) technology, have enabled researchers to understand the molecular mechanisms of cardiac development better. Many molecular signals regulate cardiac development, including various growth and transcription factors and signaling pathways, such as WNT signaling, retinoic acid signaling, and Notch signaling pathways. In addition, cilia, the extracellular matrix, epigenetic modifications, and hypoxia conditions also play important roles in cardiac development. These factors play crucial roles at one or even multiple stages of cardiac development. Recent studies have also identified roles for autophagy, metabolic transition, and macrophages in cardiac development. Deficiencies or abnormal expression of these factors can lead to various types of cardiac development abnormalities. Nowadays, congenital heart disease (CHD) management requires lifelong care, primarily involving surgical and pharmacological treatments. Advances in surgical techniques and the development of clinical genetic testing have enabled earlier diagnosis and treatment of CHD. However, these technologies still have significant limitations. The development of new technologies, such as sequencing and AI technologies, will help us better understand the molecular mechanisms of cardiac development and promote earlier prevention and treatment of CHD in the future.
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Affiliation(s)
- Yingrui Li
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianlin Du
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Songbai Deng
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaodong Jing
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuling Yan
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yajie Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Wang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaobo Zhou
- Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany
| | - Qiang She
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Alissa M, Aldurayhim M, Abdulaziz O, Alsalmi O, Awad A, Algopishi UB, Alharbi S, Safhi AY, Khan KH, Uffar C. From molecules to heart regeneration: Understanding the complex and profound role of non-coding RNAs in stimulating cardiomyocyte proliferation for cardiac repair. Curr Probl Cardiol 2024; 49:102857. [PMID: 39306148 DOI: 10.1016/j.cpcardiol.2024.102857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 09/16/2024] [Indexed: 09/29/2024]
Abstract
Recent studies of noncoding genomes have shown important implications for regulating gene expression and genetic programs during development and their association with health, including cardiovascular disease. There are nearly 2,500 microRNAs (miRNAs), 12,000 long-chain non-coding RNAs (lncRNA), and nearly 4,000 circular RNAs (circles). Even though they do not code for proteins, they make up nearly 99% of the human genome. Non-coding RNA families (ncRNAs) have recently been discovered and established as novel and necessary controllers of cardiovascular risk factors and cellular processes and, therefore, have the potential to improve the diagnosis and prediction of cardiovascular disease. The increase in the prevalence of cardiovascular disease can be explained by the shortcomings of existing therapies, which focus only on the non-coding RNAs that protein codes for. On the other hand, recent studies point to the possibility of using ncRNAs in the early detection and intervention of CVD. These findings suggest that developing diagnostic tools and therapies based on miRNAs, lncRNAs, and circRNAs will potentially enhance the clinical management of patients with cardiovascular disease. Cardiovascular diseases include CH, HF, RHD, ACS, MI, AS, MF, ARR, and PAH, of which CH is the most common cardiovascular disease, followed by HF and RHD. This paper aims to elucidate the biological and clinical significance of miRNAs, increase, and circles, as well as their expression profiles and the possibility of regulating non-coding transcripts in cardiovascular diseases to improve the application of ncRNAs in diagnosis and treatment.
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Affiliation(s)
- Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Mohammed Aldurayhim
- Department of Medical Laboratory, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Osama Abdulaziz
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21974, Saudi Arabia
| | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21974, Saudi Arabia
| | - Alsamghan Awad
- King Khalid University, College of Medicine, Family Medicine department, Saudi Arabia
| | | | - Sarah Alharbi
- Department of Medical Laboratory, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Awaji Y Safhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Khadijah Hassan Khan
- Department of Laboratory, King Faisal Medical Complex, Ministry of Health, Taif 26514, Saudi Arabia
| | - Christin Uffar
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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Xing Z, Guo L, Li S, Huang W, Su J, Chen X, Li Y, Zhang J. Skeletal muscle-derived exosomes prevent osteoporosis by promoting osteogenesis. Life Sci 2024; 357:123079. [PMID: 39326580 DOI: 10.1016/j.lfs.2024.123079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/18/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024]
Abstract
Skeletal muscle and bone are the major organs for physical activity, in which there is a parallel correlation between muscle mass and bone density throughout a lifetime. Osteoporosis is a systemic bone metabolic disorder caused by reduced bone formation and increased bone resorption. Based on the metabolic symbiosis relationship between skeletal muscle and bone, we hypothesis that skeletal muscle secretory factors could play constructive roles in osteoporosis. Exosomes have been verified to transfer bioactive factors among cells. However, the role of skeletal muscle derived-exosomes (SM-Exos) in osteoporosis is still unclear. In this study, we performed neuromuscular electrical stimulation (NMES) intervention on denervated skeletal muscles and subsequently extracted exosomes (DN + ES-Exo) from the skeletal muscles, and then injected these DN + ES-Exo into sarco-osteoporotic rats through tail vein. In vitro studies, we cocultured SM-Exos from different states with differentiated MC3T3-E1 osteoblasts. In brief, our research findings demonstrate that SM-Exos could partially promote osteogenesis both in vivo and in vitro. Further, our findings indicate that skeletal muscle contraction induced by NMES can reverse the incidence of sarco-osteoporosis to a certain degree, and DN + ES-Exo contributes to the improvement in osteoporosis by facilitating osteoblast differentiation. Then, we revealed that NMES might regulate several miRNAs in skeletal muscle, the miRNAs that are encapsulated by SM-Exos might be involved in osteogenic differentiation in a network manner. All in all, this study confirmed the effect of NMES on sarco-osteoporosis and explored the role of SM-Exos in the improvement of osteoporosis, which provide an effective theoretical support for the physical therapy of clinical sarco-osteoporosis.
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Affiliation(s)
- Zheng Xing
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
| | - Lanlan Guo
- Department of Physical Education, University of International Business and Economics, Beijing 100029, China
| | - Shitian Li
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
| | - Wenhua Huang
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
| | - Jie Su
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
| | - Xuefei Chen
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
| | - Yanjun Li
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
| | - Jing Zhang
- College of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China.
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Odimegwu CL, Uwaezuoke SN, Chikani UN, Mbanefo NR, Adiele KD, Nwolisa CE, Eneh CI, Ndiokwelu CO, Okpala SC, Ogbuka FN, Odo KE, Ohuche IO, Obiora-Izuka CE. Targeting the Epigenetic Marks in Type 2 Diabetes Mellitus: Will Epigenetic Therapy Be a Valuable Adjunct to Pharmacotherapy? Diabetes Metab Syndr Obes 2024; 17:3557-3576. [PMID: 39323929 PMCID: PMC11423826 DOI: 10.2147/dmso.s479077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/03/2024] [Indexed: 09/27/2024] Open
Abstract
Although genetic, environmental, and lifestyle factors largely contribute to type 2 diabetes mellitus (T2DM) risk, the role of epigenetics in its pathogenesis is now well established. The epigenetic mechanisms in T2DM mainly consist of DNA methylation, histone modifications and regulation by noncoding RNAs (ncRNAs). For instance, DNA methylation at CpG islands in the promoter regions of specific genes encoding insulin signaling and glucose metabolism suppresses these genes. Modulating the enzyme mediators of these epigenetic marks aims to restore standard gene expression patterns and improve glycemic control. In targeting these epigenetic marks, using epigenetic drugs such as DNA methyltransferase (DNAMT), histone deacetylase (HDAC) and histone acetyltransferase (HAT) inhibitors has led to variable success in humans and experimental murine models. Specifically, the United States' Food and Drug Administration (US FDA) has approved DNAMT inhibitors like 5-azacytidine and 5-aza-2'-deoxycytidine for use in diabetic retinopathy: a T2DM microvascular complication. These DNAMT inhibitors block the genes for methylation of mitochondrial superoxide dismutase 2 (SOD2) and matrix metallopeptidase 9 (MMP-9): the epigenetic marks in diabetic retinopathy. Traditional pharmacotherapy with metformin also have epigenetic effects in T2DM and positively alter disease outcomes when combined with epigenetic drugs like DNAMT and HDAC inhibitors, raising the prospect of using epigenetic therapy as a valuable adjunct to pharmacotherapy. However, introducing small interfering RNAs (siRNAs) in cells to silence specific target genes remains in the exploratory phase. Future research should focus on regulating gene expression in T2DM using long noncoding RNA (lncRNA) molecules, another type of ncRNA. This review discusses the epigenetics of T2DM and that of its macro- and microvascular complications, and the potential benefits of combining epigenetic therapy with pharmacotherapy for optimal results.
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Affiliation(s)
- Chioma Laura Odimegwu
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Samuel Nkachukwu Uwaezuoke
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Ugo N Chikani
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Ngozi Rita Mbanefo
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Ken Daberechi Adiele
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | | | - Chizoma Ihuarula Eneh
- Department of Pediatrics, Enugu State University Teaching Hospital (ESUTH), Enugu, Nigeria
| | - Chibuzo Obiora Ndiokwelu
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Somkenechi C Okpala
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Francis N Ogbuka
- Department of Pediatrics, Enugu State University Teaching Hospital (ESUTH), Enugu, Nigeria
| | - Kenneth E Odo
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
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Andiappan R, Govindan R, Ramasamy T, Poomarimuthu M. Circulating miR-133a-3p and miR-451a as potential biomarkers for diagnosis of coronary artery disease. Acta Cardiol 2024; 79:813-823. [PMID: 39373072 DOI: 10.1080/00015385.2024.2410599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/03/2024] [Accepted: 09/26/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Coronary artery disease (CAD) remains the leading cause of mortality and morbidity around the world. Despite significant progress in the diagnosis and treatment of cardiovascular diseases, still there is a clinical need to identify novel biomarkers for early diagnosis and treatment of CAD. The aim of the study is to investigate circulating miRNAs in CAD patients to identify potential biomarkers for early detection and therapeutic management of CAD. METHODS We assessed the expression of different candidate miRNAs (miR-21-5p, miR-133a-3p, miR-221-3p, miR-451a and miR-584-5p) in plasma from 50 CAD patients and 50 controls by qRT-PCR analysis. RESULTS The expression levels of miR-133a-3p (fold change (FC): 28.05, p < 0.0001), miR-451a (FC: 27.47, p < 0.0001), miR-584-5p (FC: 7.89, p < 0.0001), miR-21-5p (FC: 5.35, p < 0.0001) and miR-221-3p (FC: 5.03, p < 0.0001) were significantly up-regulated in CAD patients compared to controls. Receiver operating characteristic curve analysis showed that miR-133a-3p and miR-451a were powerful biomarkers for detecting CAD. CONCLUSIONS Our results suggested that miR-21-5p, miR-133a-3p, miR-221-3p, miR-451a and miR-584-5p may serve as independent biomarkers for CAD. Further, the combination of miR-133a-3p and miR-451a could be used as a specific signature in CAD diagnosis.
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Affiliation(s)
- Rathinavel Andiappan
- Department of Cardio Vascular Thoracic Surgery, Madurai Medical College & Government Rajaji Hospital, Madurai, Tamil Nadu, India
| | - Ramajayam Govindan
- Multidisciplinary Research Unit, Madurai Medical College, Madurai, Tamil Nadu, India
| | - Thirunavukkarasu Ramasamy
- Maternal-Child health Center, Translational Health Science and Technology Institute, Faridabad, Haryana, India
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10
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Liu X, Yao X, Chen L. Expanding roles of circRNAs in cardiovascular diseases. Noncoding RNA Res 2024; 9:429-436. [PMID: 38511061 PMCID: PMC10950605 DOI: 10.1016/j.ncrna.2024.02.001] [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: 12/26/2023] [Revised: 02/01/2024] [Accepted: 02/04/2024] [Indexed: 03/22/2024] Open
Abstract
CircRNAs are a class of single-stranded RNAs characterized by covalently looped structures. Emerging advances have promoted our understanding of circRNA biogenesis, nuclear export, biological functions, and functional mechanisms. Roles of circRNAs in diverse diseases have been increasingly recognized in the past decade, with novel approaches in bioinformatics analysis and new strategies in modulating circRNA levels, which have made circRNAs the hot spot for therapeutic applications. Moreover, due to the intrinsic features of circRNAs such as high stability, conservation, and tissue-/stage-specific expression, circRNAs are believed to be promising prognostic and diagnostic markers for diseases. Aiming cardiovascular disease (CVD), one of the leading causes of mortality worldwide, we briefly summarize the current understanding of circRNAs, provide the recent progress in circRNA functions and functional mechanisms in CVD, and discuss the future perspectives both in circRNA research and therapeutics based on existing knowledge.
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Affiliation(s)
- Xu Liu
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Xuelin Yao
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Liang Chen
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
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11
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Jang J, Accornero F, Li D. Epigenetic determinants and non-myocardial signaling pathways contributing to heart growth and regeneration. Pharmacol Ther 2024; 257:108638. [PMID: 38548089 PMCID: PMC11931646 DOI: 10.1016/j.pharmthera.2024.108638] [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: 01/02/2024] [Revised: 03/14/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
Congenital heart disease is the most common birth defect worldwide. Defective cardiac myogenesis is either a major presentation or associated with many types of congenital heart disease. Non-myocardial tissues, including endocardium and epicardium, function as a supporting hub for myocardial growth and maturation during heart development. Recent research findings suggest an emerging role of epigenetics in nonmyocytes supporting myocardial development. Understanding how growth signaling pathways in non-myocardial tissues are regulated by epigenetic factors will likely identify new disease mechanisms for congenital heart diseases and shed lights for novel therapeutic strategies for heart regeneration.
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Affiliation(s)
- Jihyun Jang
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43215, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA.
| | - Federica Accornero
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Deqiang Li
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43215, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA.
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12
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Wang G, Lu W, Shen WB, Karbowski M, Kaushal S, Yang P. Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes. JACC Basic Transl Sci 2024; 9:303-318. [PMID: 38559623 PMCID: PMC10978414 DOI: 10.1016/j.jacbts.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 11/22/2023] [Accepted: 11/22/2023] [Indexed: 04/04/2024]
Abstract
Most congenital heart defect (CHD) cases are attributed to nongenetic factors; however, the mechanisms underlying nongenetic factor-induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors, and this study aimed to determine whether impaired mitochondrial fusion contributes to maternal diabetes-induced CHDs and if mitochondrial fusion activators, teriflunomide and echinacoside, could reduce CHD incidence in diabetic pregnancy. We demonstrated maternal diabetes-activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Two mitochondrial fusion activators are effective in preventing CHDs in diabetic pregnancy.
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Affiliation(s)
- Guanglei Wang
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Wenhui Lu
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Wei-Bin Shen
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Mariusz Karbowski
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Sunjay Kaushal
- Division of Cardiac Surgery, Department of Surgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Peixin Yang
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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13
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Dong H, Sun Y, Nie L, Cui A, Zhao P, Leung WK, Wang Q. Metabolic memory: mechanisms and diseases. Signal Transduct Target Ther 2024; 9:38. [PMID: 38413567 PMCID: PMC10899265 DOI: 10.1038/s41392-024-01755-x] [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: 09/18/2023] [Revised: 01/18/2024] [Accepted: 01/23/2024] [Indexed: 02/29/2024] Open
Abstract
Metabolic diseases and their complications impose health and economic burdens worldwide. Evidence from past experimental studies and clinical trials suggests our body may have the ability to remember the past metabolic environment, such as hyperglycemia or hyperlipidemia, thus leading to chronic inflammatory disorders and other diseases even after the elimination of these metabolic environments. The long-term effects of that aberrant metabolism on the body have been summarized as metabolic memory and are found to assume a crucial role in states of health and disease. Multiple molecular mechanisms collectively participate in metabolic memory management, resulting in different cellular alterations as well as tissue and organ dysfunctions, culminating in disease progression and even affecting offspring. The elucidation and expansion of the concept of metabolic memory provides more comprehensive insight into pathogenic mechanisms underlying metabolic diseases and complications and promises to be a new target in disease detection and management. Here, we retrace the history of relevant research on metabolic memory and summarize its salient characteristics. We provide a detailed discussion of the mechanisms by which metabolic memory may be involved in disease development at molecular, cellular, and organ levels, with emphasis on the impact of epigenetic modulations. Finally, we present some of the pivotal findings arguing in favor of targeting metabolic memory to develop therapeutic strategies for metabolic diseases and provide the latest reflections on the consequences of metabolic memory as well as their implications for human health and diseases.
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Affiliation(s)
- Hao Dong
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuezhang Sun
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lulingxiao Nie
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Aimin Cui
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Pengfei Zhao
- Periodontology and Implant Dentistry Division, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Wai Keung Leung
- Periodontology and Implant Dentistry Division, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Qi Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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14
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Racedo SE, Liu Y, Shi L, Zheng D, Morrow BE. Dgcr8 functions in the secondary heart field for outflow tract and right ventricle development in mammals. Dev Biol 2024; 506:72-84. [PMID: 38110169 PMCID: PMC10793380 DOI: 10.1016/j.ydbio.2023.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/28/2023] [Accepted: 12/11/2023] [Indexed: 12/20/2023]
Abstract
The DGCR8 gene, encoding a critical miRNA processing protein, maps within the hemizygous region in patients with 22q11.2 deletion syndrome. Most patients have malformations of the cardiac outflow tract that is derived in part from the anterior second heart field (aSHF) mesoderm. To understand the function of Dgcr8 in the aSHF, we inactivated it in mice using Mef2c-AHF-Cre. Inactivation resulted in a fully penetrant persistent truncus arteriosus and a hypoplastic right ventricle leading to lethality by E14.5. To understand the molecular mechanism for this phenotype, we performed gene expression profiling of the aSHF and the cardiac outflow tract with right ventricle in conditional null versus normal mouse littermates at stage E9.5 prior to morphology changes. We identified dysregulation of mRNA gene expression, of which some are relevant to cardiogenesis. Many pri-miRNA genes were strongly increased in expression in mutant embryos along with reduced expression of mature miRNA genes. We further examined the individual, mature miRNAs that were decreased in expression along with pri-miRNAs that were accumulated that could be direct effects due to loss of Dgcr8. Among these genes, were miR-1a, miR-133a, miR-134, miR143 and miR145a, which have known functions in heart development. These early mRNA and miRNA changes may in part, explain the first steps that lead to the resulting phenotype in Dgcr8 aSHF conditional mutant embryos.
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Affiliation(s)
- Silvia E Racedo
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yang Liu
- Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Bell Buckle, TN, USA
| | - Lijie Shi
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bernice E Morrow
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA; Departments of Pediatrics and Ob/Gyn & Population Health, USA.
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15
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Cao Y, Zheng M, Sewani MA, Wang J. The miR-17-92 cluster in cardiac health and disease. Birth Defects Res 2024; 116:e2273. [PMID: 37984445 PMCID: PMC11418803 DOI: 10.1002/bdr2.2273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 11/22/2023]
Abstract
MicroRNAs (miRs) are small noncoding RNAs that play important roles in both physiological and pathological processes through post-transcriptional regulation. The miR-17-92 cluster includes six individual members: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1. The miR-17-92 cluster has been extensively studied and reported to broadly function in cancer biology, immunology, neurology, pulmonology, and cardiology. This review focuses on its roles in heart development and cardiac diseases. We briefly introduce the nature of the miR-17-92 cluster and its crucial roles in both normal development and the pathogenesis of various diseases. We summarize the recent progress in understanding the versatile roles of miR-17-92 during cardiac development, regeneration, and aging. Additionally, we highlight the indispensable roles of the miR-17-92 cluster in pathogenesis and therapeutic potential in cardiac birth defects and adult cardiac diseases.
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Affiliation(s)
- Yuhan Cao
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Mingjie Zheng
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Maham A Sewani
- Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston, TX 77030, USA
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA
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16
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Parsamanesh N, Poudineh M, Siami H, Butler AE, Almahmeed W, Sahebkar A. RNA interference-based therapies for atherosclerosis: Recent advances and future prospects. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 204:1-43. [PMID: 38458734 DOI: 10.1016/bs.pmbts.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.
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Affiliation(s)
- Negin Parsamanesh
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Haleh Siami
- School of Medicine, Islamic Azad University of Medical Science, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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17
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Aharon-Yariv A, Wang Y, Ahmed A, Delgado-Olguín P. Integrated small RNA, mRNA and protein omics reveal a miRNA network orchestrating metabolic maturation of the developing human heart. BMC Genomics 2023; 24:709. [PMID: 37996818 PMCID: PMC10668469 DOI: 10.1186/s12864-023-09801-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/11/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND As the fetal heart develops, cardiomyocyte proliferation potential decreases while fatty acid oxidative capacity increases in a highly regulated transition known as cardiac maturation. Small noncoding RNAs, such as microRNAs (miRNAs), contribute to the establishment and control of tissue-specific transcriptional programs. However, small RNA expression dynamics and genome-wide miRNA regulatory networks controlling maturation of the human fetal heart remain poorly understood. RESULTS Transcriptome profiling of small RNAs revealed the temporal expression patterns of miRNA, piRNA, circRNA, snoRNA, snRNA and tRNA in the developing human heart between 8 and 19 weeks of gestation. Our analysis demonstrated that miRNAs were the most dynamically expressed small RNA species throughout mid-gestation. Cross-referencing differentially expressed miRNAs and mRNAs predicted 6200 mRNA targets, 2134 of which were upregulated and 4066 downregulated as gestation progressed. Moreover, we found that downregulated targets of upregulated miRNAs, including hsa-let-7b, miR-1-3p, miR-133a-3p, miR-143-3p, miR-499a-5p, and miR-30a-5p predominantly control cell cycle progression. In contrast, upregulated targets of downregulated miRNAs, including hsa-miR-1276, miR-183-5p, miR-1229-3p, miR-615-3p, miR-421, miR-200b-3p and miR-18a-3p, are linked to energy sensing and oxidative metabolism. Furthermore, integrating miRNA and mRNA profiles with proteomes and reporter metabolites revealed that proteins encoded in mRNA targets and their associated metabolites mediate fatty acid oxidation and are enriched as the heart develops. CONCLUSIONS This study presents the first comprehensive analysis of the small RNAome of the maturing human fetal heart. Our findings suggest that coordinated activation and repression of miRNA expression throughout mid-gestation is essential to establish a dynamic miRNA-mRNA-protein network that decreases cardiomyocyte proliferation potential while increasing the oxidative capacity of the maturing human fetal heart. Our results provide novel insights into the molecular control of metabolic maturation of the human fetal heart.
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Affiliation(s)
- Adar Aharon-Yariv
- Translational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G0A4, Canada
- Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yaxu Wang
- Translational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G0A4, Canada
- Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Abdalla Ahmed
- Translational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G0A4, Canada
- Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Paul Delgado-Olguín
- Translational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G0A4, Canada.
- Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Heart & Stroke, Richard Lewar Centre of Excellence, Toronto, Ontario, Canada.
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18
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Zhao JM, Li FQY, Li XY, Jiao DR, Liu XD, Lv XY, Zhao JX. Guanidinoacetic Acid Attenuates Adipogenesis through Regulation of miR-133a in Sheep. Animals (Basel) 2023; 13:3108. [PMID: 37835715 PMCID: PMC10571753 DOI: 10.3390/ani13193108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/30/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
Guanidinoacetic acid (GAA) is an amino acid derivative, previously described in the skeletal muscle of vertebrates, that serves as an important regulator of cellular bioenergetics and has been widely used as a feed additive. Nevertheless, the effect of GAA on adipose tissue growth remains unclear. Here, we hypothesized that dietary GAA negatively affected adipose tissue development in lambs. Lambs were individually fed diets with (0.09%) or without GAA for 70 d ad libitum, and the subcutaneous adipose tissues were sampled for analysis. The results showed that dietary GAA supplementation decreased the girth rib (GR) value (p < 0.01) of lamb carcasses. Both real-time PCR and Western blot analysis suggested that dietary GAA inhibited the expression of adipogenic markers, including peroxisome proliferator-activated receptor γ (PPARγ, p < 0.05), CCAAT/enhancer-binding protein α (C/EBPα, p < 0.01) and sterol-regulatory-element-binding protein 1c (SREBP1C, p < 0.01) in subcutaneous adipose tissue. In vitro, GAA inhibited sheep stromal vascular fraction (SVF) cell proliferation, which was associated with downregulation of proliferating cell nuclear antigen (PCNA, p < 0.05), cyclin-dependent kinase 4 (CDK 4, p < 0.05) and cyclin D1 (p < 0.01). GAA suppressed adipogenesis of SVF cells. Furthermore, miRNA sequencing revealed that GAA affected the miRNA expression profile, and real-time PCR analysis confirmed that miR-133a expression in both subcutaneous adipose tissue and SVF cell was downregulated by GAA. Meanwhile, miR-133a promoted adipogenic differentiation of SVF cells by targeting Sirt1. miR-133a mimics alleviated the inhibitory effect of GAA on SVF cells' adipogenic differentiation. In summary, GAA attenuated adipogenesis of sheep SVF cells, which might occur through miR-133a-modulated Sirt1 expression.
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Affiliation(s)
- Jia-Min Zhao
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China (X.-Y.L.); (D.-R.J.)
| | - Fan-Qin-Yu Li
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China (X.-Y.L.); (D.-R.J.)
| | - Xv-Ying Li
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China (X.-Y.L.); (D.-R.J.)
| | - Dan-Rong Jiao
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China (X.-Y.L.); (D.-R.J.)
| | - Xiang-Dong Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Xiao-Yang Lv
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Jun-Xing Zhao
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China (X.-Y.L.); (D.-R.J.)
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19
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Burgon PG, Weldrick JJ, Talab OMSA, Nadeer M, Nomikos M, Megeney LA. Regulatory Mechanisms That Guide the Fetal to Postnatal Transition of Cardiomyocytes. Cells 2023; 12:2324. [PMID: 37759546 PMCID: PMC10528641 DOI: 10.3390/cells12182324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Heart disease remains a global leading cause of death and disability, necessitating a comprehensive understanding of the heart's development, repair, and dysfunction. This review surveys recent discoveries that explore the developmental transition of proliferative fetal cardiomyocytes into hypertrophic postnatal cardiomyocytes, a process yet to be well-defined. This transition is key to the heart's growth and has promising therapeutic potential, particularly for congenital or acquired heart damage, such as myocardial infarctions. Although significant progress has been made, much work is needed to unravel the complex interplay of signaling pathways that regulate cardiomyocyte proliferation and hypertrophy. This review provides a detailed perspective for future research directions aimed at the potential therapeutic harnessing of the perinatal heart transitions.
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Affiliation(s)
- Patrick G. Burgon
- Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar
| | - Jonathan J. Weldrick
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
| | | | - Muhammad Nadeer
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Michail Nomikos
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Lynn A. Megeney
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
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20
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Pezhouman A, Nguyen NB, Kay M, Kanjilal B, Noshadi I, Ardehali R. Cardiac regeneration - Past advancements, current challenges, and future directions. J Mol Cell Cardiol 2023; 182:75-85. [PMID: 37482238 DOI: 10.1016/j.yjmcc.2023.07.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023]
Abstract
Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Despite improvements in the standard of care for patients with heart diseases, including innovation in pharmacotherapy and surgical interventions, none have yet been proven effective to prevent the progression to heart failure. Cardiac transplantation is the last resort for patients with severe heart failure, but donor shortages remain a roadblock. Cardiac regenerative strategies include cell-based therapeutics, gene therapy, direct reprogramming of non-cardiac cells, acellular biologics, and tissue engineering methods to restore damaged hearts. Significant advancements have been made over the past several decades within each of these fields. This review focuses on the advancements of: 1) cell-based cardiac regenerative therapies, 2) the use of noncoding RNA to induce endogenous cell proliferation, and 3) application of bioengineering methods to promote retention and integration of engrafted cells. Different cell sources have been investigated, including adult stem cells derived from bone marrow and adipose cells, cardiosphere-derived cells, skeletal myoblasts, and pluripotent stem cells. In addition to cell-based transplantation approaches, there have been accumulating interest over the past decade in inducing endogenous CM proliferation for heart regeneration, particularly with the use of noncoding RNAs such as miRNAs and lncRNAs. Bioengineering applications have focused on combining cell-transplantation approaches with fabrication of a porous, vascularized scaffold using biomaterials and advanced bio-fabrication techniques that may offer enhanced retention of transplanted cells, with the hope that these cells would better engraft with host tissue to improve cardiac function. This review summarizes the present status and future challenges of cardiac regenerative therapies.
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Affiliation(s)
- Arash Pezhouman
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States
| | - Ngoc B Nguyen
- Baylor College of Medicine, Department of Internal Medicine, Houston, Texas 77030, United States
| | - Maryam Kay
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, United States
| | - Baishali Kanjilal
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Iman Noshadi
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Reza Ardehali
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States.
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21
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Salvatori F, D’Aversa E, Serino ML, Singh AV, Secchiero P, Zauli G, Tisato V, Gemmati D. miRNAs Epigenetic Tuning of Wall Remodeling in the Early Phase after Myocardial Infarction: A Novel Epidrug Approach. Int J Mol Sci 2023; 24:13268. [PMID: 37686073 PMCID: PMC10487654 DOI: 10.3390/ijms241713268] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Myocardial infarction (MI) is one of the leading causes of death in Western countries. An early diagnosis decreases subsequent severe complications such as wall remodeling or heart failure and improves treatments and interventions. Novel therapeutic targets have been recognized and, together with the development of direct and indirect epidrugs, the role of non-coding RNAs (ncRNAs) yields great expectancy. ncRNAs are a group of RNAs not translated into a product and, among them, microRNAs (miRNAs) are the most investigated subgroup since they are involved in several pathological processes related to MI and post-MI phases such as inflammation, apoptosis, angiogenesis, and fibrosis. These processes and pathways are finely tuned by miRNAs via complex mechanisms. We are at the beginning of the investigation and the main paths are still underexplored. In this review, we provide a comprehensive discussion of the recent findings on epigenetic changes involved in the first phases after MI as well as on the role of the several miRNAs. We focused on miRNAs function and on their relationship with key molecules and cells involved in healing processes after an ischemic accident, while also giving insight into the discrepancy between males and females in the prognosis of cardiovascular diseases.
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Affiliation(s)
- Francesca Salvatori
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.S.)
| | - Elisabetta D’Aversa
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.S.)
| | - Maria Luisa Serino
- Centre Haemostasis & Thrombosis, University of Ferrara, 44121 Ferrara, Italy
| | - Ajay Vikram Singh
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany
| | - Paola Secchiero
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.S.)
| | - Giorgio Zauli
- Department of Environmental Science and Prevention, University of Ferrara, 44121 Ferrara, Italy
| | - Veronica Tisato
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.S.)
- LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
- University Centre for Studies on Gender Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Donato Gemmati
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.S.)
- Centre Haemostasis & Thrombosis, University of Ferrara, 44121 Ferrara, Italy
- University Centre for Studies on Gender Medicine, University of Ferrara, 44121 Ferrara, Italy
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22
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Kabłak-Ziembicka A, Badacz R, Okarski M, Wawak M, Przewłocki T, Podolec J. Cardiac microRNAs: diagnostic and therapeutic potential. Arch Med Sci 2023; 19:1360-1381. [PMID: 37732050 PMCID: PMC10507763 DOI: 10.5114/aoms/169775] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/18/2023] [Indexed: 09/22/2023] Open
Abstract
MicroRNAs are small non-coding post-translational biomolecules which, when expressed, modify their target genes. It is estimated that microRNAs regulate production of approximately 60% of all human proteins and enzymes that are responsible for major physiological processes. In cardiovascular disease pathophysiology, there are several cells that produce microRNAs, including endothelial cells, vascular smooth muscle cells, macrophages, platelets, and cardiomyocytes. There is a constant crosstalk between microRNAs derived from various cell sources. Atherosclerosis initiation and progression are driven by many pro-inflammatory and pro-thrombotic microRNAs. Atherosclerotic plaque rupture is the leading cause of cardiovascular death resulting from acute coronary syndrome (ACS) and leads to cardiac remodeling and fibrosis following ACS. MicroRNAs are powerful modulators of plaque progression and transformation into a vulnerable state, which can eventually lead to plaque rupture. There is a growing body of evidence which demonstrates that following ACS, microRNAs might inhibit fibroblast proliferation and scarring, as well as harmful apoptosis of cardiomyocytes, and stimulate fibroblast reprogramming into induced cardiac progenitor cells. In this review, we focus on the role of cardiomyocyte-derived and cardiac fibroblast-derived microRNAs that are involved in the regulation of genes associated with cardiomyocyte and fibroblast function and in atherosclerosis-related cardiac ischemia. Understanding their mechanisms may lead to the development of microRNA cocktails that can potentially be used in regenerative cardiology.
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Affiliation(s)
- Anna Kabłak-Ziembicka
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
- Noninvasive Cardiovascular Laboratory, the John Paul II Hospital, Krakow, Poland
| | - Rafał Badacz
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
- Department of Interventional Cardiology, the John Paul II Hospital, Krakow, Poland
| | - Michał Okarski
- Student Scientific Group of Modern Cardiac Therapy at the Department of Interventional Cardiology, Jagiellonian University Medical College, Krakow, Poland
| | - Magdalena Wawak
- Department of Interventional Cardiology, the John Paul II Hospital, Krakow, Poland
| | - Tadeusz Przewłocki
- Noninvasive Cardiovascular Laboratory, the John Paul II Hospital, Krakow, Poland
- Department of Cardiac and Vascular Diseases Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
| | - Jakub Podolec
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
- Department of Interventional Cardiology, the John Paul II Hospital, Krakow, Poland
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23
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Yu YN, Ren YY, Shao ZL, Chen BL, Cui BY, Chao CY, Guo LJ, Guo S, Zhang MX, Wang SX, Zhu ML, Yin YL, Li P. Perillaldehyde improves diabetic cardiomyopathy by upregulating miR-133a-3p to regulate GSK-3β. Eur J Pharmacol 2023; 953:175836. [PMID: 37329971 DOI: 10.1016/j.ejphar.2023.175836] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/04/2023] [Accepted: 06/06/2023] [Indexed: 06/19/2023]
Abstract
Diabetic cardiomyopathy (DCM) is part of the most important causes of death from cardiovascular disease. Perillaldehyde (PAE), a major component of the herb perilla, has been shown to ameliorate doxorubicin-induced cardiotoxicity, but it is unclear whether PAE exerts beneficial effects on DCM. Exploring the potential molecular mechanisms of PAE for the treatment of DCM through network pharmacology and molecular docking. The SD rat type 1 diabetes model was established by a single intraperitoneal injection of streptozotocin (60 mg/kg), the cardiac function indexes of each group were detected by echocardiography; the morphological changes, apoptosis, protein expression of P-GSK-3β (S9), collagen I (Col-Ⅰ), collagen III (Col-Ⅲ) and alpha-smooth muscle actin (α-SMA), and miR-133a-3p expression levels were detected. An DCM model of H9c2 cells was established in vitro and transfected with Mimic and Inhibitor of miR-133a-3p. The results showed that PAE ameliorated cardiac dysfunction, reduced fasting glucose and cardiac weight index, and improved myocardial injury and apoptosis in DCM rats. It reduced high glucose-induced apoptosis, promoted migration and improved mitochondrial division injury in H9c2 cells. PAE decreased P-GSK-3β (S9), Col-Ⅰ, Col-Ⅲ and α-SMA protein expression and upregulated miR-133a-3p expression levels. After miR-133a-3p Inhibitor treatment, the expression of P-GSK-3β (S9) and α-SMA expression were significantly increased; after miR-133a-3p Mimic treatment, the expression of P-GSK-3β (S9) and α-SMA decreased significantly in H9c2 cells. It suggests that the mechanism of action of PAE to improve DCM may be related to the upregulation of miR-133a-3p and inhibition of P-GSK-3β expression.
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Affiliation(s)
- Ya-Nan Yu
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yuan-Yuan Ren
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China
| | - Zhen-Lei Shao
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China
| | - Bu-Lei Chen
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China
| | - Bao-Yue Cui
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China
| | | | - Li-Juan Guo
- Department of Oncology, Xinxiang Medical University First Affiliated Hospital, Xinxiang, 453119, China
| | - Shuang Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China
| | - Ming-Xiang Zhang
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China
| | - Shuang-Xi Wang
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China.
| | - Mo-Li Zhu
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China.
| | - Ya-Ling Yin
- School of Basic Medical Sciences, Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang, 453003, China.
| | - Peng Li
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang, 453003, China.
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24
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Juni RP, Kocken JMM, Abreu RC, Ottaviani L, Davalan T, Duygu B, Poels EM, Vasilevich A, Hegenbarth JC, Appari M, Bitsch N, Olieslagers S, Schrijvers DM, Stoll M, Heineke J, de Boer J, de Windt LJ, da Costa Martins PA. MicroRNA-216a is essential for cardiac angiogenesis. Mol Ther 2023; 31:1807-1828. [PMID: 37073128 PMCID: PMC10277893 DOI: 10.1016/j.ymthe.2023.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 04/20/2023] Open
Abstract
While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.
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Affiliation(s)
- Rio P Juni
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Physiology, Amsterdam University Medical Centers, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
| | - Jordy M M Kocken
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Ricardo C Abreu
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Biomaterials and Stem Cell Based Therapeutics Group, CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC, Biotech Parque Tecnológico de Cantanhede, 3060-197 Coimbra, Portugal
| | - Lara Ottaviani
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Tim Davalan
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Burcu Duygu
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Ella M Poels
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Aliaksei Vasilevich
- Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands
| | - Jana C Hegenbarth
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Mahesh Appari
- Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU United Kingdom
| | - Nicole Bitsch
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Serve Olieslagers
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Dorien M Schrijvers
- Laboratory of Physiopharmacology, University of Antwerp, 2610 Wilrijk, Belgium
| | - Monika Stoll
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, 48149 Münster, Germany; Department of Biochemistry, CARIM School for Cardiovascular Diseases, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Joerg Heineke
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; DZHK, Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
| | - Jan de Boer
- Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands
| | - Leon J de Windt
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Paula A da Costa Martins
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal.
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25
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Mannar V, Boro H, Patel D, Agstam S, Dalvi M, Bundela V. Epigenetics of the Pathogenesis and Complications of Type 2 Diabetes Mellitus. TOUCHREVIEWS IN ENDOCRINOLOGY 2023; 19:46-53. [PMID: 37313245 PMCID: PMC10258626 DOI: 10.17925/ee.2023.19.1.46] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/23/2023] [Indexed: 06/15/2023]
Abstract
Epigenetics of type 2 diabetes mellitus (T2DM) has widened our knowledge of various aspects of the disease. The aim of this review is to summarize the important epigenetic changes implicated in the disease risks, pathogenesis, complications and the evolution of therapeutics in our current understanding of T2DM. Studies published in the past 15 years, from 2007 to 2022, from three primary platforms namely PubMed, Google Scholar and Science Direct were included. Studies were searched using the primary term 'type 2 diabetes and epigenetics' with additional terms such as 'risks', 'pathogenesis', 'complications of diabetes' and 'therapeutics'. Epigenetics plays an important role in the transmission of T2DM from one generation to another. Epigenetic changes are also implicated in the two basic pathogenic components of T2DM, namely insulin resistance and impaired insulin secretion. Hyperglycaemia-i nduced permanent epigenetic modifications of the expression of DNA are responsible for the phenomenon of metabolic memory. Epigenetics influences the development of micro-and macrovascular complications of T2DM. They can also be used as biomarkers in the prediction of these complications. Epigenetics has expanded our understanding of the action of existing drugs such as metformin, and has led to the development of newer targets to prevent vascular complications. Epigenetic changes are involved in almost all aspects of T2DM, from risks, pathogenesis and complications, to the development of newer therapeutic targets.
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Affiliation(s)
- Velmurugan Mannar
- Department of Medicine, Aarupadai Veedu Medical College, Puducherry, India
| | - Hiya Boro
- Department of Endocrinology and Metabolism, Aadhar Health Institute, Hisar, India
| | - Deepika Patel
- Department of Endocrinology, Mediheal Hospital, Nairobi, Kenya
| | - Sourabh Agstam
- Department of Cardiology, VMMC and Safdarjung Hospital, New Delhi, India
| | - Mazhar Dalvi
- Department of Endocrinology, Mediclinic Al Noor Hospital, Abu Dhabi, United Arab Emirates
| | - Vikash Bundela
- Department of Gastroenterology, Aadhar Health Institute, Hisar, India
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26
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Vand-Rajabpour F, Savage M, Belote RL, Judson-Torres RL. Critical Considerations for Investigating MicroRNAs during Tumorigenesis: A Case Study in Conceptual and Contextual Nuances of miR-211-5p in Melanoma. EPIGENOMES 2023; 7:9. [PMID: 37218870 PMCID: PMC10204420 DOI: 10.3390/epigenomes7020009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 05/24/2023] Open
Abstract
MicroRNAs are non-coding RNAs fundamental to metazoan development and disease. Although the aberrant regulation of microRNAs during mammalian tumorigenesis is well established, investigations into the contributions of individual microRNAs are wrought with conflicting observations. The underlying cause of these inconsistencies is often attributed to context-specific functions of microRNAs. We propose that consideration of both context-specific factors, as well as underappreciated fundamental concepts of microRNA biology, will permit a more harmonious interpretation of ostensibly diverging data. We discuss the theory that the biological function of microRNAs is to confer robustness to specific cell states. Through this lens, we then consider the role of miR-211-5p in melanoma progression. Using literature review and meta-analyses, we demonstrate how a deep understating of domain-specific contexts is critical for moving toward a concordant understanding of miR-211-5p and other microRNAs in cancer biology.
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Affiliation(s)
- Fatemeh Vand-Rajabpour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, P.O. Box 14155-6447, Tehran 14176-13151, Iran
| | - Meghan Savage
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
| | - Rachel L. Belote
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Robert L. Judson-Torres
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
- Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA
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27
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Dimasi CG, Darby JRT, Morrison JL. A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth. J Physiol 2023; 601:1319-1341. [PMID: 36872609 PMCID: PMC10952280 DOI: 10.1113/jp284137] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/17/2023] [Indexed: 03/07/2023] Open
Abstract
Mammalian cardiomyocytes undergo major maturational changes in preparation for birth and postnatal life. Immature cardiomyocytes contribute to cardiac growth via proliferation and thus the heart has the capacity to regenerate. To prepare for postnatal life, structural and metabolic changes associated with increased cardiac output and function must occur. This includes exit from the cell cycle, hypertrophic growth, mitochondrial maturation and sarcomeric protein isoform switching. However, these changes come at a price: the loss of cardiac regenerative capacity such that damage to the heart in postnatal life is permanent. This is a significant barrier to the development of new treatments for cardiac repair and contributes to heart failure. The transitional period of cardiomyocyte growth is a complex and multifaceted event. In this review, we focus on studies that have investigated this critical transition period as well as novel factors that may regulate and drive this process. We also discuss the potential use of new biomarkers for the detection of myocardial infarction and, in the broader sense, cardiovascular disease.
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Affiliation(s)
- Catherine G. Dimasi
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health SciencesUniversity of South AustraliaAdelaideSAAustralia
| | - Jack R. T. Darby
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health SciencesUniversity of South AustraliaAdelaideSAAustralia
| | - Janna L. Morrison
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health SciencesUniversity of South AustraliaAdelaideSAAustralia
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28
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Tasopoulou KM, Argiriou C, Tsaroucha AK, Georgiadis GS. Circulating miRNAs as biomarkers for diagnosis, surveillance and post-operative follow-up of abdominal aortic aneurysms. Ann Vasc Surg 2023:S0890-5096(23)00144-9. [PMID: 36921794 DOI: 10.1016/j.avsg.2023.02.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/15/2023]
Abstract
OBJECTIVE To provide a summary of the current state of research in English medical literature on circulating miRNAs, as biomarkers for AAA. Additionally, for the most commonly mentioned circulating miRNAs in the literature, to attempt a documentation of the biological mechanisms underlying their role in AAA development. METHODS A literature search was undertaken in the MEDLINE database. Only reports that involved peripheral blood samples (whole blood, plasma, serum) were included. The following terms were used in combination: microrna, mirna, abdominal aortic aneurysm, human, circulating, plasma, serum, endovascular and EVAR. RESULTS A total of 25 reports, published from 2012 to 2022 were included with a total of 1259 patients with AAA, predominantly men (N= 1040, 90%). Six of these reports recruited healthy donors who underwent ultrasound screening for AAA as control samples. The majority of studies were undertaken in plasma samples and the most preferred microRNA profiling method was Real - Time quantitative polymerase chain reaction (qRT-PCR). The following nine miRNAs (out of a total of 76) were studied in more than two references: miR-145, miR-24, miR-33, miR-125, let-7, miR-15, miR-191, miR-29 and miR-133. CONCLUSION The nine miRNAs described in this study, are implicated in known pathogenetic mechanisms of AAA such as atherosclerosis, vascular smooth muscle cell phenotype switch and apoptosis, vascular inflammation, extracellular matrix degradation and lipid metabolism. Identifying disease-specific miRNAs, in combination with other clinical parameters, as indicators of AAA, is crucial for early diagnosis as well as follow-up of AAAs. For future research on miRNAs as AAA biomarkers, strict case and control group definitions, sample acquisition protocols, and miRNA expression profiling techniques are warranted.
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Affiliation(s)
- Kalliopi-Maria Tasopoulou
- Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece.
| | - Christos Argiriou
- Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
| | - Alexandra K Tsaroucha
- Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - George S Georgiadis
- Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
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29
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Xie X, Shirasu T, Li J, Guo LW, Kent KC. miR579-3p is an inhibitory modulator of neointimal hyperplasia and transcription factors c-MYB and KLF4. Cell Death Discov 2023; 9:73. [PMID: 36813774 PMCID: PMC9946956 DOI: 10.1038/s41420-023-01364-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 01/28/2023] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
Neointimal hyperplasia (IH) is a common vascular pathology that typically manifests in in-stent restenosis and bypass vein graft failure. Smooth muscle cell (SMC) phenotypic switching is central to IH, both regulated by some microRNAs, yet the role of miR579-3p, a scarcely studied microRNA, is not known. Unbiased bioinformatic analysis suggested that miR579-3p was repressed in human primary SMCs treated with different pro-IH cytokines. Moreover, miR579-3p was software-predicted to target both c-MYB and KLF4 - two master transcription factors known to promote SMC phenotypic switching. Interestingly, treating injured rat carotid arteries via local infusion of miR579-3p-expressing lentivirus reduced IH 14 days after injury. In cultured human SMCs, transfection with miR579-3p inhibited SMC phenotypic switching, as indicated by decreased proliferation/migration and increased SMC contractile proteins. miR579-3p transfection downregulated c-MYB and KLF4, and luciferase assays indicated miR579-3p's targeting of the 3'UTRs of the c-MYB and KLF4 mRNAs. In vivo, immunohistochemistry showed that treatment of injured rat arteries with the miR579-3p lentivirus reduced c-MYB and KLF4 and increased SMC contractile proteins. Thus, this study identifies miR579-3p as a previously unrecognized small-RNA inhibitor of IH and SMC phenotypic switch involving its targeting of c-MYB and KLF4. Further studies on miR579-3p may provide an opportunity for translation to develop IH-mitigating new therapeutics.
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Affiliation(s)
- Xiujie Xie
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
| | - Takuro Shirasu
- grid.27755.320000 0000 9136 933XDepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908 USA
| | - Jing Li
- grid.27755.320000 0000 9136 933XDepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908 USA
| | - Lian-Wang Guo
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA. .,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, 22908, USA. .,Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, 22908, USA.
| | - K. Craig Kent
- grid.27755.320000 0000 9136 933XDepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908 USA
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30
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Zhang Z, Freeman M, Zhang Y, El-Nachef D, Davenport G, Williams A, MacLellan WR. Hippo signaling and histone methylation control cardiomyocyte cell cycle re-entry through distinct transcriptional pathways. PLoS One 2023; 18:e0281610. [PMID: 36780463 PMCID: PMC9925018 DOI: 10.1371/journal.pone.0281610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 01/26/2023] [Indexed: 02/15/2023] Open
Abstract
AIMS Accumulating data demonstrates that new adult cardiomyocytes (CMs) are generated throughout life from pre-existing CMs, although the absolute magnitude of CM self-renewal is very low. Modifying epigenetic histone modifications or activating the Hippo-Yap pathway have been shown to promote adult CM cycling and proliferation. Whether these interventions work through common pathways or act independently is unknown. For the first time we have determined whether lysine demethylase 4D (KDM4D)-mediated CM-specific H3K9 demethylation and Hippo pathways inhibition have additive or redundant roles in promoting CM cell cycle re-entry. METHODS AND RESULTS We found that activating Yap1 in cultured neonatal rat ventricular myocytes (NRVM) through overexpressing Hippo pathway inhibitor, miR-199, preferentially increased S-phase CMs, while H3K9me3 demethylase KDM4D preferentially increased G2/M markers in CMs. Together KDM4D and miR-199 further increased total cell number of NRVMs in culture. Inhibition of Hippo signaling via knock-down of Salvador Family WW Domain Containing Protein 1 (Sav1) also led to S-phase reactivation and additional cell cycle re-entry was seen when combined with KDM4D overexpression. Inducible activating KDM4D (iKDM4D) in adult transgenic mice together with shRNA mediated knock-down of Sav1 (iKDM4D+Sav1-sh) resulted in a significant increase in cycling CMs compared to either intervention alone. KDM4D preferentially induced expression of genes regulating late (G2/M) phases of the cell cycle, while miR-199 and si-Sav1 preferentially up-regulated genes involved in G1/S phase. KDM4D upregulated E2F1 and FoxM1 expression, whereas miR-199 and si-Sav1 induced Myc. Using transgenic mice over-expressing KDM4D together with Myc, we demonstrated that KDM4D/Myc significantly increased CM cell cycling but did not affect cardiac function. CONCLUSIONS KDM4D effects on CM cell cycle activity are additive with the Hippo-Yap1 pathway and appear to preferentially regulate different cell cycle regulators. This may have important implications for strategies that target cardiac regeneration in treating heart disease.
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Affiliation(s)
- Zhenhe Zhang
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - Miles Freeman
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - Yiqiang Zhang
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
- Department of Anatomy, Biochemistry and Physiology, John A. Burn School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Danny El-Nachef
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - George Davenport
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - Allison Williams
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - W. Robb MacLellan
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
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31
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Ahmed RE, Tokuyama T, Anzai T, Chanthra N, Uosaki H. Sarcomere maturation: function acquisition, molecular mechanism, and interplay with other organelles. Philos Trans R Soc Lond B Biol Sci 2022; 377:20210325. [PMID: 36189811 PMCID: PMC9527934 DOI: 10.1098/rstb.2021.0325] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 06/15/2022] [Indexed: 12/31/2022] Open
Abstract
During postnatal cardiac development, cardiomyocytes mature and turn into adult ones. Hence, all cellular properties, including morphology, structure, physiology and metabolism, are changed. One of the most important aspects is the contractile apparatus, of which the minimum unit is known as a sarcomere. Sarcomere maturation is evident by enhanced sarcomere alignment, ultrastructural organization and myofibrillar isoform switching. Any maturation process failure may result in cardiomyopathy. Sarcomere function is intricately related to other organelles, and the growing evidence suggests reciprocal regulation of sarcomere and mitochondria on their maturation. Herein, we summarize the molecular mechanism that regulates sarcomere maturation and the interplay between sarcomere and other organelles in cardiomyocyte maturation. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.
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Affiliation(s)
- Razan E. Ahmed
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Takeshi Tokuyama
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Tatsuya Anzai
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
- Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Nawin Chanthra
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Hideki Uosaki
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
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32
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Behera JK, Bhattacharya M, Mishra P, Mishra A, Dash AA, Kar NB, Behera B, Patra BC. Regulatory role of miRNAs in Wnt signaling pathway linked with cardiovascular diseases. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100133. [PMID: 36568258 PMCID: PMC9780067 DOI: 10.1016/j.crphar.2022.100133] [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: 07/01/2022] [Revised: 09/15/2022] [Accepted: 09/30/2022] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) are discovered in science about 23 years ago. These are short, a series of non-coding, single-stranded and evolutionary conserved RNA molecules found in eukaryotic cells. It involved post-transcriptional fine-tune protein expression and repressing the target of mRNA in different biological processes. These miRNAs binds with the 3'-UTR region of specific mRNAs to phosphorylate the mRNA degradation and inhibit the translation process in various tissues. Therefore, aberrant expression in miRNAs induces numerous cardiovascular diseases and developmental defects. Subsequently, the miRNAs and Wnt singling pathway are regulating a cellular process in cardiac development and regeneration, maintain the homeostasis and associated heart diseases. In Wnt signaling pathway majority of the signaling components are expressed and regulated by miRNAs, whereas the inhibition or dysfunction of the Wnt signaling pathway induces cardiovascular diseases. Moreover, inadequate studies about the important role of miRNAs in heart development and diseases through Wnt signaling pathway has been exist still now. For this reason in present review we summarize and update the involvement of miRNAs and the role of Wnt signaling in cardiovascular diseases. We have discussed the mechanism of miRNA functions which regulates the Wnt components in cellular signaling pathway. The fundamental understanding of Wnt signaling regulation and mechanisms of miRNAs is quite essential for study of heart development and related diseases. This approach definitely enlighten the future research to provide a new strategy for formulation of novel therapeutic approaches against cardiovascular diseases.
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Affiliation(s)
- Jiban Kumar Behera
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Manojit Bhattacharya
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Pabitra Mishra
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Akansha Mishra
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Adya Anindita Dash
- Department of Biosciences and Biotechnology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Niladri Bhusan Kar
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Bhaskar Behera
- Department of Biosciences and Biotechnology, Fakir Mohan University, Vyasa Vihar, Balasore, 756089, Odisha, India
| | - Bidhan Chandra Patra
- Department of Zoology, Vidyasagar University, Midnapore, 721102, West Bengal, India
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The negative regulation of gene expression by microRNAs as key driver of inducers and repressors of cardiomyocyte differentiation. Clin Sci (Lond) 2022; 136:1179-1203. [PMID: 35979890 PMCID: PMC9411751 DOI: 10.1042/cs20220391] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 11/28/2022]
Abstract
Cardiac muscle damage-induced loss of cardiomyocytes (CMs) and dysfunction of the remaining ones leads to heart failure, which nowadays is the number one killer worldwide. Therapies fostering effective cardiac regeneration are the holy grail of cardiovascular research to stop the heart failure epidemic. The main goal of most myocardial regeneration protocols is the generation of new functional CMs through the differentiation of endogenous or exogenous cardiomyogenic cells. Understanding the cellular and molecular basis of cardiomyocyte commitment, specification, differentiation and maturation is needed to devise innovative approaches to replace the CMs lost after injury in the adult heart. The transcriptional regulation of CM differentiation is a highly conserved process that require sequential activation and/or repression of different genetic programs. Therefore, CM differentiation and specification have been depicted as a step-wise specific chemical and mechanical stimuli inducing complete myogenic commitment and cell-cycle exit. Yet, the demonstration that some microRNAs are sufficient to direct ESC differentiation into CMs and that four specific miRNAs reprogram fibroblasts into CMs show that CM differentiation must also involve negative regulatory instructions. Here, we review the mechanisms of CM differentiation during development and from regenerative stem cells with a focus on the involvement of microRNAs in the process, putting in perspective their negative gene regulation as a main modifier of effective CM regeneration in the adult heart.
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Zheng G, He Z, Lu Y, Zhu Q, Jiang Y, Chen D, Lin S, Zhu C, Schwartz R. SRF-derived miR210 and miR30c both repress beating cardiomyocyte formation in the differentiation system of embryoid body. Biochem Biophys Res Commun 2022; 626:58-65. [PMID: 35970045 DOI: 10.1016/j.bbrc.2022.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 07/16/2022] [Accepted: 08/04/2022] [Indexed: 11/02/2022]
Abstract
Serum response factor (SRF) cooperates with various co-factors to manage the specification of diverse cell lineages during heart development. Many microRNAs mediate the function of SRF in this process. However, how are miR210 and miR30c involved in the decision of cardiac cell fates remains to be explored. In this study, we found that SRF directly controlled the cardiac expression of miR210. Both miR210 and miR30c blocked the formation of beating cardiomyocyte during embryoid body (EB) differentiation, a cellular model widely used for studying cardiogenesis. Both of anticipated microRNA targets and differentially expressed genes in day8 EBs were systematically determined and enriched with gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) and Reactome. Functional enrichments of prediction microRNA targets and down-regulated genes in day8 EBs of miR210 suggested the importance of PI3K-Akt signal and ETS2 in miR210 inhibition of cardiomyocyte differentiation. Similar analyses revealed that miR30c repressed both developmental progress and the adrenergic signaling in cardiomyocytes during the differentiation of EBs. Taken together, SRF directs the expression of miR210 and miR30c, and they repress cardiac development via inhibiting the differentiation of cardiac muscle cell lineage as well as the cell proliferation. Through the regulation of specific microRNAs, the complication of SRF's function in heart development is emphasized.
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Affiliation(s)
- Guoxing Zheng
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Department of Biology and Biochemistry, The University of Houston, Houston, TX, USA.
| | - Zhuzhen He
- Shenzhen Amcare Maternity Hospital, Shenzhen, Guangdong, 518052, China
| | - Yingsi Lu
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Qingqing Zhu
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Yizhou Jiang
- Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, 518060, China
| | - Demeng Chen
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuibin Lin
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Chengming Zhu
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Robert Schwartz
- Department of Biology and Biochemistry, The University of Houston, Houston, TX, USA.
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35
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Defining the molecular underpinnings controlling cardiomyocyte proliferation. Clin Sci (Lond) 2022; 136:911-934. [PMID: 35723259 DOI: 10.1042/cs20211180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 05/27/2022] [Accepted: 05/31/2022] [Indexed: 12/11/2022]
Abstract
Shortly after birth, mammalian cardiomyocytes (CM) exit the cell cycle and cease to proliferate. The inability of adult CM to replicate renders the heart particularly vulnerable to injury. Restoration of CM proliferation would be an attractive clinical target for regenerative therapies that can preserve contractile function and thus prevent the development of heart failure. Our review focuses on recent progress in understanding the tight regulation of signaling pathways and their downstream molecular mechanisms that underly the inability of CM to proliferate in vivo. In this review, we describe the temporal expression of cell cycle activators e.g., cyclin/Cdk complexes and their inhibitors including p16, p21, p27 and members of the retinoblastoma gene family during gestation and postnatal life. The differential impact of members of the E2f transcription factor family and microRNAs on the regulation of positive and negative cell cycle factors is discussed. This review also highlights seminal studies that identified the coordination of signaling mechanisms that can potently activate CM cell cycle re-entry including the Wnt/Ctnnb1, Hippo, Pi3K-Akt and Nrg1-Erbb2/4 pathways. We also present an up-to-date account of landmark studies analyzing the effect of various genes such as Argin, Dystrophin, Fstl1, Meis1, Pitx2 and Pkm2 that are responsible for either inhibition or activation of CM cell division. All these reports describe bona fide therapeutically targets that could guide future clinical studies toward cardiac repair.
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36
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Abdallah HY, Hassan R, Fareed A, Abdelgawad M, Mostafa SA, Mohammed EAM. Identification of a circulating microRNAs biomarker panel for non-invasive diagnosis of coronary artery disease: case-control study. BMC Cardiovasc Disord 2022; 22:286. [PMID: 35751015 PMCID: PMC9233383 DOI: 10.1186/s12872-022-02711-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/09/2022] [Indexed: 12/07/2022] Open
Abstract
Background Circulating microRNAs (miRNAs) are considered a hot spot of research that can be employed for monitoring and/or diagnostic purposes in coronary artery disease (CAD). Since different disease features might be reflected on altered profiles or plasma miRNAs concentrations, a combination of miRNAs can provide more reliable non-invasive biomarkers for CAD. Subjects and methods We investigated a panel of 14-miRNAs selected using bioinformatics databases and current literature searching for miRNAs involved in CAD using quantitative real-time PCR technique in 73 CAD patients compared to 73 controls followed by function and pathway enrichment analysis for the 14-miRNAs. Results Our results revealed three out of the 14 circulating miRNAs understudy; miRNAs miR133a, miR155 and miR208a were downregulated. While 11 miRNAs were up-regulated in a descending order from highest fold change to lowest: miR-182, miR-145, miR-21, miR-126, miR-200b, miR-146A, miR-205, miR-135b, miR-196b, miR-140b and, miR-223. The ROC curve analysis indicated that miR-145, miR-182, miR-133a and, miR-205 were excellent biomarkers with the highest AUCs as biomarkers in CAD. All miRNAs under study except miR-208 revealed a statistically significant relation with dyslipidemia. MiR-126 and miR-155 showed significance with BMI grade, while only miR-133a showed significance with the obese patients in general. MiR-135b and miR-140b showed a significant correlation with the Wall Motion Severity Index. Pathway enrichment analysis for the miRNAS understudy revealed pathways relevant to the fatty acid biosynthesis, ECM-receptor interaction, proteoglycans in cancer, and adherens junction. Conclusion The results of this study identified a differentially expressed circulating miRNAs signature that can discriminate CAD patients from normal subjects. These results provide new insights into the significant role of miRNAs expression associated with CAD pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02711-9.
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Affiliation(s)
- Hoda Y Abdallah
- Medical Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt. .,Center of Excellence in Molecular & Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Ranya Hassan
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Ahmed Fareed
- Department of Cardiology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Mai Abdelgawad
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, 62511, Egypt
| | - Sally Abdallah Mostafa
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman Abdel-Moemen Mohammed
- Medical Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.,Center of Excellence in Molecular & Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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37
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Deshpande A, Shetty PMV, Frey N, Rangrez AY. SRF: a seriously responsible factor in cardiac development and disease. J Biomed Sci 2022; 29:38. [PMID: 35681202 PMCID: PMC9185982 DOI: 10.1186/s12929-022-00820-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 05/27/2022] [Indexed: 11/10/2022] Open
Abstract
The molecular mechanisms that regulate embryogenesis and cardiac development are calibrated by multiple signal transduction pathways within or between different cell lineages via autocrine or paracrine mechanisms of action. The heart is the first functional organ to form during development, which highlights the importance of this organ in later stages of growth. Knowledge of the regulatory mechanisms underlying cardiac development and adult cardiac homeostasis paves the way for discovering therapeutic possibilities for cardiac disease treatment. Serum response factor (SRF) is a major transcription factor that controls both embryonic and adult cardiac development. SRF expression is needed through the duration of development, from the first mesodermal cell in a developing embryo to the last cell damaged by infarction in the myocardium. Precise regulation of SRF expression is critical for mesoderm formation and cardiac crescent formation in the embryo, and altered SRF levels lead to cardiomyopathies in the adult heart, suggesting the vital role played by SRF in cardiac development and disease. This review provides a detailed overview of SRF and its partners in their various functions and discusses the future scope and possible therapeutic potential of SRF in the cardiovascular system.
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Affiliation(s)
- Anushka Deshpande
- Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.,Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Prithviraj Manohar Vijaya Shetty
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Ashraf Yusuf Rangrez
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany. .,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
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38
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Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function. Nat Commun 2022; 13:3180. [PMID: 35676269 PMCID: PMC9178026 DOI: 10.1038/s41467-022-30778-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 05/07/2022] [Indexed: 11/08/2022] Open
Abstract
Formation and maintenance of neuromuscular junctions (NMJs) are essential for skeletal muscle function, allowing voluntary movements and maintenance of the muscle tone, thereby preventing atrophy. Generation of NMJs depends on the interaction of motor neurons with skeletal muscle fibers, which initiates a cascade of regulatory events that is essential for patterning of acetylcholine receptor (AChR) clusters at specific sites of the sarcolemma. Here, we show that muscle-specific miRNAs of the miR-1/206/133 family are crucial regulators of a signaling cascade comprising DOK7-CRK-RAC1, which is critical for stabilization and anchoring of postsynaptic AChRs during NMJ development and maintenance. We describe that posttranscriptional repression of CRK by miR-1/206/133 is essential for balanced activation of RAC1. Failure to adjust RAC1 activity severely compromises NMJ function, causing respiratory failure in neonates and neuromuscular symptoms in adult mice. We conclude that miR-1/206/133 serve a specific function for NMJs but are dispensable for skeletal muscle development. The miR-1/133/206 gene family codes for the most abundant microRNAs in striated muscles. Here, Klockner et al show that inactivation of all family members in skeletal muscle prevents formation of normal neuromuscular junctions due to increased expression of the adaptor protein CRK.
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39
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Zhu W, Sun J, Bishop SP, Sadek H, Zhang J. Turning back the clock: A concise viewpoint of cardiomyocyte cell cycle activation for myocardial regeneration and repair. J Mol Cell Cardiol 2022; 170:15-21. [PMID: 35660800 PMCID: PMC9391298 DOI: 10.1016/j.yjmcc.2022.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 04/18/2022] [Accepted: 05/14/2022] [Indexed: 11/25/2022]
Abstract
Patients with acute myocardial infarction (MI) could progress to end-stage congestive heart failure, which is one of the most significant problems in public health. From the molecular and cellular perspective, heart failure often results from the loss of cardiomyocytes-the fundamental contractile unit of the heart-and the damage caused by myocardial injury in adult mammals cannot be repaired, in part because mammalian cardiomyocytes undergo cell-cycle arrest during the early perinatal period. However, recent studies in the hearts of neonatal small and large mammals suggest that the onset of cardiomyocyte cell-cycle arrest can be reversed, which may lead to the development of entirely new strategies for the treatment of heart failure. In this Viewpoint, we summarize these and other provocative findings about the cellular and molecular mechanisms that regulate cardiomyocyte proliferation and how they may be targeted to turn back the clock of cardiomyocyte cell-cycle arrest and improve recovery from cardiac injury and disease.
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Affiliation(s)
- Wuqiang Zhu
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center for Regenerative Medicine, Mayo Clinic, Scottsdale, AZ 85259, United States of America
| | - Jiacheng Sun
- Department of Biomedical Engineering, School of Medicine and School of Engineering, the University of Alabama at Birmingham, Birmingham, AL 35294, United States of America
| | - Sanford P Bishop
- Department of Biomedical Engineering, School of Medicine and School of Engineering, the University of Alabama at Birmingham, Birmingham, AL 35294, United States of America
| | - Hesham Sadek
- Division of Cardiovascular Diseases, UT Southwestern Medical Center, United States of America
| | - Jianyi Zhang
- Department of Biomedical Engineering, School of Medicine and School of Engineering, the University of Alabama at Birmingham, Birmingham, AL 35294, United States of America; Department of Medicine, Division of Cardiovascular Diseases, School of Medicine, the University of Alabama at Birmingham, Birmingham, AL 35294, United States of America.
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40
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McAndry C, Collins M, Tills O, Spicer JI, Truebano M. Regulation of gene expression during ontogeny of physiological function in the brackishwater amphipod Gammarus chevreuxi. Mar Genomics 2022; 63:100948. [PMID: 35427917 DOI: 10.1016/j.margen.2022.100948] [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: 12/03/2021] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 10/18/2022]
Abstract
Embryonic development is a complex process involving the co-ordinated onset and integration of multiple morphological features and physiological functions. While the molecular basis of morphological development in embryos is relatively well known for traditional model species, the molecular underpinning of the development of physiological functions is not. Here, we used global gene expression profiling to investigate the transcriptional changes associated with the development of morphological and physiological function in the amphipod crustacean Gammarus chevreuxi. We compared the transcriptomes at three timepoints during the latter half of development, characterised by different stages of the development of heart form and function: 10 days post fertilisation (dpf, Early: no heart structure visible), 15 dpf (Middle: heart present but not fully functional), and 18 dpf (Late: regular heartbeat). Gene expression profiles differed markedly between developmental stages, likely representing a change in the activity of different processes throughout the latter period of G. chevreuxi embryonic development. Differentially expressed genes belonged to one of three distinct clusters based on their expression patterns across development. One of these clusters, which included key genes relating to cardiac contractile machinery and calcium handling, displayed a pattern of sequential up-regulation throughout the developmental period studied. Further analyses of these transcripts could reveal genes that may influence the onset of a regular heartbeat. We also identified morphological and physiological processes that may occur alongside heart development, such as development of digestive caeca and the cuticle. Elucidating the mechanisms underpinning morphological and physiological development of non-model organisms will support improved understanding of conserved mechanisms, addressing the current phylogenetic gap between relatively well known model species.
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Affiliation(s)
- C McAndry
- Marine Biology and Ecology Research Centre, School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - M Collins
- Marine Biology and Ecology Research Centre, School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - O Tills
- Marine Biology and Ecology Research Centre, School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - J I Spicer
- Marine Biology and Ecology Research Centre, School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - M Truebano
- Marine Biology and Ecology Research Centre, School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK.
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41
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Utilization and Potential of RNA-Based Therapies in Cardiovascular Disease. JACC Basic Transl Sci 2022; 7:956-969. [PMID: 36317129 PMCID: PMC9617127 DOI: 10.1016/j.jacbts.2022.02.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/01/2022] [Accepted: 02/01/2022] [Indexed: 12/15/2022]
Abstract
RNA-based therapeutics have the potential to reach previously “undruggable” pathways in cardiovascular disease RNA-based therapeutics constitute a vast array of technologies, including unique forms, chemistries, and modalities of delivery Rapid development of RNA-based vaccines was made possible by decades of foundational work Specificity and efficacy of targeting and determination of mechanism(s) of action remain a distinct challenge Cardiovascular disease (CVD) remains the largest cause of mortality worldwide. The development of new effective therapeutics is a major unmet need. The current review focuses broadly on the concept of nucleic acid (NA)–based therapies, considering the use of various forms of NAs, including mRNAs, miRNAs, siRNA, and guide RNAs, the latter specifically for the purpose of CRISPR-Cas directed gene editing. We describe the current state-of-the-art of RNA target discovery and development, the status of RNA therapeutics in the context of CVD, and some of the challenges and hurdles to be overcome.
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42
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Leveraging Extracellular Non-coding RNAs to Diagnose and Treat Heart Diseases. J Cardiovasc Transl Res 2022; 15:456-468. [PMID: 35419773 DOI: 10.1007/s12265-022-10252-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/04/2022] [Indexed: 12/13/2022]
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, emerge to be crucial mediators of cell-to-cell communication in multiple organs. Non-coding RNAs loaded inside EVs contribute as one major mechanism for remote information transfer among different cell types or organs. Increasing evidence suggests that EV-associated non-coding RNAs derived from cardiovascular or non-cardiac cells regulate cardiovascular pathophysiology in heart development and diseases. The functional relevance of the EV-associated ncRNAs in heart diseases provides an avenue to develop novel diagnostic tools and therapies for heart diseases. In this review, we summarize the recent advancement of EV-associated ncRNAs in different cardiovascular diseases, including myocardial infarction, arrhythmias, cardiac hypertrophy, and heart failure, with an emphasis on the underlying molecular mechanisms.
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Inhibition of RhoA and Cdc42 by miR-133a Modulates Retinoic Acid Signalling during Early Development of Posterior Cardiac Tube Segment. Int J Mol Sci 2022; 23:ijms23084179. [PMID: 35456995 PMCID: PMC9025022 DOI: 10.3390/ijms23084179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/15/2022] Open
Abstract
It is well known that multiple microRNAs play crucial roles in cardiovascular development, including miR-133a. Additionally, retinoic acid regulates atrial marker expression. In order to analyse the role of miR-133a as a modulator of retinoic acid signalling during the posterior segment of heart tube formation, we performed functional experiments with miR-133a and retinoic acid by means of microinjections into the posterior cardiac precursors of both primitive endocardial tubes in chick embryos. Subsequently, we subjected embryos to whole mount in situ hybridisation, immunohistochemistry and qPCR analysis. Our results demonstrate that miR-133a represses RhoA and Cdc42, as well as Raldh2/Aldh1a2, and the specific atrial markers Tbx5 and AMHC1, which play a key role during differentiation. Furthermore, we observed that miR-133a upregulates p21 and downregulates cyclin A by repressing RhoA and Cdc42, respectively, thus functioning as a cell proliferation inhibitor. Additionally, retinoic acid represses miR-133a, while it increases Raldh2, Tbx5 and AMHC1. Given that RhoA and Cdc42 are involved in Raldh2 expression and that they are modulated by miR-133a, which is influenced by retinoic acid signalling, our results suggest the presence of a negative feedback mechanism between miR-133a and retinoic acid during early development of the posterior cardiac tube segment. Despite additional unexplored factors being possible contributors to this negative feedback mechanism, miR-133a might also be considered as a potential therapeutic tool for the diagnosis, therapy and prognosis of cardiac diseases.
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Liu ZQ, Cheng M, Fu F, Li R, Han J, Yang X, Deng Q, Li LS, Lei TY, Li DZ, Liao C. Identification of differential microRNAs and messenger RNAs resulting from ASXL transcriptional regulator 3 knockdown during during heart development. Bioengineered 2022; 13:9948-9961. [PMID: 35435106 PMCID: PMC9161854 DOI: 10.1080/21655979.2022.2062525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/25/2022] [Accepted: 03/30/2022] [Indexed: 11/30/2022] Open
Abstract
Congenital heart disease (CHD) is the most common birth defect. Although ASXL transcriptional regulator 3 (ASXL3) has been reported to cause hereditary CHD, ASXL3-mediated mechanisms in heart development remain unclear. In this study, we used dimethyl sulfoxide (DMSO) to induce differentiation in P19 cells, observed cell morphology using light microscopy after ASXL3 knockdown, and determined the levels of associated myocardial cell markers using reverse transcription-quantitative polymerase chain reaction and western blotting. Subsequently, we used microRNA sequencing, messenger RNA (mRNA) sequencing, and bioinformatics to initially identify the possible mechanisms through which ASXL3-related microRNAs and mRNAs affect heart development. The results indicated that DMSO induced P19 cell differentiation, which could be inhibited by ASXL3 knockdown. We screened 1214 and 1652 differentially expressed microRNAs and mRNAs, respectively, through ASXL3 knockdown and sequencing; these differentially expressed miRNAs were largely enriched in PI3K-Akt, mitogen-activated protein kinase, and Rap1 signaling pathways. Additionally, 11 miRNAs associated with heart development were selected through a literature review. Our analysis indicated the involvement of mmu-miR-323-3p in P19 cell differentiation through the PI3K-Akt pathway. In conclusion, ASXL3 may be involved in the regulation of heart development. This comprehensive study of differentially expressed microRNAs and mRNAs through ASXL3 knockdown in P19 cells provides new insights that may aid the prevention and treatment of CHD.
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Affiliation(s)
- Ze-Qun Liu
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Mi Cheng
- Department of Obstetrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Fang Fu
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Ru Li
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Jin Han
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Xin Yang
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Qiong Deng
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Lu-Shan Li
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Ting-Ying Lei
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Dong-Zhi Li
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
| | - Can Liao
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, GuangzhouGuangdong, China
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Li H, Zhan J, Chen C, Wang D. MicroRNAs in cardiovascular diseases. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:140-168. [PMID: 37724243 PMCID: PMC10471109 DOI: 10.1515/mr-2021-0001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 12/29/2021] [Indexed: 09/20/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death and disability worldwide, despite the wide diversity of molecular targets identified and the development of therapeutic methods. MicroRNAs (miRNAs) are a class of small (about 22 nucleotides) non-coding RNAs (ncRNAs) that negatively regulate gene expression at the post-transcriptional level in the cytoplasm and play complicated roles in different CVDs. While miRNA overexpression in one type of cell protects against heart disease, it promotes cardiac dysfunction in another type of cardiac cell. Moreover, recent studies have shown that, apart from cytosolic miRNAs, subcellular miRNAs such as mitochondria- and nucleus-localized miRNAs are dysregulated in CVDs. However, the functional properties of cellular- and subcellular-localized miRNAs have not been well characterized. In this review article, by carefully revisiting animal-based miRNA studies in CVDs, we will address the regulation and functional properties of miRNAs in various CVDs. Specifically, the cell-cell crosstalk and subcellular perspective of miRNAs are highlighted. We will provide the background for attractive molecular targets that might be useful in preventing the progression of CVDs and heart failure (HF) as well as insights for future studies.
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Affiliation(s)
- Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Jiabing Zhan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Daowen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
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Huang Y, Wang WF, Huang CX, Li XH, Liu H, Wang HL. miR-731 modulates the zebrafish heart morphogenesis via targeting Calcineurin/Nfatc3a pathway. Biochim Biophys Acta Gen Subj 2022; 1866:130133. [PMID: 35346765 DOI: 10.1016/j.bbagen.2022.130133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Zebrafish miR-731 is orthologous of human miR-425, which has been demonstrated to have cardio-protective roles by a variety of mechanisms. The miR-731 morphants show pericardium enlargement, and many DEGs (differentially expressed genes) are enriched in 'Cardiac muscle contraction' and 'Calcium signaling pathway', implying that miR-731 plays a potential role in heart function and development. However，the in vivo physiological role of miR-731 in the heart needs to be fully defined. METHODS Zebrafish miR-731 morphants were generated by morpholino knockdown, and miR-731 knockout zebrafish was generated by CRISRP/Cas9. We observed cardiac morphogenesis based on whole-mount in situ hybridization. Furthermore, RNA-seq and qRT-PCR were used to elucidate the molecular mechanism and analyze the gene expression. Double luciferase verification and Western blot were used to verify the target gene. RESULTS The depletion of miR-731 in zebrafish embryos caused the deficiency of cardiac development and function, which was associated with reduced heart rate, ventricular enlargement and heart looping disorder. In addition, mechanistic study demonstrated that Calcineurin/Nfatc3a signaling involved in miR-731 depletion induced abnormal cardiac function and developmental defects. CONCLUSION MiR-731 regulates cardiac function and morphogenesis through Calcineurin/Nfatc3a signaling. GENERAL SIGNIFICANCE Our studies highlight the potential importance of miR-731 in cardiac development.
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Affiliation(s)
- Yan Huang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Wei-Feng Wang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Chun-Xiao Huang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Xuan-Hui Li
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Hong Liu
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Huan-Ling Wang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China.
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Li X, Bi H, Xie S, Cui W. MiR-208b Regulates the Conversion of Skeletal Muscle Fiber Types by Inhibiting Mettl8 Expression. Front Genet 2022; 13:820464. [PMID: 35281804 PMCID: PMC8905228 DOI: 10.3389/fgene.2022.820464] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/09/2022] [Indexed: 01/02/2023] Open
Abstract
Skeletal muscle, the main source of animal meat products, contains muscle fiber as a key unit. It is well known that transformation takes place between different types of muscle fibers, however, the conversion mechanism is not clear. In a previous study, our lab has demonstrated that there is a decrease in type I muscle fibers and an increase in type IIB muscle fibers in skeletal muscle of myostatin gene-edited Meishan pigs. Very interestingly, we observed the down regulation of miR-208b expression and an increase in expression the predicted target gene Mettl8 (Methyltransferase like 8) in skeletal muscle of MSTN gene-edited Meishan pigs. These results reveal that there is a potential connection between the conversion of skeletal muscle fiber types and miR-208b and Mettl8 expression. In this study, we first explored the expression patterns of miR-208b and Mettl8 in skeletal muscle in Meishan pigs; and then C2C12 cells were used to simulate the development and maturation of muscle fibers. Our results indicated that Myh4 expression level decreased and Myh7 expression level increased following overexpression of miR-208b in C2C12 cells. We therefore speculate that miR-208b can promote the conversion of fast-twitch fibers to slow-twitch fibers. The targeting relationship between Mettl8 and miR-208b was confirmed by results obtained using dual luciferase assay, RT-qPCR, and WB analysis. Following the transfection of Mettl8 siRNA into C2C12 cells, we observed that Mettl8 expression decreased significantly while Myh7 expression increased and Myh4 expression decreased, indicating that Mettl8 promotes the conversion of slow muscle fibers to fast muscle fibers. Additionally, changes in skeletal muscle fiber types are observed in those mice where miR-208b and Mettl8 genes are knocked out. The miR-208b knockout inhibits the formation of slow muscle fibers, and the Mettl8 knockout inhibits the formation of fast muscle fibers. In conclusion, our research results show that miR-208b regulates the conversion of different muscle fiber types by inhibiting Mettl8 expression.
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Affiliation(s)
- Xiang Li
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hanfang Bi
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Shanshan Xie
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Wentao Cui
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
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Garbern JC, Lee RT. Heart regeneration: 20 years of progress and renewed optimism. Dev Cell 2022; 57:424-439. [PMID: 35231426 PMCID: PMC8896288 DOI: 10.1016/j.devcel.2022.01.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease is a leading cause of death worldwide, and thus there remains great interest in regenerative approaches to treat heart failure. In the past 20 years, the field of heart regeneration has entered a renaissance period with remarkable progress in the understanding of endogenous heart regeneration, stem cell differentiation for exogenous cell therapy, and cell-delivery methods. In this review, we highlight how this new understanding can lead to viable strategies for human therapy. For the near term, drugs, electrical and mechanical devices, and heart transplantation will remain mainstays of cardiac therapies, but eventually regenerative therapies based on fundamental regenerative biology may offer more permanent solutions for patients with heart failure.
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Affiliation(s)
- Jessica C. Garbern
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA,Department of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Richard T. Lee
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA,Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA,Corresponding author and lead contact: Richard T. Lee, Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, Phone: 617-496-5394, Fax: 617-496-8351,
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Noncoding RNAs in Cardiac Hypertrophy and Heart Failure. Cells 2022; 11:cells11050777. [PMID: 35269399 PMCID: PMC8908994 DOI: 10.3390/cells11050777] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/20/2022] [Accepted: 02/22/2022] [Indexed: 02/01/2023] Open
Abstract
Heart failure is a major global health concern. Noncoding RNAs (ncRNAs) are involved in physiological processes and in the pathogenesis of various diseases, including heart failure. ncRNAs have emerged as critical components of transcriptional regulatory pathways that govern cardiac development, stress response, signaling, and remodeling in cardiac pathology. Recently, studies of ncRNAs in cardiovascular disease have achieved significant development. Here, we discuss the roles of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) that modulate the cardiac hypertrophy and heart failure.
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Shah V, Shah J. Restoring Ravaged Heart: Molecular Mechanisms and Clinical Application of miRNA in Heart Regeneration. Front Cardiovasc Med 2022; 9:835138. [PMID: 35224063 PMCID: PMC8866653 DOI: 10.3389/fcvm.2022.835138] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/17/2022] [Indexed: 11/28/2022] Open
Abstract
Human heart development is a complex and tightly regulated process, conserving proliferation, and multipotency of embryonic cardiovascular progenitors. At terminal stage, progenitor cell type gets suppressed for terminal differentiation and maturation. In the human heart, most cardiomyocytes are terminally differentiated and so have limited proliferation capacity. MicroRNAs (miRNAs) are non-coding single-stranded RNA that regulate gene expression and mRNA silencing at the post-transcriptional level. These miRNAs play a crucial role in numerous biological events, including cardiac development, and cardiomyocyte proliferation. Several cardiac cells specific miRNAs have been discovered. Inhibition or overexpression of these miRNAs could induce cardiac regeneration, cardiac stem cell proliferation and cardiomyocyte proliferation. Clinical application of miRNAs extends to heart failure, wherein the cell cycle arrest of terminally differentiated cardiac cells inhibits the heart regeneration. The regenerative capacity of the myocardium can be enhanced by cardiomyocyte specific miRNAs controlling the cell cycle. In this review, we focus on cardiac-specific miRNAs involved in cardiac regeneration and cardiomyocyte proliferation, and their potential as a new clinical therapy for heart regeneration.
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