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Stojanović SD, Thum T, Bauersachs J. Anti-senescence therapies: a new concept to address cardiovascular disease. Cardiovasc Res 2025; 121:730-747. [PMID: 40036821 PMCID: PMC12101330 DOI: 10.1093/cvr/cvaf030] [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] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/16/2024] [Accepted: 01/22/2025] [Indexed: 03/06/2025] Open
Abstract
Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.
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Affiliation(s)
- Stevan D Stojanović
- Department of Cardiology and Angiology, Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
- PRACTIS Clinician Scientist Program, Dean’s Office for Academic Career Development, Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
- Center for Translational Regenerative Medicine, Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
- Center for Translational Regenerative Medicine, Hannover Medical School, Carl Neuberg Str. 1, Hannover 30625, Germany
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2
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Wang Z, Zhu H, Xiong W. Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective. Front Med 2025; 19:200-225. [PMID: 39821730 DOI: 10.1007/s11684-024-1116-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 11/04/2024] [Indexed: 01/19/2025]
Abstract
The pursuit of healthy aging has long rendered aging and senescence captivating. Age-related ailments, such as cardiovascular diseases, diabetes, and neurodegenerative disorders, pose significant threats to individuals. Recent studies have shed light on the intricate mechanisms encompassing genetics, epigenetics, transcriptomics, and metabolomics in the processes of senescence and aging, as well as the establishment of age-related pathologies. Amidst these underlying mechanisms governing aging and related pathology metabolism assumes a pivotal role that holds promise for intervention and therapeutics. The advancements in metabolomics techniques and analysis methods have significantly propelled the study of senescence and aging, particularly with the aid of multiscale metabolomics which has facilitated the discovery of metabolic markers and therapeutic potentials. This review provides an overview of senescence and aging, emphasizing the crucial role metabolism plays in the aging process as well as age-related diseases.
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Affiliation(s)
- Ziyi Wang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Hongying Zhu
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China.
- CAS Key Laboratory of Brain Function and Disease, Hefei, 230026, China.
- Anhui Province Key Laboratory of Biomedical Aging Research, Hefei, 230026, China.
| | - Wei Xiong
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China.
- CAS Key Laboratory of Brain Function and Disease, Hefei, 230026, China.
- Anhui Province Key Laboratory of Biomedical Aging Research, Hefei, 230026, China.
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Liberale L, Tual-Chalot S, Sedej S, Ministrini S, Georgiopoulos G, Grunewald M, Bäck M, Bochaton-Piallat ML, Boon RA, Ramos GC, de Winther MPJ, Drosatos K, Evans PC, Ferguson JF, Forslund-Startceva SK, Goettsch C, Giacca M, Haendeler J, Kallikourdis M, Ketelhuth DFJ, Koenen RR, Lacolley P, Lutgens E, Maffia P, Miwa S, Monaco C, Montecucco F, Norata GD, Osto E, Richardson GD, Riksen NP, Soehnlein O, Spyridopoulos I, Van Linthout S, Vilahur G, Wentzel JJ, Andrés V, Badimon L, Benetos A, Binder CJ, Brandes RP, Crea F, Furman D, Gorbunova V, Guzik TJ, Hill JA, Lüscher TF, Mittelbrunn M, Nencioni A, Netea MG, Passos JF, Stamatelopoulos KS, Tavernarakis N, Ungvari Z, Wu JC, Kirkland JL, Camici GG, Dimmeler S, Kroemer G, Abdellatif M, Stellos K. Roadmap for alleviating the manifestations of ageing in the cardiovascular system. Nat Rev Cardiol 2025:10.1038/s41569-025-01130-5. [PMID: 39972009 DOI: 10.1038/s41569-025-01130-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2025] [Indexed: 02/21/2025]
Abstract
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
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Affiliation(s)
- Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Simon Tual-Chalot
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | | | - Myriam Grunewald
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Magnus Bäck
- Translational Cardiology, Centre for Molecular Medicine, Department of Medicine Solna, and Department of Cardiology, Heart and Vascular Centre, Karolinska Institutet, Stockholm, Sweden
- Inserm, DCAC, Université de Lorraine, Nancy, France
| | | | - Reinier A Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC location VUmc, Amsterdam, Netherlands
| | - Gustavo Campos Ramos
- Department of Internal Medicine I/Comprehensive Heart Failure Centre, University Hospital Würzburg, Würzburg, Germany
| | - Menno P J de Winther
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis and Ischaemic Syndromes; Amsterdam Infection and Immunity: Inflammatory Diseases, Amsterdam UMC location AMC, Amsterdam, Netherlands
| | - Konstantinos Drosatos
- Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Paul C Evans
- William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jane F Ferguson
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Claudia Goettsch
- Department of Internal Medicine I, Division of Cardiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Mauro Giacca
- British Heart foundation Centre of Reseach Excellence, King's College London, London, UK
| | - Judith Haendeler
- Cardiovascular Degeneration, Medical Faculty, University Hospital and Heinrich-Heine University, Düsseldorf, Germany
| | - Marinos Kallikourdis
- Adaptive Immunity Lab, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
| | - Daniel F J Ketelhuth
- Cardiovascular and Renal Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Rory R Koenen
- CARIM-School for Cardiovascular Diseases, Department of Biochemistry, Maastricht University, Maastricht, Netherlands
| | | | - Esther Lutgens
- Department of Cardiovascular Medicine & Immunology, Mayo Clinic, Rochester, MN, USA
| | - Pasquale Maffia
- School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Satomi Miwa
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Claudia Monaco
- Kennedy Institute, NDORMS, University of Oxford, Oxford, UK
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Elena Osto
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Gavin D Richardson
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Oliver Soehnlein
- Institute of Experimental Pathology, University of Münster, Münster, Germany
| | - Ioakim Spyridopoulos
- Translational and Clinical Research Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Sophie Van Linthout
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätmedizin Berlin, Berlin, Germany
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu y Sant Pau l, IIB-Sant Pau, Barcelona, Spain
| | - Jolanda J Wentzel
- Cardiology, Biomedical Engineering, Erasmus MC, Rotterdam, Netherlands
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBERCV, Madrid, Spain
| | - Lina Badimon
- Cardiovascular Health and Innovation Research Foundation (FICSI) and Cardiovascular Health and Network Medicine Department, University of Vic (UVIC-UCC), Barcelona, Spain
| | - Athanase Benetos
- Department of Geriatrics, University Hospital of Nancy and Inserm DCAC, Université de Lorraine, Nancy, France
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany
| | - Filippo Crea
- Centre of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina - Gemelli Isola, Roma, Italy
| | - David Furman
- Buck Institute for Research on Aging, Novato, CA, USA
| | - Vera Gorbunova
- Departments of Biology and Medicine, University of Rochester, Rochester, NY, USA
| | - Tomasz J Guzik
- Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK
| | - Joseph A Hill
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Thomas F Lüscher
- Heart Division, Royal Brompton and Harefield Hospital and National Heart and Lung Institute, Imperial College, London, UK
| | - María Mittelbrunn
- Consejo Superior de Investigaciones Científicas (CSIC), Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Alessio Nencioni
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- Dipartimento di Medicina Interna e Specialità Mediche-DIMI, Università degli Studi di Genova, Genova, Italy
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - João F Passos
- Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Kimon S Stamatelopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nektarios Tavernarakis
- Medical School, University of Crete, and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
| | - Zoltan Ungvari
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - James L Kirkland
- Center for Advanced Gerotherapeutics, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm, Institut Universitaire de France, Paris, France
| | | | - Konstantinos Stellos
- Department of Cardiovascular Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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4
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Gao Z, Santos RB, Rupert J, Van Drunen R, Yu Y, Eckel‐Mahan K, Kolonin MG. Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging. Aging Cell 2024; 23:e14138. [PMID: 38475941 PMCID: PMC11296101 DOI: 10.1111/acel.14138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/31/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
It has remained unclear how aging of endothelial cells (EC) contributes to pathophysiology of individual organs. Cell senescence results in part from inactivation of telomerase (TERT). Here, we analyzed mice with Tert knockout specifically in EC. Tert loss in EC induced transcriptional changes indicative of senescence and tissue hypoxia in EC and in other cells. We demonstrate that EC-Tert-KO mice have leaky blood vessels. The blood-brain barrier of EC-Tert-KO mice is compromised, and their cognitive function is impaired. EC-Tert-KO mice display reduced muscle endurance and decreased expression of enzymes responsible for oxidative metabolism. Our data indicate that Tert-KO EC have reduced mitochondrial content and function, which results in increased dependence on glycolysis. Consistent with this, EC-Tert-KO mice have metabolism changes indicative of increased glucose utilization. In EC-Tert-KO mice, expedited telomere attrition is observed for EC of adipose tissue (AT), while brain and skeletal muscle EC have normal telomere length but still display features of senescence. Our data indicate that the loss of Tert causes EC senescence in part through a telomere length-independent mechanism undermining mitochondrial function. We conclude that EC-Tert-KO mice is a model of expedited vascular senescence recapitulating the hallmarks aging, which can be useful for developing revitalization therapies.
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Affiliation(s)
- Zhanguo Gao
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Rafael Bravo Santos
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Joseph Rupert
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Rachel Van Drunen
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Yongmei Yu
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Kristin Eckel‐Mahan
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Mikhail G. Kolonin
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
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5
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Roth‐Walter F, Adcock IM, Benito‐Villalvilla C, Bianchini R, Bjermer L, Caramori G, Cari L, Chung KF, Diamant Z, Eguiluz‐Gracia I, Knol EF, Jesenak M, Levi‐Schaffer F, Nocentini G, O'Mahony L, Palomares O, Redegeld F, Sokolowska M, Van Esch BCAM, Stellato C. Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology. Allergy 2024; 79:1089-1122. [PMID: 38108546 PMCID: PMC11497319 DOI: 10.1111/all.15977] [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: 09/13/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/19/2023]
Abstract
The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.
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Affiliation(s)
- F. Roth‐Walter
- Comparative Medicine, The Interuniversity Messerli Research Institute of the University of Veterinary Medicine ViennaMedical University Vienna and University ViennaViennaAustria
- Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria
| | - I. M. Adcock
- Molecular Cell Biology Group, National Heart & Lung InstituteImperial College LondonLondonUK
| | - C. Benito‐Villalvilla
- Department of Biochemistry and Molecular Biology, School of ChemistryComplutense University of MadridMadridSpain
| | - R. Bianchini
- Comparative Medicine, The Interuniversity Messerli Research Institute of the University of Veterinary Medicine ViennaMedical University Vienna and University ViennaViennaAustria
| | - L. Bjermer
- Department of Respiratory Medicine and Allergology, Lung and Allergy research, Allergy, Asthma and COPD Competence CenterLund UniversityLundSweden
| | - G. Caramori
- Department of Medicine and SurgeryUniversity of ParmaPneumologiaItaly
| | - L. Cari
- Department of Medicine, Section of PharmacologyUniversity of PerugiaPerugiaItaly
| | - K. F. Chung
- Experimental Studies Medicine at National Heart & Lung InstituteImperial College London & Royal Brompton & Harefield HospitalLondonUK
| | - Z. Diamant
- Department of Respiratory Medicine and Allergology, Institute for Clinical ScienceSkane University HospitalLundSweden
- Department of Respiratory Medicine, First Faculty of MedicineCharles University and Thomayer HospitalPragueCzech Republic
- Department of Clinical Pharmacy & PharmacologyUniversity Groningen, University Medical Center Groningen and QPS‐NLGroningenThe Netherlands
| | - I. Eguiluz‐Gracia
- Allergy UnitHospital Regional Universitario de Málaga‐Instituto de Investigación Biomédica de Málaga (IBIMA)‐ARADyALMálagaSpain
| | - E. F. Knol
- Departments of Center of Translational Immunology and Dermatology/AllergologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - M. Jesenak
- Department of Paediatrics, Department of Pulmonology and Phthisiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in MartinUniversity Teaching HospitalMartinSlovakia
| | - F. Levi‐Schaffer
- Institute for Drug Research, Pharmacology Unit, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
| | - G. Nocentini
- Department of Medicine, Section of PharmacologyUniversity of PerugiaPerugiaItaly
| | - L. O'Mahony
- APC Microbiome IrelandUniversity College CorkCorkIreland
- Department of MedicineUniversity College CorkCorkIreland
- School of MicrobiologyUniversity College CorkCorkIreland
| | - O. Palomares
- Department of Biochemistry and Molecular Biology, School of ChemistryComplutense University of MadridMadridSpain
| | - F. Redegeld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of ScienceUtrecht UniversityUtrechtThe Netherlands
| | - M. Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZürichDavosSwitzerland
- Christine Kühne – Center for Allergy Research and Education (CK‐CARE)DavosSwitzerland
| | - B. C. A. M. Van Esch
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of ScienceUtrecht UniversityUtrechtThe Netherlands
| | - C. Stellato
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”University of SalernoSalernoItaly
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6
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Kwon JY, Maeng YS. Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction). Int J Mol Sci 2024; 25:4444. [PMID: 38674031 PMCID: PMC11050478 DOI: 10.3390/ijms25084444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare-through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence-the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.
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Affiliation(s)
- Ja-Young Kwon
- Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea;
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yong-Sun Maeng
- Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea;
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
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7
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Ziegler DV, Czarnecka-Herok J, Vernier M, Scholtes C, Camprubi C, Huna A, Massemin A, Griveau A, Machon C, Guitton J, Rieusset J, Vigneron AM, Giguère V, Martin N, Bernard D. Cholesterol biosynthetic pathway induces cellular senescence through ERRα. NPJ AGING 2024; 10:5. [PMID: 38216569 PMCID: PMC10786911 DOI: 10.1038/s41514-023-00128-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 10/30/2023] [Indexed: 01/14/2024]
Abstract
Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate pathway-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes the transcriptional activity of ERRα that could lead to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis or level in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.
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Affiliation(s)
- Dorian V Ziegler
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Joanna Czarnecka-Herok
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
- Equipe Labellisée la Ligue Contre le Cancer, Lyon, France
| | - Mathieu Vernier
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
- Equipe Labellisée la Ligue Contre le Cancer, Lyon, France
- Goodman Cancer Research Centre, McGill University, Quebec, Montreal, Canada
| | - Charlotte Scholtes
- Goodman Cancer Research Centre, McGill University, Quebec, Montreal, Canada
| | - Clara Camprubi
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Anda Huna
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
- Equipe Labellisée la Ligue Contre le Cancer, Lyon, France
| | - Amélie Massemin
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
- Equipe Labellisée la Ligue Contre le Cancer, Lyon, France
| | - Audrey Griveau
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Christelle Machon
- Biochemistry and Pharmacology-Toxicology Laboratory, Lyon-Sud Hospital, Hospices Civils de Lyon, F-69495, Pierre Bénite, France
| | - Jérôme Guitton
- Biochemistry and Pharmacology-Toxicology Laboratory, Lyon-Sud Hospital, Hospices Civils de Lyon, F-69495, Pierre Bénite, France
| | | | - Arnaud M Vigneron
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Vincent Giguère
- Goodman Cancer Research Centre, McGill University, Quebec, Montreal, Canada
- Departments of Biochemistry, Medicine and Oncology, McGill University, Montreal, Quebec, Montreal, Canada
| | - Nadine Martin
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France.
- Equipe Labellisée la Ligue Contre le Cancer, Lyon, France.
| | - David Bernard
- Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France.
- Equipe Labellisée la Ligue Contre le Cancer, Lyon, France.
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8
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Yang J, Li J, Wei TT, Pang JY, Du YH. Marine Compound Exerts Antiaging Effect in Human Endothelial Progenitor Cells via Increasing Sirtuin1 Expression. ACS Pharmacol Transl Sci 2023; 6:1673-1680. [PMID: 37974619 PMCID: PMC10644422 DOI: 10.1021/acsptsci.3c00136] [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: 07/04/2023] [Indexed: 11/19/2023]
Abstract
Aging is associated with an increased risk of cardiovascular disease. Previous studies have demonstrated that compound 3 (C3), a derivative of marine compound xyloallenoide A isolated from the mangrove fungus Xylaria sp. (no. 2508), exhibited strong angiogenic activities in zebrafish. In this study, we examined the effects of C3 on the senescence of endothelial progenitor cells isolated from human peripheral blood (hEPCs). The results showed that treatment with angiotensin II (AngII) for 24 h induced hEPC senescence, as demonstrated by increased SA-β-galactosidase staining. Moreover, there is a significant decrease in telomerase activity and cellular viability in AngII-treated hEPCs. These changes in aging hEPCs were greatly recovered by C3 in a dose-dependent manner. Furthermore, C3 significantly restored the AngII-induced decrease of sirtuin type 1 (SIRT1) expression, a well-known antiaging protein. In addition, AngII increased AMP-activated protein kinase (AMPK) phosphorylation and reduced Akt phosphorylation in aging hEPCs, which were also reversed by C3. Importantly, the inhibition of C3 on hEPC senescence and AMPK/Akt dysregulation was significantly attenuated by the SIRT1-specific inhibitor nicotinoyl. These results indicated that C3 protects hEPC against AngII-induced senescence by increasing SIRT1 expression levels and balancing the AMPK/Akt signaling pathway. The inhibition of hEPCs senescence by C3 might protect EPCs against dysfunction induced by pathological factors in the elderly population. C3 may provide a novel drug candidate for the treatment of aging-related disorders.
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Affiliation(s)
- Jing Yang
- Department
of Pharmacology, Cardiac & Cerebral Vascular Research Center,
Zhongshan School of Medicine, Sun Yat-Sen
University, Guangzhou 510080, China
| | - Jie Li
- Department
of Anesthesiology, The Second Affiliated
Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Ting-Ting Wei
- Department
of Pharmacology, Cardiac & Cerebral Vascular Research Center,
Zhongshan School of Medicine, Sun Yat-Sen
University, Guangzhou 510080, China
| | - Ji-Yan Pang
- School
of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China
| | - Yan-Hua Du
- Department
of Pharmacology, Cardiac & Cerebral Vascular Research Center,
Zhongshan School of Medicine, Sun Yat-Sen
University, Guangzhou 510080, China
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9
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Fularski P, Krzemińska J, Lewandowska N, Młynarska E, Saar M, Wronka M, Rysz J, Franczyk B. Statins in Chronic Kidney Disease-Effects on Atherosclerosis and Cellular Senescence. Cells 2023; 12:1679. [PMID: 37443712 PMCID: PMC10340582 DOI: 10.3390/cells12131679] [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: 05/21/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Chronic kidney disease (CKD) is a serious health problem that can affect various systems in the human body. Renal failure promotes mechanisms of premature cellular aging and also features of generalized inflammation in the body, which translates into a close relationship between kidney dysfunction and cardiovascular disease (CVD). As kidney function deteriorates, cardiovascular risk and mortality increase in this group of patients. Oxidative stress and inflammation are two closely related processes that initiate a vicious cycle by activating each other. Together with aging, they represent the key factors that cause and exacerbate CVD in CKD. Patients with CKD are particularly vulnerable to the accumulation of aging endothelial cells, vascular smooth muscle and macrophages, increasing the risk of atherosclerosis. Several mechanisms are known that can lead to the progression of the aforementioned problems, such as the accumulation of uremic toxins, persistent inflammation, impaired lipid and electrolyte metabolism, nitric oxide (NO) deficiency, the increased production of reactive oxygen species (ROS) and damage to deoxyribonucleic acid (DNA) and mitochondria. According to research, we can distinguish a group of drugs that effectively counteract the negative effects of CKD-statins. This is a group of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and affect a number of cellular processes and pathways, resulting in the overall slowing of atherosclerosis and cellular aging.
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Affiliation(s)
- Piotr Fularski
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
| | - Julia Krzemińska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
| | - Natalia Lewandowska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
| | - Maciej Saar
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
| | - Magdalena Wronka
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland;
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (P.F.); (J.K.); (N.L.); (M.S.); (M.W.); (B.F.)
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10
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Li C, Yao Z, Ma L, Song X, Wang W, Wan C, Ren S, Chen D, Zheng Y, Zhu YT, Chang G, Wu S, Miao K, Luo F, Zhao XY. Lovastatin promotes the self-renewal of murine and primate spermatogonial stem cells. Stem Cell Reports 2023; 18:969-984. [PMID: 37044069 PMCID: PMC10147841 DOI: 10.1016/j.stemcr.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 02/24/2023] [Accepted: 02/24/2023] [Indexed: 04/14/2023] Open
Abstract
The spermatogonial stem cell (SSC) niche is critical for SSC maintenance and subsequent spermatogenesis. Numerous reproductive hazards impair the SSC niche, thereby resulting in aberrant SSC self-renewal and male infertility. However, promising agents targeting the impaired SSC niche to promote SSC self-renewal are still limited. Here, we screen out and assess the effects of Lovastatin on the self-renewal of mouse SSCs (mSSCs). Mechanistically, Lovastatin promotes the self-renewal of mSSCs and inhibits its inflammation and apoptosis through the regulation of isoprenoid intermediates. Remarkably, treatment by Lovastatin could promote the proliferation of undifferentiated spermatogonia in the male gonadotoxicity model generated by busulfan injection. Of note, we demonstrate that Lovastatin could enhance the proliferation of primate undifferentiated spermatogonia. Collectively, our findings uncover that lovastatin could promote the self-renewal of both murine and primate SSCs and have implications for the treatment of certain types of male infertility using small compounds.
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Affiliation(s)
- Chaohui Li
- Shunde Hospital of Southern Medical University, Shunde, Guangdong, China; State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhaokai Yao
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Linzi Ma
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiuling Song
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Wen Wang
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Cong Wan
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Shaofang Ren
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Dingyao Chen
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Zheng
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yong-Tong Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Gang Chang
- Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, Guangdong, China
| | - Shihao Wu
- Shunde Hospital of Southern Medical University, Shunde, Guangdong, China
| | - Kai Miao
- Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China.
| | - Fang Luo
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
| | - Xiao-Yang Zhao
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China; Sino-America Joint Research Center for Translational Medicine in Developmental Disabilities, Guangzhou, China; Department of Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; National Clinical Research Canter for Kidney Disease, Guangzhou, China; Key Laboratory of Mental Health of the Ministry of Education, Guangzhou, China.
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11
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Matsubayashi S, Ito S, Araya J, Kuwano K. Drugs against metabolic diseases as potential senotherapeutics for aging-related respiratory diseases. Front Endocrinol (Lausanne) 2023; 14:1079626. [PMID: 37077349 PMCID: PMC10106576 DOI: 10.3389/fendo.2023.1079626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 03/22/2023] [Indexed: 04/05/2023] Open
Abstract
Recent advances in aging research have provided novel insights for the development of senotherapy, which utilizes cellular senescence as a therapeutic target. Cellular senescence is involved in the pathogenesis of various chronic diseases, including metabolic and respiratory diseases. Senotherapy is a potential therapeutic strategy for aging-related pathologies. Senotherapy can be classified into senolytics (induce cell death in senescent cells) and senomorphics (ameliorate the adverse effects of senescent cells represented by the senescence-associated secretory phenotype). Although the precise mechanism has not been elucidated, various drugs against metabolic diseases may function as senotherapeutics, which has piqued the interest of the scientific community. Cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are aging-related respiratory diseases. Large-scale observational studies have reported that several drugs, such as metformin and statins, may ameliorate the progression of COPD and IPF. Recent studies have reported that drugs against metabolic diseases may exert a pharmacological effect on aging-related respiratory diseases that can be different from their original effect on metabolic diseases. However, high non-physiological concentrations are needed to determine the efficacy of these drugs under experimental conditions. Inhalation therapy may increase the local concentration of drugs in the lungs without exerting systemic adverse effects. Thus, the clinical application of drugs against metabolic diseases, especially through an inhalation treatment modality, can be a novel therapeutic approach for aging-related respiratory diseases. This review summarizes and discusses accumulating evidence on the mechanisms of aging, as well as on cellular senescence and senotherapeutics, including drugs against metabolic diseases. We propose a developmental strategy for a senotherapeutic approach for aging-related respiratory diseases with a special focus on COPD and IPF.
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12
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Ahmadi Y, Fard JK, Ghafoor D, Eid AH, Sahebkar A. Paradoxical effects of statins on endothelial and cancer cells: the impact of concentrations. Cancer Cell Int 2023; 23:43. [PMID: 36899388 PMCID: PMC9999585 DOI: 10.1186/s12935-023-02890-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 03/04/2023] [Indexed: 03/12/2023] Open
Abstract
In addition to their lipid-lowering functions, statins elicit additional pleiotropic effects on apoptosis, angiogenesis, inflammation, senescence, and oxidative stress. Many of these effects have been reported in cancerous and noncancerous cells like endothelial cells (ECs), endothelial progenitor cells (EPCs) and human umbilical vein cells (HUVCs). Not surprisingly, statins' effects appear to vary largely depending on the cell context, especially as pertains to modulation of cell cycle, senescence, and apoptotic processes. Perhaps the most critical reason for this discordance is the bias in selecting the applied doses in various cells. While lower (nanomolar) concentrations of statins impose anti-senescence, and antiapoptotic effects, higher concentrations (micromolar) appear to precipitate opposite effects. Indeed, most studies performed in cancer cells utilized high concentrations, where statin-induced cytotoxic and cytostatic effects were noted. Some studies report that even at low concentrations, statins induce senescence or cytostatic impacts but not cytotoxic effects. However, the literature appears to be relatively consistent that in cancer cells, statins, in both low or higher concentrations, induce apoptosis or cell cycle arrest, anti-proliferative effects, and cause senescence. However, statins' effects on ECs depend on the concentrations; at micromolar concentrations statins cause cell senescence and apoptosis, while at nonomolar concentrations statins act reversely.
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Affiliation(s)
- Yasin Ahmadi
- College of Science, Department of Medical Laboratory Sciences, Komar University of Science and Technology, 46001, Sulaymania, Iraq.
| | - Javad Khalili Fard
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dlzar Ghafoor
- College of Science, Department of Medical Laboratory Sciences, Komar University of Science and Technology, 46001, Sulaymania, Iraq
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - 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.
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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13
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Meyer N, Richter K, Brodowski L, von Kaisenberg C, Melk A, Schmidt B, Limbourg FP, Schröder-Heurich B, von Versen-Höynck F. Impairment of endothelial progenitor cells in women after kidney transplantation. Microcirculation 2023; 30:e12794. [PMID: 36484638 DOI: 10.1111/micc.12794] [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: 06/16/2022] [Revised: 11/04/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The long-term survival of kidney transplant patients has substantially improved. However, there is a higher risk for cardiovascular events after transplantation, partly due to immunosuppression. A diminished number of endothelial progenitor cells (EPCs), which play an important role in angiogenesis and the repair of endothelial damage, are associated with an increased cardiovascular risk. The aim of this study was to evaluate whether kidney transplantation affects EPCs in women. METHODS Twenty-four healthy women and 22 female kidney transplant recipients were recruited. The ratio of angiogenic and non-angiogenic circulating progenitor cells (CPCs) was determined by multicolor flow cytometry and related to clinical parameters. Cord blood-derived endothelial colony-forming cells (ECFCs), a proliferative subgroup of endothelial progenitor cells, were treated with pooled sera from transplant patients or healthy controls and tested for their functional integrity using in vitro models. RESULTS Kidney transplant recipients displayed a reduced ratio of angiogenic and non-angiogenic CPCs compared to healthy controls. Differences were especially pronounced in premenopausal women. Exposure to sera of transplanted women led to a significant impairment of ECFC proliferation, migration, and angiogenesis ability. CONCLUSIONS Alterations of EPC populations may contribute to the higher cardiovascular risks after organ transplantation and should be considered in therapeutic strategies.
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Affiliation(s)
- Nadia Meyer
- Gynecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Katja Richter
- Gynecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Lars Brodowski
- Gynecology Research Unit, Hannover Medical School, Hannover, Germany.,Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | | | - Anette Melk
- Children's Hospital, Hannover Medical School, Hannover, Germany
| | - Bernhard Schmidt
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Florian P Limbourg
- Department of Nephrology, Vascular Medicine Research, Hannover Medical School, Hannover, Germany
| | | | - Frauke von Versen-Höynck
- Gynecology Research Unit, Hannover Medical School, Hannover, Germany.,Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
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14
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Zafirovic S, Macvanin M, Stanimirovic J, Obradovic M, Radovanovic J, Melih I, Isenovic E. Association Between Telomere Length and Cardiovascular Risk: Pharmacological Treatments Affecting Telomeres and Telomerase Activity. Curr Vasc Pharmacol 2022; 20:465-474. [PMID: 35986545 DOI: 10.2174/1570161120666220819164240] [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: 02/18/2022] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 01/25/2023]
Abstract
Telomeres represent the ends of chromosomes, and they are composed of an extensive number of - TTAGGG nucleotide sequence repeats in humans. Telomeres prevent chromosome degradation, participate in stabilization, and regulate the DNA repair system. Inflammation and oxidative stress have been identified as important processes causing cardiovascular disease and accelerating telomere shortening rate. This review investigates the link between telomere length and pathological vascular conditions from experimental and human studies. Also, we discuss pharmacological treatments affecting telomeres and telomerase activity.
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Affiliation(s)
- Sonja Zafirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Mirjana Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Julijana Stanimirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Milan Obradovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Irena Melih
- Faculty of Stomatology, Pancevo, University Business Academy, 21000 Novi Sad, Serbia
| | - Esma Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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15
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Shu X, Wu J, Zhang T, Ma X, Du Z, Xu J, You J, Wang L, Chen N, Luo M, Wu J. Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue. Nutrients 2022; 14:nu14204365. [PMID: 36297049 PMCID: PMC9607568 DOI: 10.3390/nu14204365] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/11/2022] [Accepted: 10/17/2022] [Indexed: 11/16/2022] Open
Abstract
Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated β-galactosidase (SA-β-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.
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Affiliation(s)
- Xin Shu
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Jiaqi Wu
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Tao Zhang
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Xiaoyu Ma
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Zuoqin Du
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Jin Xu
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Jingcan You
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Liqun Wang
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Ni Chen
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Mao Luo
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
| | - Jianbo Wu
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China
- Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Southwest Medical University, Luzhou 646000, China
- Correspondence: ; Tel./Fax: +86-830-3161702
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16
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Inci N, Kamali D, Akyildiz EO, Tahir Turanli E, Bozaykut P. Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models. FRONTIERS IN AGING 2022; 3:828058. [PMID: 35821852 PMCID: PMC9261353 DOI: 10.3389/fragi.2022.828058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/12/2022] [Indexed: 01/10/2023]
Abstract
Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.
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Affiliation(s)
- Nurcan Inci
- Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Dilanur Kamali
- Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Erdogan Oguzhan Akyildiz
- Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Eda Tahir Turanli
- Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Perinur Bozaykut
- Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
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17
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Xiang Q, Tian F, Xu J, Du X, Zhang S, Liu L. New insight into dyslipidemia‐induced cellular senescence in atherosclerosis. Biol Rev Camb Philos Soc 2022; 97:1844-1867. [PMID: 35569818 PMCID: PMC9541442 DOI: 10.1111/brv.12866] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 04/18/2022] [Accepted: 04/28/2022] [Indexed: 11/28/2022]
Abstract
Atherosclerosis, characterized by lipid‐rich plaques in the arterial wall, is an age‐related disorder and a leading cause of mortality worldwide. However, the specific mechanisms remain complex. Recently, emerging evidence has demonstrated that senescence of various types of cells, such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), macrophages, endothelial progenitor cells (EPCs), and adipose‐derived mesenchymal stem cells (AMSCs) contributes to atherosclerosis. Cellular senescence and atherosclerosis share various causative stimuli, in which dyslipidemia has attracted much attention. Dyslipidemia, mainly referred to elevated plasma levels of atherogenic lipids or lipoproteins, or functional impairment of anti‐atherogenic lipids or lipoproteins, plays a pivotal role both in cellular senescence and atherosclerosis. In this review, we summarize the current evidence for dyslipidemia‐induced cellular senescence during atherosclerosis, with a focus on low‐density lipoprotein (LDL) and its modifications, hydrolysate of triglyceride‐rich lipoproteins (TRLs), and high‐density lipoprotein (HDL), respectively. Furthermore, we describe the underlying mechanisms linking dyslipidemia‐induced cellular senescence and atherosclerosis. Finally, we discuss the senescence‐related therapeutic strategies for atherosclerosis, with special attention given to the anti‐atherosclerotic effects of promising geroprotectors as well as anti‐senescence effects of current lipid‐lowering drugs.
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Affiliation(s)
- Qunyan Xiang
- Department of Geriatrics, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Institute of Aging and Age‐related Disease Research Central South University Changsha Hunan 410011 PR China
| | - Feng Tian
- Department of Geriatric Cardiology The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450000 PR China
| | - Jin Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Research Institute of Blood Lipid and Atherosclerosis Central South University Changsha Hunan 410011 PR China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province Changsha Hunan 410011 PR China
- Cardiovascular Disease Research Center of Hunan Province Changsha Hunan 410011 PR China
| | - Xiao Du
- Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Research Institute of Blood Lipid and Atherosclerosis Central South University Changsha Hunan 410011 PR China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province Changsha Hunan 410011 PR China
- Cardiovascular Disease Research Center of Hunan Province Changsha Hunan 410011 PR China
| | - Shilan Zhang
- Department of Gastroenterology, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
| | - Ling Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Research Institute of Blood Lipid and Atherosclerosis Central South University Changsha Hunan 410011 PR China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province Changsha Hunan 410011 PR China
- Cardiovascular Disease Research Center of Hunan Province Changsha Hunan 410011 PR China
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18
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Wiley CD, Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab 2021; 3:1290-1301. [PMID: 34663974 PMCID: PMC8889622 DOI: 10.1038/s42255-021-00483-8] [Citation(s) in RCA: 340] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022]
Abstract
Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.
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Affiliation(s)
- Christopher D Wiley
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, CA, USA.
- Buck Institute for Research on Aging, Novato, CA, USA.
| | - Judith Campisi
- Buck Institute for Research on Aging, Novato, CA, USA
- Lawrence Berkeley National Laboratory, Berkeley, CA, USA
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Atorvastatin Pretreatment Ameliorates Mesenchymal Stem Cell Migration through miR-146a/CXCR4 Signaling. Tissue Eng Regen Med 2021; 18:863-873. [PMID: 34260048 DOI: 10.1007/s13770-021-00362-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/07/2021] [Accepted: 06/10/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND We previously found that atorvastatin (ATV) enhanced mesenchymal stem cells (MSCs) migration, by a yet unknown mechanism. CXC chemokine receptor 4 (CXCR4) is critical to cell migration and regulated by microRNA-146a (miR-146a). Therefore, this study aimed to assess whether ATV ameliorates MSCs migration through miR-146a/CXCR4 signaling. METHODS Expression of CXCR4 was evaluated by flow cytometry. Expression of miR-146a was examined by reverse transcription-quantitative polymerase chain reaction. A transwell system was used to assess the migration ability of MSCs. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague-Dawley rats with acute myocardial infarction (AMI). Mimics of miR-146a were used in vitro, and miR-146a overexpression lentivirus was used in vivo, to assess the role of miR-146a in the migration ability of MSCs. RESULTS The results showed that ATV pretreatment in vitro upregulated CXCR4 and induced MSCs migration. In addition, flow cytometry demonstrated that miR-146a mimics suppressed CXCR4, and ATV pretreatment no longer ameliorated MSCs migration because of decreased CXCR4. In the AMI model, miR-146a-overexpressing MSCs increased infarct size and fibrosis. CONCLUSION The miR-146a/CXCR4 signaling pathway contributes to MSCs migration and homing induced by ATV pretreatment. miR-146a may be a novel therapeutic target for stimulating MSCs migration to the ischemic tissue for improved repair.
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20
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Tousian H, Razavi BM, Hosseinzadeh H. In search of elixir: Pharmacological agents against stem cell senescence. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:868-880. [PMID: 34712416 PMCID: PMC8528253 DOI: 10.22038/ijbms.2021.51917.11773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 03/02/2021] [Indexed: 12/13/2022]
Abstract
Stem cell senescence causes different complications. In addition to the aging phenomenon, stem cell senescence has been investigated in various concepts such as cancer, adverse drug effects, and as a limiting factor in cell therapy. This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. We searched the databases such as EMBASE, PubMed, and Web of Science with the keywords "stem cell," "progenitor cell," "satellite," "senescence" and excluded the keywords "cancer," "tumor," "malignancy" and "carcinoma" until June 2020. Among these results, we chose 47 relevant studies. Our investigation indicates that most of these studies examined endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells, and a few others were about less-discussed types of stem cells such as cardiac stem cells, myeloblasts, and induced pluripotent stem cells. From another aspect, 17β-Estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents, while the main protective mechanism was through telomerase activity enhancement or oxidative damage ablation. Although many of these studies are in vitro, they are still worthwhile. Stem cell senescence in the in vitro expansion stage is an essential concern in clinical procedures of cell therapy. Moreover, in vitro studies are the first step for further in vivo and clinical studies. It is noteworthy to mention the fact that these protective agents have been used in the clinical setting for various purposes for a long time. Given that, we only need to examine their systemic anti-senescence effects and effective dosages.
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Affiliation(s)
- Hourieh Tousian
- Vice-chancellery of Food and Drug,Shahroud University of Medical Sciences, Shahroud, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Comparison of Transcriptomic Profiles of MiaPaCa-2 Pancreatic Cancer Cells Treated with Different Statins. Molecules 2021; 26:molecules26123528. [PMID: 34207840 PMCID: PMC8226792 DOI: 10.3390/molecules26123528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 01/24/2023] Open
Abstract
Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.
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22
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Cholesterol-lowering drug pitavastatin targets lung cancer and angiogenesis via suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling. Anticancer Drugs 2021; 31:377-384. [PMID: 32011362 DOI: 10.1097/cad.0000000000000885] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Therapeutic agents that target both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy, particularly in lung cancer due to the critical roles of angiogenesis during lung cancer progression and metastasis. In this work, we showed that pitavastatin, a novel cholesterol-lowering drug, potently inhibited lung cancer cells and angiogenesis. This was achieved by the induction of apoptosis and inhibition of proliferation of lung cancer cells and human lung tumor-associated endothelial cell. Pitavastatin was not only effective to chemo-sensitive but also chemo-resistant lung cancer cells. This was also consistent with the finding that pitavastatin significantly enhanced cisplatin's efficacy in lung cancer xenograft model without causing toxicity in mice. We further showed that pitavastatin inhibited lung tumor angiogenesis in vitro and in vivo through suppressing human lung tumor-associated endothelial cell migration and morphogenesis without affecting adhesion. Mechanistically, we showed that pitavastatin acted on lung cancer cells and human lung tumor-associated endothelial cell through suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling. Our work is the first to demonstrate the inhibitory effects of pitavastatin on Ras-mediated signaling. Our findings provide pre-clinical evidence to repurpose pitavastatin for the treatment of lung cancer.
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23
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Oh KS, Febres-Aldana CA, Kuritzky N, Ujueta F, Arenas IA, Sriganeshan V, Medina AM, Poppiti R. Cellular senescence evaluated by P16INK4a immunohistochemistry is a prevalent phenomenon in advanced calcific aortic valve disease. Cardiovasc Pathol 2021; 52:107318. [PMID: 33450362 DOI: 10.1016/j.carpath.2021.107318] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific aortic valve disease (CAVD), a leading cause of morbidity and mortality in the aging population. Cellular senescence contributes to a functional decay in chronic diseases by intensifying tissue remodeling and impairing tissue regeneration. We evaluated the expression of P16INK4A and P53 as surrogate markers of senescence in CAVD. METHODS Aortic valves from 27 individuals with severe CAVD requiring aortic valve replacement were selected for routine histologic processing. Immunohistochemical expression of P16INK4A and P53 was quantified using computerized image analysis on fields matching compartments with varying degrees of tissue remodeling. RESULTS All aortic valves demonstrated P16INK4A and P53-positive cells. The percentage of P16INK4A -positive cells, but not of P53, was higher in areas of calcification and/or ossification (57.21%±26.31, n=40) and severe fibrosis (54.79%±27.19, n=25) than in areas with minimal to mild tissue remodeling (13.69% ± 11.88, n=16, P<.0001). P16INK4A expression was observed in interstitial valve cells within all compartments proportional to the degree of fibrosis and did not correlate with age, severity of aortic stenosis, or P53 expression. Multiple linear regression analysis by backward elimination revealed P16INK4A expression was lower among statin users (P<.01). CONCLUSIONS P16INK4A- expression is ubiquitous in calcified aortic valves and correlates with severity of tissue remodeling, suggesting a role of cellular senescence in the progression of CAVD. Further research is needed to identify possible treatment modalities as disease modifying agents for CAVD.
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Affiliation(s)
- Kei Shing Oh
- Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA.
| | - Christopher A Febres-Aldana
- Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Nicholas Kuritzky
- Department of Radiation Oncology, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Francisco Ujueta
- Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Ivan A Arenas
- Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Vathany Sriganeshan
- Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Ana Maria Medina
- Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Robert Poppiti
- Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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24
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Meyer N, Brodowski L, Richter K, von Kaisenberg CS, Schröder-Heurich B, von Versen-Höynck F. Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro. J Clin Med 2021; 10:E183. [PMID: 33419165 PMCID: PMC7825508 DOI: 10.3390/jcm10020183] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/28/2020] [Accepted: 12/31/2020] [Indexed: 12/15/2022] Open
Abstract
Endothelial dysfunction is a primary feature of several cardiovascular diseases. Endothelial colony-forming cells (ECFCs) represent a highly proliferative subtype of endothelial progenitor cells (EPCs), which are involved in neovascularization and vascular repair. Statins are known to improve the outcome of cardiovascular diseases via pleiotropic effects. We hypothesized that treatment with the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor pravastatin increases ECFCs' functional capacities and regulates the expression of proteins which modulate endothelial health in a favourable manner. Umbilical cord blood derived ECFCs were incubated with different concentrations of pravastatin with or without mevalonate, a key intermediate in cholesterol synthesis. Functional capacities such as migration, proliferation and tube formation were addressed in corresponding in vitro assays. mRNA and protein levels or phosphorylation of protein kinase B (AKT), endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1), vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and endoglin (Eng) were analyzed by real time PCR or immunoblot, respectively. Proliferation, migration and tube formation of ECFCs were enhanced after pravastatin treatment, and AKT- and eNOS-phosphorylation were augmented. Further, expression levels of HO-1, VEGF-A and PlGF were increased, whereas expression levels of sFlt-1 and Eng were decreased. Pravastatin induced effects were reversible by the addition of mevalonate. Pravastatin induces beneficial effects on ECFC function, angiogenic signaling and protein expression. These effects may contribute to understand the pleiotropic function of statins as well as to provide a promising option to improve ECFCs' condition in cell therapy in order to ameliorate endothelial dysfunction.
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Affiliation(s)
- Nadia Meyer
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
| | - Lars Brodowski
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
| | - Katja Richter
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
| | - Constantin S. von Kaisenberg
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
| | - Bianca Schröder-Heurich
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
| | - Frauke von Versen-Höynck
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
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25
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Wu H, Xiao C, Zhao Y, Yin H, Yu M. Liraglutide Improves Endothelial Function via the mTOR Signaling Pathway. J Diabetes Res 2021; 2021:2936667. [PMID: 34447854 PMCID: PMC8384515 DOI: 10.1155/2021/2936667] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/28/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) is crucial for endothelial function. This study is aimed at assessing whether the glucagon-like peptide-1 (GLP-1) analogue liraglutide has a protective effect on endothelial function via the mTOR signaling pathway. METHODS Human umbilical vein endothelial cells (HUVECs) were administered liraglutide (100 nM) for 0, 10, 30, 60, 720, and 1440 minutes, respectively. Then, the expression and phosphorylation levels of mTOR, mTOR-Raptor complex (mTORC1), and mTOR-Rictor complex (mTORC2) were determined by Western blot and immunoprecipitation, while mTORC1 and mTORC2 expression was blocked by siRNA-Raptor and siRNA-Rictor, respectively. Akt phosphorylation was detected by Western blot. HUVECs were then incubated with liraglutide in the absence or presence of Akt inhibitor IV. Nitric oxide (NO) release was assessed by the nitrate reductase method. Phosphorylated endothelial nitric oxide synthase (eNOS), human telomerase reverse transcriptase (hTERT), and apoptosis-related effectors were assessed for protein levels by Western blot. Telomerase activity was evaluated by ELISA. RESULTS Sustained mTOR phosphorylation, mTORC2 formation, and mTORC2-dependent Akt phosphorylation were induced by liraglutide. In addition, eNOS phosphorylation, NO production, nuclear hTERT accumulation, and nuclear telomerase activity were enhanced by mTORC2-mediated Akt activation. Liraglutide also showed an antiapoptotic effect by upregulating antiapoptotic proteins and downregulating proapoptotic proteins in an mTORC2-Akt activation-dependent manner. CONCLUSION Liraglutide significantly improves endothelial function, at least partially via the mTORC2/Akt signaling pathway.
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Affiliation(s)
- Han Wu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Cheng Xiao
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yiting Zhao
- Department of PET-CT Center, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Hongchao Yin
- Department of Pathology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
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26
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Cianflone E, Cappetta D, Mancuso T, Sabatino J, Marino F, Scalise M, Albanese M, Salatino A, Parrotta EI, Cuda G, De Angelis A, Berrino L, Rossi F, Nadal-Ginard B, Torella D, Urbanek K. Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells. Int J Mol Sci 2020; 21:ijms21217927. [PMID: 33114544 PMCID: PMC7663580 DOI: 10.3390/ijms21217927] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/20/2022] Open
Abstract
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.
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Affiliation(s)
- Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Donato Cappetta
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Teresa Mancuso
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Jolanda Sabatino
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Michele Albanese
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Alessandro Salatino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Elvira Immacolata Parrotta
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Giovanni Cuda
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Liberato Berrino
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Francesco Rossi
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Bernardo Nadal-Ginard
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
- Correspondence: (D.T.); (K.U.)
| | - Konrad Urbanek
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
- Correspondence: (D.T.); (K.U.)
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Tan Q, Yu D, Song L. Atorvastatin disrupts primary human brain microvascular endothelial cell functions via prenylation-dependent mitochondrial inhibition and oxidative stress. Fundam Clin Pharmacol 2020; 35:341-350. [PMID: 33047339 DOI: 10.1111/fcp.12615] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/30/2020] [Accepted: 10/07/2020] [Indexed: 01/20/2023]
Abstract
Primary human brain microvascular endothelial cell (HBMEC) is the major component of the blood-brain barrier (BBB). Atorvastatin, a HMG-CoA reductase inhibitor, is a cholesterol-lowering drug commonly used to reduce the risk for cardiovascular disease. Numerous studies have reported the pleiotropic effects of atorvastatin on endothelial cells, but the findings are controversial and inconclusive. In addition, little is known about the biological effects of atorvastatin on HBMEC. In this work, we demonstrate that atorvastatin at micromolar but not nanomolar concentrations induces dysfunctions of a number of HBMEC events, including differentiation into capillary network, migration and growth but not cell adhesion. We further show that the inhibitory effects of atorvastatin on HBMEC are independent of angiogenesis stimulators. Atorvastatin induces HBMEC apoptosis even in the presence of vascular endothelial growth factor (VEGF) and serum. Mechanism studies indicate that atorvastatin at micromolar concentration leads to protein prenylation inhibition, mitochondrial dysfunction and thereby subsequent oxidative stress and damage in HBMEC. Rescue experiments confirm that atorvastatin inhibits HBMEC functions via prenylation-dependent mitochondrial inhibition. Our work reveals the inhibitory effects of atorvastatin on HBMEC and suggests the possible negative influence of atorvastatin in blood-brain barrier.
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Affiliation(s)
- Qian Tan
- Department of Neurology, Hubei Hospital of Integrated Traditional Chinese and Western Medicine, Wuhan, China
| | - Danfang Yu
- Department of Neurology, Hubei Hospital of Integrated Traditional Chinese and Western Medicine, Wuhan, China
| | - Lin Song
- Department of Neurology, Hubei Hospital of Integrated Traditional Chinese and Western Medicine, Wuhan, China
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28
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Abstract
HMG-CoA reductase inhibitors (known as statins) are commonly prescribed worldwide for the management of coronary heart disease and the underlying dyslipidemia. This class of drugs has been shown to infer a significant decrease in the risk of cardiovascular morbidity and mortality. Only recently though have the beneficial effects of statins in other diseases such as non-alcoholic steatohepatitis been highlighted. Importantly, also, multiple studies have revealed that statin use was associated with lower cancer-associated mortality across multiple types of cancers. This work aims to review those studies with a particular focus on liver cancer. We also provide a review of the proposed mechanisms of action describing how statins can induce chemo-preventive and antitumor effects.
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Affiliation(s)
- Ghazal Alipour Talesh
- miRCaDe team, Univ. Bordeaux, INSERM, BMGIC, U1035, F-33000 Bordeaux, France.,Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Véronique Trézéguet
- miRCaDe team, Univ. Bordeaux, INSERM, BMGIC, U1035, F-33000 Bordeaux, France
| | - Aksam Merched
- miRCaDe team, Univ. Bordeaux, INSERM, BMGIC, U1035, F-33000 Bordeaux, France
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29
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Endothelial Progenitor Cells Induce Angiogenesis: a Potential Mechanism Underlying Neovascularization in Encephaloduroarteriosynangiosis. Transl Stroke Res 2020; 12:357-365. [PMID: 32632776 DOI: 10.1007/s12975-020-00834-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/10/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022]
Abstract
Encephaloduroarteriosynangiosis (EDAS) is one of the most commonly used indirect vascular reconstruction methods. EDAS aids in the formation of collateral vessels from the extracranial to the intracranial circulation in patients with moyamoya disease (MMD). However, the underlying mechanism of collateral vessel formation is not well understood. Endothelial progenitor cells (EPCs) differentiate to form the vascular endothelial cells and play a very important role in angiogenesis. We designed this prospective clinical trial to investigate the presence of EPCs in patients with MMD and to explore the neovascularization mechanism mediated by the EPCs in EDAS. The patients who were diagnosed with MMD were recruited between February 5, 2017, and January 7, 2018. The blood samples were obtained from an antecubital vein and were analyzed using flow cytometry. EPCs were defined as CD34brCD133+CD45dimKDR+. All the patients enrolled in the study underwent EDAS. Cerebral arteriography was performed 6 months post-EDAS to assess the efficacy of synangiosis. The correlation between EPC count and good collateral circulation was evaluated. Among the 116 patients with MMD enrolled in this study, 73 were women and 43 were men. The average age of the patients was 33.8 ± 15.2 years. The EPC count of the patients with MMD was 0.071% ± 0.050% (expressed as percentage of the peripheral blood mononuclear cells). The EPC count in the good postoperative collateral circulation group was significantly higher (0.085% ± 0.054%) than that in the poor collateral circulation group (0.048% ± 0.034%) (P = 0.000). The age, modified Suzuki-Mugikura grade, and EPC count were significantly correlated with the good collateral circulation post-EDAS in the multivariate analysis (P = 0.018, P = 0.007, and P = 0.003, respectively). The formation of collateral vessels by EDAS is primarily driven by angiogenesis. The EPC count may be the most critical factor for collateral circulation. The therapeutic effect of EDAS is more likely to benefit younger or severe ischemic patients with MMD.
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30
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Oktaviono YH, Hutomo SA, Al-Farabi MJ, Chouw A, Sandra F. Human umbilical cord blood-mesenchymal stem cell-derived secretome in combination with atorvastatin enhances endothelial progenitor cells proliferation and migration. F1000Res 2020; 9:537. [PMID: 34394921 PMCID: PMC8358709 DOI: 10.12688/f1000research.23547.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2021] [Indexed: 12/29/2022] Open
Abstract
Background: Human umbilical cord blood-mesenchymal stem cell (hUCB-MSC)-derived secretome is known to be able to promote neovascularization and angiogenesis, so it is also thought to have a capability to modulate endothelial progenitor cell (EPC) functions. Atorvastatin is the cornerstone of coronary artery disease (CAD) treatment which can enhance EPCs proliferation and migration. This study aims to analyze the effect of the hUCB-MSC-derived secretome and its combination with atorvastatin toward EPCs proliferation and migration. Methods: EPCs were isolated from a CAD patient's peripheral blood. Cultured EPCs were divided into a control group and treatment group of 2.5 µM atorvastatin, hUCB-MSC-derived secretome (2%, 10%, and 20% concentration) and its combination. EPCs proliferation was evaluated using an MTT cell proliferation assay, and EPC migration was evaluated using a Transwell migration assay kit. Results: This research showed that hUCB-MSC-derived secretomes significantly increase EPC proliferation and migration in a dose-dependent manner. The high concentration of hUCB-MSC-derived secretome were shown to be superior to atorvastatin in inducing EPC proliferation and migration (p<0.001). A combination of the hUCB-MSC-derived secretome and atorvastatin shown to improve EPCs proliferation and migration compared to hUCB-MSC-derived secretome treatment or atorvastatin alone (p<0.001). Conclusions: This study concluded that the hUCB-MSC-derived secretome work synergistically with atorvastatin treatment in improving EPCs proliferation and migration.
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Affiliation(s)
- Yudi Her Oktaviono
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Suryo Ardi Hutomo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Makhyan Jibril Al-Farabi
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Angliana Chouw
- Stem Cell Division, Prodia Laboratory, Jakarta, Indonesia
| | - Ferry Sandra
- Department of Biochemistry and Molecular Biology, Faculty of Dentistry, Universitas Trisakti, Jakarta, Indonesia
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31
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Oktaviono YH, Hutomo SA, Al-Farabi MJ, Chouw A, Sandra F. Human umbilical cord blood-mesenchymal stem cell-derived secretome in combination with atorvastatin enhances endothelial progenitor cells proliferation and migration. F1000Res 2020; 9:537. [PMID: 34394921 PMCID: PMC8358709 DOI: 10.12688/f1000research.23547.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2020] [Indexed: 12/21/2022] Open
Abstract
Background: Human umbilical cord blood-mesenchymal stem cell (hUCB-MSC)-derived secretome is known to be able to promote neovascularization and angiogenesis, so it is also thought to have a capability to modulate endothelial progenitor cell (EPC) functions. Atorvastatin is the cornerstone of coronary artery disease (CAD) treatment which can enhance EPCs proliferation and migration. This study aims to analyze the effect of the hUCB-MSC-derived secretome and its combination with atorvastatin toward EPCs proliferation and migration. Methods: EPCs were isolated from a CAD patient's peripheral blood. Cultured EPCs were divided into a control group and treatment group of 2.5 µM atorvastatin, hUCB-MSC-derived secretome (2%, 10%, and 20% concentration) and its combination. EPCs proliferation was evaluated using an MTT cell proliferation assay, and EPC migration was evaluated using a Transwell migration assay kit. Results: This research showed that hUCB-MSC-derived secretomes significantly increase EPC proliferation and migration in a dose-dependent manner. The high concentration of hUCB-MSC-derived secretome were shown to be superior to atorvastatin in inducing EPC proliferation and migration (p<0.001). A combination of the hUCB-MSC-derived secretome and atorvastatin shown to improve EPCs proliferation and migration compared to hUCB-MSC-derived secretome treatment or atorvastatin alone (p<0.001). Conclusions: This study concluded that the hUCB-MSC-derived secretome work synergistically with atorvastatin treatment in improving EPCs proliferation and migration.
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Affiliation(s)
- Yudi Her Oktaviono
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Suryo Ardi Hutomo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Makhyan Jibril Al-Farabi
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Angliana Chouw
- Stem Cell Division, Prodia Laboratory, Jakarta, Indonesia
| | - Ferry Sandra
- Department of Biochemistry and Molecular Biology, Faculty of Dentistry, Universitas Trisakti, Jakarta, Indonesia
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32
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Polonis K, Becari C, Chahal CAA, Zhang Y, Allen AM, Kellogg TA, Somers VK, Singh P. Chronic Intermittent Hypoxia Triggers a Senescence-like Phenotype in Human White Preadipocytes. Sci Rep 2020; 10:6846. [PMID: 32321999 PMCID: PMC7176724 DOI: 10.1038/s41598-020-63761-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 04/03/2020] [Indexed: 12/13/2022] Open
Abstract
Obstructive sleep apnea (OSA) is a common sleep disorder associated with obesity. Emerging evidence suggest that OSA increases the risk of cardiovascular morbidity and mortality partly via accelerating the process of cellular aging. Thus, we sought to examine the effects of intermittent hypoxia (IH), a hallmark of OSA, on senescence in human white preadipocytes. We demonstrate that chronic IH is associated with an increased generation of mitochondrial reactive oxygen species along with increased prevalence of cells with nuclear localization of γH2AX & p16. A higher prevalence of cells positive for senescence-associated β-galactosidase activity was also evident with chronic IH exposure. Intervention with aspirin, atorvastatin or renin-angiotensin system (RAS) inhibitors effectively attenuated IH-mediated senescence-like phenotype. Importantly, the validity of in vitro findings was confirmed by examination of the subcutaneous abdominal adipose tissue which showed that OSA patients had a significantly higher percentage of cells with nuclear localization of γH2AX & p16 than non-OSA individuals (20.1 ± 10.8% vs. 10.3 ± 2.7%, Padjusted < 0.001). Furthermore, the frequency of dual positive γH2AX & p16 nuclei in adipose tissue of OSA patients receiving statin, aspirin, and/or RAS inhibitors was comparable to non-OSA individuals. This study identifies chronic IH as a trigger of senescence-like phenotype in preadipocytes. Together, our data suggest that OSA may be considered as a senescence-related disorder.
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Affiliation(s)
- Katarzyna Polonis
- Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA
| | - Christiane Becari
- Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA
- Department of Surgery and Anatomy, Ribeirao Preto Medical School, Ribeirão Preto, SP, Brazil
| | - C Anwar A Chahal
- Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA
- Mayo Clinic Graduate School of Biomedical Sciences, MN, Rochester, USA
| | - Yuebo Zhang
- Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA
| | - Alina M Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic, MN, Rochester, USA
| | | | - Virend K Somers
- Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA
| | - Prachi Singh
- Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA.
- Pennington Biomedical Research Center, LA, Baton Rouge, USA.
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33
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Wang ST, Huang SW, Liu KT, Lee TY, Shieh JJ, Wu CY. Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway. Cell Death Discov 2020; 6:17. [PMID: 32257389 PMCID: PMC7105491 DOI: 10.1038/s41420-020-0252-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 03/02/2020] [Accepted: 03/10/2020] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC), a hepatic malignancy, has a poor prognosis and contributes to cancer-related death worldwide. Cellular senescence is an anticancer therapeutic strategy that causes irreversible cell cycle arrest and enables immune-mediated clearance of cancer cells. Atorvastatin, an HMG-CoA reductase inhibitor, has been shown to inhibit tumor growth and induce apoptosis or autophagy in malignant tumors. However, whether atorvastatin can induce HCC cell senescence and the mechanisms involved are poorly understood. The effects of atorvastatin-induced senescence were examined in both HCC cells and mouse xenograft models. The phenomenon and mechanism of senescence were examined by cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining and western blotting in HCC cells, and HCC tissues from mice were analyzed by immunohistochemical (IHC) staining. We demonstrated that atorvastatin induced cell growth inhibition and G0/G1 phase cell cycle arrest, leading to senescence in HCC cells. Atorvastatin-induced senescence was independent of p53, p14, and p16, and atorvastatin not only decreased the secretion of IL-6, a major senescence-associated secretory phenotype (SASP) factor, and the phosphorylation of STAT3 but also inhibited the expression of hTERT, a catalytic subunit of telomerase. Supplementation with exogenous IL-6 reversed both atorvastatin-induced suppression of STAT3 phosphorylation and hTERT expression and atorvastatin-induced senescence. Overexpression of constitutively activated STAT3 rescued HCC cells from atorvastatin-induced hTERT suppression and senescence. Moreover, atorvastatin decreased tumor growth in mouse xenograft models. Consistent with these results, atorvastatin decreased the IL-6, p-STAT3, and hTERT levels and increased β-gal expression in tumor sections. Taken together, these data indicate that atorvastatin can induce atypical cellular senescence in HCC cells to inhibit tumor growth, an effect mediated by downregulation of hTERT through suppression of the IL-6/STAT3 pathway.
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Affiliation(s)
- Sin-Ting Wang
- Division of Translational Research and Center of Excellence for Cancer Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shi-Wei Huang
- Center for Cell Therapy and Translation Research, China Medical University Hospital, Taichung, Taiwan
| | - Kuang-Ting Liu
- Department of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Pathology & Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Jeng-Jer Shieh
- Department of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Life Sciences and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chun-Ying Wu
- Division of Translational Research and Center of Excellence for Cancer Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Biomedical Informatics, Institute of Clinical Medicine, and Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
- Department of Public Health, China Medical University, Taichung, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
- Taiwan Microbiota Consortium, Taipei, Taiwan
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34
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Bahrami A, Bo S, Jamialahmadi T, Sahebkar A. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ageing: Molecular mechanisms. Ageing Res Rev 2020; 58:101024. [PMID: 32006687 DOI: 10.1016/j.arr.2020.101024] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 12/11/2019] [Accepted: 01/27/2020] [Indexed: 12/15/2022]
Abstract
Human ageing is determined by degenerative alterations and processes with different manifestations such as gradual organ dysfunction, tissue function loss, increased population of aged (senescent) cells, incapability of maintaining homeostasis and reduced repair capacity, which collectively lead to an increased risk of diseases and death. The inhibitors of HMG-CoA reductase (statins) are the most widely used lipid-lowering agents, which can reduce cardiovascular morbidity and mortality. Accumulating evidence has documented several pleiotropic effects of statins in addition to their lipid-lowering properties. Recently, several studies have highlighted that statins may have the potential to delay the ageing process and inhibit the onset of senescence. In this review, we focused on the anti-ageing mechanisms of statin drugs and their effects on cardiovascular and non-cardiovascular diseases.
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35
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Lin L, Zhang L, Li XT, Ji JK, Chen XQ, Li YL, Li C. Rhynchophylline Attenuates Senescence of Endothelial Progenitor Cells by Enhancing Autophagy. Front Pharmacol 2020; 10:1617. [PMID: 32047439 PMCID: PMC6997466 DOI: 10.3389/fphar.2019.01617] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/11/2019] [Indexed: 12/25/2022] Open
Abstract
The increase of blood pressure accelerates endothelial progenitor cells (EPCs) senescence, hence a significant reduction in the number of EPCs is common in patients with hypertension. Autophagy is a defense and stress regulation mechanism to assist cell homeostasis and organelle renewal. A growing number of studies have found that autophagy has a positive role in repairing vascular injury, but the potential mechanism between autophagy and senescence of EPCs induced by hypertension has rarely been studied. Therefore, in this study, we aim to explore the relationship between senescence and autophagy, and investigate the protective effect of rhynchophylline (Rhy) on EPCs. In angiotensin II (Ang II)-treated EPCs, enhancing autophagy through rapamycin mitigated Ang II-induced cell senescence, on the contrary, 3-methyladenine aggravated the senescence by weakening autophagy. Similarly, Rhy attenuated senescence and improved cellular function by rescuing the impaired autophagy in Ang II-treated EPCs. Furthermore, we found that Rhy promoted autophagy by activating AMP-activated protein kinase (AMPK) signaling pathway. Our results show that enhanced autophagy attenuates EPCs senescence and Rhy rescues autophagy impairment to protect EPCs against Ang II injury.
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Affiliation(s)
- Lin Lin
- Institute of Traditional Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Zhang
- The First Faculty of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xin-Tong Li
- Institute of Education and Psychological Sciences, University of Jinan, Jinan, China
| | - Jing-Kang Ji
- Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao-Qing Chen
- Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yun-Lun Li
- Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chao Li
- Institute of Traditional Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan, China.,Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, China
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36
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Wang G, Shang W, Ren Y, Liu S, Ren X, Wei S, Han D. Benefits of statins in chronic obstructive pulmonary disease patients with pulmonary hypertension: A meta-analysis. Eur J Intern Med 2019; 70:39-42. [PMID: 31679886 DOI: 10.1016/j.ejim.2019.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 08/29/2019] [Accepted: 09/14/2019] [Indexed: 11/28/2022]
Abstract
PURPOSE This meta-analysis was performed to evaluate the efficacy of statins in chronic obstructive pulmonary disease (COPD) patients with pulmonary hypertension (PH). METHODS A systematic search was made of MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases. Randomized clinical trials on treatment of COPD-PH with the statins, compared with placebo, were reviewed. Studies were pooled to weighted mean differences (WMD), with 95% confidence interval (CI). RESULTS Five trials (enrolling 270 participants) met the inclusion criteria. Compared with placebo, the statins presented significant effects on systolic pulmonary artery pressure (WMD -4.52 mmHg; 95% CI -6.32 to -2.72 mmHg) and 6-min walk distance (6MWD) (WMD 32.46 m; 95% CI 13.63-51.29 m). CONCLUSIONS Statins therapy significantly improves PH and 6MWD in COPD patients with PH.
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Affiliation(s)
- Guizuo Wang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Wenli Shang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Yajuan Ren
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Sining Liu
- Department of General Medicine, Xi'an Medical University, Xi'an, Shaanxi 710068, PR China
| | - Xiaoping Ren
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Shenghong Wei
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Dong Han
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China.
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37
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Wu TC, Chen JS, Wang CH, Huang PH, Lin FY, Lin LY, Lin SJ, Chen JW. Activation of heme oxygenase-1 by Ginkgo biloba extract differentially modulates endothelial and smooth muscle-like progenitor cells for vascular repair. Sci Rep 2019; 9:17316. [PMID: 31754254 PMCID: PMC6872755 DOI: 10.1038/s41598-019-53818-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 10/17/2019] [Indexed: 01/09/2023] Open
Abstract
Vascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.
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Affiliation(s)
- Tao-Cheng Wu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Jia-Shiong Chen
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Chao-Hung Wang
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Po-Hsun Huang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Feng-Yen Lin
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Liang-Yu Lin
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shing-Jong Lin
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jaw-Wen Chen
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. .,Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan. .,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. .,Precision Medicine Research Center, Taipei Veterans General Hospital, Taipei, Taiwan. .,Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
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Nantavisai S, Rodprasert W, Pathanachai K, Wikran P, Kitcharoenthaworn P, Smithiwong S, Archasappawat S, Sawangmak C. Simvastatin enhances proliferation and pluripotent gene expression by canine bone marrow-derived mesenchymal stem cells (cBM-MSCs) in vitro. Heliyon 2019; 5:e02663. [PMID: 31687506 PMCID: PMC6820287 DOI: 10.1016/j.heliyon.2019.e02663] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 07/05/2019] [Accepted: 10/11/2019] [Indexed: 01/08/2023] Open
Abstract
Establishing the intervention to enhance proliferation and differentiation potential is crucial for the clinical translation of stem cell-based therapy. In this study, the effects of simvastatin on these regards were explored. Canine bone marrow-derived mesenchymal stem cells (cBM-MSCs) were treated with 4 doses of simvastatin, 0.1, 1, 10, and 100 nM. Simvastatin in low-dose range, 0.1 and 1 nM, enhanced dose-dependent cell proliferation at day 5 and 7. Exploration of the mechanisms revealed that simvastatin in low-dose range dose-dependently upregulated sets of cell cycle regulators, Cyclin D1 and Cyclin D2; proliferation marker, Ki-67; and anti-apoptotic gene; Bcl-2. Interestingly, pluripotent markers, Rex1 and Oct4, were dramatically increased upon the low-dose treatment. Contrastingly, treatment with high-dose simvastatin suppressed the expression of those genes. Thus, the results suggested beneficial effects of simvastatin on cBM-MSCs proliferation and expansion. Further study regarding differentiation potential and underlying mechanisms will accelerate the clinical application of the molecule on veterinary stem cell-based therapy.
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Affiliation(s)
- Sirirat Nantavisai
- Veterinary Pharmacology and Stem Cell Research Laboratory, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.,Special Task Force for Activating Research (STAR) in Biology of Embryo and Stem Cell Research in Veterinary Science, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Watchareewan Rodprasert
- Veterinary Pharmacology and Stem Cell Research Laboratory, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.,Special Task Force for Activating Research (STAR) in Biology of Embryo and Stem Cell Research in Veterinary Science, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Koranis Pathanachai
- Veterinary Pharmacology and Stem Cell Research Laboratory, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.,Special Task Force for Activating Research (STAR) in Biology of Embryo and Stem Cell Research in Veterinary Science, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.,Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Parattakorn Wikran
- Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | | | | | | | - Chenphop Sawangmak
- Veterinary Pharmacology and Stem Cell Research Laboratory, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.,Special Task Force for Activating Research (STAR) in Biology of Embryo and Stem Cell Research in Veterinary Science, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.,Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
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Piccirillo F, Carpenito M, Verolino G, Chello C, Nusca A, Lusini M, Spadaccio C, Nappi F, Di Sciascio G, Nenna A. Changes of the coronary arteries and cardiac microvasculature with aging: Implications for translational research and clinical practice. Mech Ageing Dev 2019; 184:111161. [PMID: 31647940 DOI: 10.1016/j.mad.2019.111161] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 12/28/2022]
Abstract
Aging results in functional and structural changes in the cardiovascular system, translating into a progressive increase of mechanical vessel stiffness, due to a combination of changes in micro-RNA expression patterns, autophagy, arterial calcification, smooth muscle cell migration and proliferation. The two pivotal mechanisms of aging-related endothelial dysfunction are oxidative stress and inflammation, even in the absence of clinical disease. A comprehensive understanding of the aging process is emerging as a primary concern in literature, as vascular aging has recently become a target for prevention and treatment of cardiovascular disease. Change of life-style, diet, antioxidant regimens, anti-inflammatory treatments, senolytic drugs counteract the pro-aging pathways or target senescent cells modulating their detrimental effects. Such therapies aim to reduce the ineluctable burden of age and contrast aging-associated cardiovascular dysfunction. This narrative review intends to summarize the macrovascular and microvascular changes related with aging, as a better understanding of the pathways leading to arterial aging may contribute to design new mechanism-based therapeutic approaches to attenuate the features of vascular senescence and its clinical impact on the cardiovascular system.
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Affiliation(s)
| | | | | | - Camilla Chello
- Dermatology, Università "La Sapienza" di Roma, Rome, Italy
| | | | - Mario Lusini
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | | | - Francesco Nappi
- Cardiac surgery, Centre Cardiologique du Nord de Saint Denis, Paris, France
| | | | - Antonio Nenna
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
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Atorvastatin and Conditioned Media from Atorvastatin-Treated Human Hematopoietic Stem/Progenitor-Derived Cells Show Proangiogenic Activity In Vitro but Not In Vivo. Mediators Inflamm 2019; 2019:1868170. [PMID: 31396016 PMCID: PMC6664685 DOI: 10.1155/2019/1868170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/22/2019] [Accepted: 02/14/2019] [Indexed: 01/16/2023] Open
Abstract
Myeloid angiogenic cells (MAC) derive from hematopoietic stem/progenitor cells (HSPCs) that are mobilized from the bone marrow. They home to sites of neovascularization and contribute to angiogenesis by production of paracrine factors. The number and function of proangiogenic cells are impaired in patients with diabetes or cardiovascular diseases. Both conditions can be accompanied by decreased levels of heme oxygenase-1 (HMOX1), cytoprotective, heme-degrading enzyme. Our study is aimed at investigating whether precursors of myeloid angiogenic cells (PACs) treated with known pharmaceuticals would produce media with better proangiogenic activity in vitro and if such media can be used to stimulate blood vessel growth in vivo. We used G-CSF-mobilized CD34+ HSPCs, FACS-sorted from healthy donor peripheral blood mononuclear cells (PBMCs). Sorted cells were predominantly CD133+. CD34+ cells after six days in culture were stimulated with atorvastatin (AT), acetylsalicylic acid (ASA), sulforaphane (SR), resveratrol (RV), or metformin (Met) for 48 h. Conditioned media from such cells were then used to stimulate human aortic endothelial cells (HAoECs) to enhance tube-like structure formation in a Matrigel assay. The only stimulant that enhanced PAC paracrine angiogenic activity was atorvastatin, which also had ability to stabilize endothelial tubes in vitro. On the other hand, the only one that induced heme oxygenase-1 expression was sulforaphane, a known activator of a HMOX1 inducer—NRF2. None of the stimulants changed significantly the levels of 30 cytokines and growth factors tested with the multiplex test. Then, we used atorvastatin-stimulated cells or conditioned media from them in the Matrigel plug in vivo angiogenic assay. Neither AT alone in control media nor conditioned media nor AT-stimulated cells affected numbers of endothelial cells in the plug or plug's vascularization. Concluding, high concentrations of atorvastatin stabilize tubes and enhance the paracrine angiogenic activity of human PAC cells in vitro. However, the effect was not observed in vivo. Therefore, the use of conditioned media from atorvastatin-treated PAC is not a promising therapeutic strategy to enhance angiogenesis.
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Hu K, Wan Q. Biphasic influence of pravastatin on human cardiac microvascular endothelial cell functions under pathological and physiological conditions. Biochem Biophys Res Commun 2019; 511:476-481. [PMID: 30803760 DOI: 10.1016/j.bbrc.2019.02.090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 02/17/2019] [Indexed: 01/24/2023]
Abstract
HMG-CoA reductase inhibitor statins are used to treat patients with hypercholesterolemia. The pleiotropic effects of statins have been recently extended to the regulation of angiogenesis. However, the observations on the effects of statins on endothelial cells seem to be contradictory. In this work, we systematically analysed the effects of pravastatin at concentrations covering 10,000-fold range on the functions of human cardiac microvascular endothelial cells (HMVEC-C) under H2O2-induced oxidative stress and normal physiological conditions. We observed the biphasic effects of pravastatin in protecting HMVEC-C dysfunctions induced by H2O2: pravastatin at low concentrations significantly enhanced vascular network formation, growth, migration and survival under H2O2-induced oxidative stress condition whereas this effect disappeared at higher concentrations. Interestingly, pravastatin at low concentrations did not affect HMVEC-C functions but at high concentrations significantly inhibited HMVEC-C vascular network formation, growth, migration and survival in a dose-dependent manner. We further demonstrated the different molecular mechanisms of the action of pravastatin at low and high concentrations on HMVEC-C: pravastatin at low concentrations alleviates H2O2-induced oxidative stress and damage and at high concentrations inhibits prenylation. Our work provides better understanding on the multiple differential effects and the underlying mechanisms of pravastatin on HMVEC-C, which may be of relevance to the influence of statins in cardiovascular system.
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Affiliation(s)
- Kun Hu
- Department of Vascular Surgery, The Second Clinical Medical College, Yangtze University, Jingzhou Central Hospital, Jingzhou, People's Republic of China.
| | - Qian Wan
- Department of Thoracic Surgery, Xiantao First People's Hospital, Xiantao, People's Republic of China
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Atorvastatin increases oxidative stress and inhibits cell migration of oral squamous cell carcinoma in vitro. Oral Oncol 2019; 90:109-114. [PMID: 30846168 DOI: 10.1016/j.oraloncology.2019.01.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 12/18/2018] [Accepted: 01/27/2019] [Indexed: 01/11/2023]
Abstract
OBJECTIVE This study aimed to evaluate the effect of atorvastatin treatment on reactive oxygen species (ROS) production and tumor angiogenesis in oral squamous cell carcinomas. MATERIAL AND METHODS An HN13 cell line was treated with 1 µM, 5 µM, and 10 µM of atorvastatin. VEGF-A gene expression was evaluated by quantitative real time PCR. VEGF-A protein expression was quantified from total protein and conditioned media by ELISA. Cellular oxidative stress was measured using 2',7'-dichlorfluorescein-diacetate (DCFH-DA). Angiogenesis assay was performed using human umbilical vein endothelial cells (HUVEC). The effect of atorvastatin on cell migration was evaluated by wound healing assay. RESULTS 5 µM and 10 µM of atorvastatin significantly increased VEGF-A gene expression in the HN13 cell line. Intracellular expression of the VEGF-A protein was higher in the cells treated with 5 µM and 10 µM than in the control cells. VEGF-A protein expression was also higher in the conditioned media from the atorvastatin-treated cells than in the media from the DMSO-treated cells. 5 µM and 10 µM of atorvastatin increased oxidative stress. Regarding angiogenesis assay, 5 µM of atorvastatin resulted in higher numbers of branch points, compared to the solvent. 10 µM of atorvastatin treatment resulted in significantly reduced cell migration. CONCLUSIONS This study showed that atorvastatin increases the oxidative stress and angiogenesis in oral squamous cell carcinomas. The decrease of cell migration indicates atorvastatin's inhibitory effect in oral tumors. These results suggest that atorvastatin could increase the intracellular oxidative stress in these cells, leading to a toxic microenvironment and inhibiting their metastasis.
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Abstract
Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers. In this context, statin use has been correlated, variably, with a decrease in deaths from breast cancer. However, there is no extant model for this effect, and the extent of efficacy is open to question.The overarching goal of this article is to communicate to the reader of the potential of statins to reduce breast cancer progression and mortality. This is the use as a secondary prevention measure, and not as a therapy to directly counter active cancer. First, salient aspects of statin pharmacology, as relates to cardiovascular disease, will be discussed. Second, the basic and clinical research studies that investigate statin usage in breast cancer will be presented. Additionally, statin effects in other cancer types will be included for context. Finally, proposals for future basic and clinical research studies to determine the role of statins in breast cancer management will be presented.
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Affiliation(s)
- Colin H. Beckwitt
- Department of Pathology, University of Pittsburgh, Pittsburgh, 15231 PA USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15231 USA
- Pittsburgh VA Health System, Pittsburgh, 15240 PA USA
| | - Adam Brufsky
- Magee-Women’s Hospital of Pittsburgh, 300 Halket St., Pittsburgh, 15213 PA USA
| | - Zoltán N. Oltvai
- Department of Pathology, University of Pittsburgh, Pittsburgh, 15231 PA USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, 15231 PA USA
| | - Alan Wells
- Department of Pathology, University of Pittsburgh, Pittsburgh, 15231 PA USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, 15231 PA USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, 15231 PA USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15231 USA
- Pittsburgh VA Health System, Pittsburgh, 15240 PA USA
- Magee-Women’s Hospital of Pittsburgh, 300 Halket St., Pittsburgh, 15213 PA USA
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Dang H, Song B, Dong R, Zhang H. Atorvastatin reverses the dysfunction of human umbilical vein endothelial cells induced by angiotensin II. Exp Ther Med 2018; 16:5286-5297. [PMID: 30542486 DOI: 10.3892/etm.2018.6846] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/22/2018] [Indexed: 12/18/2022] Open
Abstract
Statins exert pleiotropic effects on endothelial cells, in addition to lowering cholesterol. This study evaluated angiotensin II (Ang II)-induced dysfunction in human umbilical vein endothelial cells (HUVECs), and the effects of atorvastatin (Ator) on induced HUVECs in vitro. The cytotoxicity of Ang II and Ator was determined by the MTT assay. A series of cellular responses were screened, including oxidative stress, cellular apoptosis, inflammatory response, autophagy, expression of endothelial nitric oxide synthase and the angiogenic function of HUVECs. Ator returned these cellular responses to a normal level. The present study also examined cellular organelle dysfunction. In HUVECs, Ang II triggered mitochondrial damage, as demonstrated by a decreased mitochondrial membrane potential, while Ator attenuated this Ang II-induced damage. The observed cellular dysfunction may cause endothelial senescence due to excessive cell injury. The current study examined several aging markers, which revealed that these disorders of cellular functions triggered endothelial senescence, which was delayed by Ator. Ator also suppressed Ang II-induced angiogenesis damage. The data presented in this study strongly suggested that Ang II induced a series of processes that lead to cellular dysfunction in HUVECs, including oxidative stress, inflammation, and mitochondrial damage, leading to apoptosis and endothelial senescence. However, Ator significantly reversed these effects and modulated intracellular stability. The present study indicated that Ator serves an antagonistic role against HUVEC dysfunction and may potentially prevent several diseases, including coronary disease and atherosclerosis, by maintaining cellular homeostasis.
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Affiliation(s)
- Haiming Dang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Chaoyang, Beijing 100029, P.R. China
| | - Bangrong Song
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Chaoyang, Beijing 100029, P.R. China
| | - Ran Dong
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Chaoyang, Beijing 100029, P.R. China
| | - Hongjia Zhang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Chaoyang, Beijing 100029, P.R. China
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Lo Gullo A, Aragona CO, Scuruchi M, Versace AG, Saitta A, Imbalzano E, Loddo S, Campo GM, Mandraffino G. Endothelial progenitor cells and rheumatic disease modifying therapy. Vascul Pharmacol 2018; 108:8-14. [PMID: 29842927 DOI: 10.1016/j.vph.2018.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/12/2018] [Accepted: 05/18/2018] [Indexed: 02/07/2023]
Abstract
Rheumatic diseases are associated with accelerated atherosclerosis and with increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the higher prevalence of cardiovascular disease are not completely clarified, but it is likely that a pivotal role is played by vascular inflammation and consequently to altered vascular endothelium homeostasis. Also, high prevalence of traditional risk factors, proatherogenic activation and endothelial dysfunction further contribute to vascular damage. Circulating endothelial progenitor cells (EPCs) can restore dysfunctional endothelium and protect against atherosclerotic vascular disease. However, abnormalities in number and function of these cells in patients with rheumatic condition have been extensively reported. During the last years, growing interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD has been shown; in addition, pioneering studies show that EPC dysfunction might be improved with pharmacological strategies. However, how to restore EPC function, and whether achieving this aim may be effective in preventing cardiovascular complications in rheumatic disease, remain to be established. In this review we report an overview on the current stand of knowledge on the effect of pharmaceutical and lifestyle intervention in improving EPCs number and function in rheumatic disease.
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Affiliation(s)
- Alberto Lo Gullo
- Department of Clinical and Experimental Medicine, University of Messina, Italy.
| | | | - Michele Scuruchi
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | | | - Antonino Saitta
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Egidio Imbalzano
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Saverio Loddo
- Department of Clinical and Experimental Medicine, University of Messina, Italy
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Wang GS, Shen YS, Chou WY, Tang CH, Yeh HI, Wang LY, Yen JY, Huang TY, Liu SC, Yang CY, Lin TY, Chen C, Wang SW. Senescence Induces Dysfunctions in Endothelial Progenitor Cells and Osteoblasts by Interfering Translational Machinery and Bioenergetic Homeostasis. Int J Mol Sci 2018; 19:ijms19071997. [PMID: 29987212 PMCID: PMC6073720 DOI: 10.3390/ijms19071997] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/01/2018] [Accepted: 07/03/2018] [Indexed: 01/05/2023] Open
Abstract
Age-related bone diseases are partly caused by impaired bone integrity, which are closely related to osteoblasts’ activity and angiogenesis. Endothelial progenitor cells (EPCs) are the initiators of angiogenesis and found to have senescent-induced dysfunctions. The aim of this study is to investigate the effects of senescence in EPCs on osteogenesis and angiogenesis. Human primary EPCs and a murine osteoblast cell line (MC3T3-E1) are utilized in this study. The senescence of EPCs are induced by serial passages. When co-cultured with senescent EPCs, the osteoblasts demonstrate weakened alkaline phosphatase (ALP) activity and mineral deposition. On the other hand, osteoblast-induced migration decreases in senescent EPCs. As for the intracellular alterations of senescent EPCs, the activation of Akt/mTOR/p70S6K pathway, MnSOD and catalase are diminished. In contrast, the level of reactive oxygen species are significantly higher in senescent EPCs. Furthermore, senescent EPCs has decreased level intracellular ATP level and coupling efficiency for oxidative phosphorylation while the non-mitochondrial respiration and glycolysis are elevated. The senescence of EPCs impairs the functions of both osteoblasts and EPCs, suggesting EPCs’ role in the pathophysiology of age-related bone diseases. Targeting the alterations found in this study could be potential treatments.
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Affiliation(s)
- Guo-Shou Wang
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei 10491, Taiwan.
| | - Yung-Shuen Shen
- Holistic Education Center, Mackay Medical College, New Taipei City 252, Taiwan.
| | - Wen-Yi Chou
- Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital Medical Center, Kaohsiung 833, Taiwan.
| | - Chih-Hsin Tang
- Department of Pharmacology, School of Medicine, China Medical University, Taichung 404, Taiwan.
- Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan.
- Department of Biotechnology, College of Health Science, Asia University, Taichung 413, Taiwan.
| | - Hung-I Yeh
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
- Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10491, Taiwan.
| | - Li-Yu Wang
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
| | - Juei-Yu Yen
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
| | - Te-Yang Huang
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei 10491, Taiwan.
| | - Shih-Chia Liu
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei 10491, Taiwan.
| | - Chen-Yu Yang
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei 10491, Taiwan.
| | - Ting-Yi Lin
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei 10491, Taiwan.
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
| | - Chi Chen
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
- Department of Education and Research, Taipei City Hospital Renai Branch, Taipei 106, Taiwan.
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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Atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p. Mech Ageing Dev 2018; 169:10-18. [DOI: 10.1016/j.mad.2017.12.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 12/08/2017] [Accepted: 12/11/2017] [Indexed: 12/20/2022]
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48
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Sandesara PB, Ramjee V, Ghasemzadeh N, Guo Y, Bhatia N, Li Q, Vaughn L, Nell-Dybdahl C, Waller EK, Mahar EA, Brigham K, Wilson PWF, Quyyumi A, Le NA, Sperling LS. Circulating progenitor cells in patients with familial hypercholesterolemia. J Clin Apher 2017; 33:404-408. [PMID: 29114919 DOI: 10.1002/jca.21601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 06/14/2017] [Accepted: 10/19/2017] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Familial hypercholesterolemia (FH) is a genetic disease with very high levels of circulating low density lipoprotein cholesterol (LDL-C) levels that leads to accelerated atherosclerosis. Lipoprotein apheresis is an effective treatment option for patients with FH and results in reduced cardiovascular morbidity and mortality. Circulating progenitor cells (CPCs) are markers of overall vascular health and diminished levels have been associated with decreased reparative potential and worse outcomes. We assessed the short-term change in CPC levels following a single lipoprotein apheresis session in FH patients who are already on stable lipoprotein apheresis therapy. We hypothesized that in addition to a reduction in atherogenic lipids, the cardiovascular benefit from lipoprotein apheresis therapy is mediated by enhanced vascular reparative capacity through mobilization of CPCs. METHODS Eight FH patients (1 homozygous and 7 heterozygous) on stable lipoprotein apheresis therapy for at least three months had CPCs measured at baseline (prior to apheresis) and two hours after apheresis. Results were compared with data from age-matched hyperlipidemic (HLP) patients on statin therapy and healthy volunteers. RESULTS FH patients had higher baseline circulating levels of CD34+/CD133+ and CD34+/CD133+/CXCR4+ cells compared to HLP and healthy subjects. There was no significant change in CPCs after apheresis in FH patients. CONCLUSIONS FH patients had higher CPC counts at baseline compared to age-matched HLP and healthy controls, suggesting activation of reparative mechanism in this high risk population. Larger studies are needed to better characterize differences in CPC counts between FH subjects and HLP patients over time.
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Affiliation(s)
- P B Sandesara
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - V Ramjee
- Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
| | - N Ghasemzadeh
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - Y Guo
- Emory University School of Public Health, 1518 Clifton Road, Atlanta, Georgia 30322
| | - N Bhatia
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - Q Li
- Emory University School of Public Health, 1518 Clifton Road, Atlanta, Georgia 30322
| | - L Vaughn
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - C Nell-Dybdahl
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - E K Waller
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - E A Mahar
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - K Brigham
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - P W F Wilson
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322.,Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, Georgia 30033
| | - A Quyyumi
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
| | - N-A Le
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322.,Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, Georgia 30033
| | - L S Sperling
- Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, Georgia 30322
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Hwang ES, Ok JS, Song S. Chemical and Physical Approaches to Extend the Replicative and Differentiation Potential of Stem Cells. Stem Cell Rev Rep 2017; 12:315-26. [PMID: 27085715 DOI: 10.1007/s12015-016-9652-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cell therapies using mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are increasing in regenerative medicine, with applications to a growing number of aging-associated dysfunctions and degenerations. For successful therapies, a certain mass of cells is needed, requiring extensive ex vivo expansion of the cells. However, the proliferation of both MSCs and EPCs is limited as a result of telomere shortening-induced senescence. As cells approach senescence, their proliferation slows down and differentiation potential decreases. Therefore, ways to delay senescence and extend the replicative lifespan these cells are needed. Certain proteins and pathways play key roles in determining the replicative lifespan by regulating ROS generation, damage accumulation, or telomere shortening. And, their agonists and gene activators exert positive effects on lifespan. In many of the treatments, importantly, the lifespan is extended with the retention of differentiation potential. Furthermore, certain culture conditions, including the use of specific atmospheric conditions and culture substrates, exert positive effects on not only the proliferation rate, but also the extent of proliferation and differentiation potential as well as lineage determination. These strategies and known underlying mechanisms are introduced in this review, with an evaluation of their pros and cons in order to facilitate safe and effective MSC expansion ex vivo.
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Affiliation(s)
- Eun Seong Hwang
- Department of Life Science, University of Seoul, Dongdaemun-gu, Seoulsiripdaero 163, Seoul, 02504, Republic of Korea.
| | - Jeong Soo Ok
- Department of Life Science, University of Seoul, Dongdaemun-gu, Seoulsiripdaero 163, Seoul, 02504, Republic of Korea
| | - SeonBeom Song
- Department of Life Science, University of Seoul, Dongdaemun-gu, Seoulsiripdaero 163, Seoul, 02504, Republic of Korea
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Hypoxia induces the dysfunction of human endothelial colony-forming cells via HIF-1α signaling. Respir Physiol Neurobiol 2017; 247:87-95. [PMID: 28964937 DOI: 10.1016/j.resp.2017.09.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 08/29/2017] [Accepted: 09/22/2017] [Indexed: 12/15/2022]
Abstract
Endothelial injury is considered as a trigger of pulmonary vascular lesions in the pathogenesis of hypoxic pulmonary hypertension (HPH). Although endothelial colony-forming cells (ECFCs) have vascular regeneration potential to maintain endothelial integrity, hypoxia-induced precise alteration in ECFCs function remains controversial. This study investigated the impact of hypoxia on human ECFCs function in vitro and the underlying mechanism. We found that hypoxia inhibited ECFCs proliferation, migration and angiogenesis. Compared with no treatment, the expression of hypoxia inducible factor-1α (HIF-1α) in hypoxia-treated ECFCs was increased, with an up-regulation of p27 and a down-regulation of cyclin D1. The over-secreted vascular endothelial growth factor (VEGF) was detected, with the imbalanced expression of fetal liver kinase 1 (flk-1) and fms related tyrosine kinase 1 (flt-1). Hypoxia-induced changes in ECFCs could be reversed by HIF-1α inhibitor KC7F2. These data suggest that HIF-1α holds the key in regulating ECFCs function which may open a new perspective of ECFCs in HPH management.
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