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Colucci M, Sarill M, Maddalena M, Valdata A, Troiani M, Massarotti M, Bolis M, Bressan S, Kohl A, Robesti D, Saponaro M, Shi Q, Song P, Brina D, Calì B, Alimonti A. Senescence in cancer. Cancer Cell 2025:S1535-6108(25)00224-7. [PMID: 40513577 DOI: 10.1016/j.ccell.2025.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 05/09/2025] [Accepted: 05/23/2025] [Indexed: 06/16/2025]
Abstract
Cellular senescence is a state of stable cell-cycle arrest induced by various intrinsic and extrinsic stressors, serving as a protective mechanism to prevent the proliferation of damaged cells. While this process is crucial for tissue homeostasis and tumor suppression, the progressive accumulation of senescent cells (SnCs) over time is implicated in age-related pathologies, including immune dysfunction and cancer. In oncology, senescence plays a paradoxical role: it can inhibit tumor development by halting the growth of potentially malignant cells, yet it may also facilitate tumor progression through the senescence-associated secretory phenotype (SASP). This review explores the defining features of senescence in cancer, its complex interactions with tumor cells, the stroma, and the immune system, and its context-dependent outcomes. We also discuss current and emerging therapeutic strategies that target SnCs-either by inducing or eliminating them-as well as AI-driven approaches for their detection and characterization in cancer.
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Affiliation(s)
- Manuel Colucci
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Miles Sarill
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Martino Maddalena
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Aurora Valdata
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Martina Troiani
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Bioinformatics Core Unit, Swiss Institute of Bioinformatics, Bellinzona, Switzerland
| | - Martina Massarotti
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Marco Bolis
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Bioinformatics Core Unit, Swiss Institute of Bioinformatics, Bellinzona, Switzerland; Computational Oncology Unit, Department of Experimental Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' IRCCS, 20156 Milano, Italy
| | - Silvia Bressan
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Anna Kohl
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland; AGORA Cancer Research Center, Lausanne, Switzerland
| | - Daniele Robesti
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Surgery, Service of Urology, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Miriam Saponaro
- Department of Urology and Pediatric Urology, University Medical Center Bonn, Bonn, Germany
| | - Qiu Shi
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Pan Song
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Daniela Brina
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Bianca Calì
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Andrea Alimonti
- Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland; Department of Medicine, University of Padova, Padova, Italy; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
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Yesilyurt-Dirican ZE, Qi C, Wang YC, Simm A, Deelen L, Hafiz Abbas Gasim A, Lewis-McDougall F, Ellison-Hughes GM. SGLT2 inhibitors as a novel senotherapeutic approach. NPJ AGING 2025; 11:35. [PMID: 40348751 PMCID: PMC12065912 DOI: 10.1038/s41514-025-00227-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 04/23/2025] [Indexed: 05/14/2025]
Abstract
Cellular senescence is the permanent cessation of cell proliferation and growth. Senescent cells accumulating in tissues and organs with aging contribute to many chronic diseases, mainly through the secretion of a pro-inflammatory senescence-associated secretory phenotype (SASP). Senotherapeutic (senolytic or senomorphic) strategies targeting senescent cells or/and their SASP are being developed to prolong healthy lifespan and treat age-related pathologies. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that promote the renal excretion of glucose, resulting in lower blood glucose levels. Beyond their glucose-lowering effects, SGLT2 inhibitors have demonstrated protective effects against cardiovascular and renal events. Moreover, SGLT2 inhibitors have recently been associated with the inhibition of cell senescence, making them a promising therapeutic approach for targeting senescence and aging. This review examines the latest research on the senotherapeutic potential of SGLT2 inhibitors.
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Affiliation(s)
- Zeynep Elif Yesilyurt-Dirican
- Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Ce Qi
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Yi-Chian Wang
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Annika Simm
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Laura Deelen
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, UK
- Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Alia Hafiz Abbas Gasim
- Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Fiona Lewis-McDougall
- Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Georgina M Ellison-Hughes
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK.
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Ji XM, Dong XX, Li JP, Tai GJ, Qiu S, Wei W, Silumbwe CW, Damdinjav D, Otieno JN, Li XX, Xu M. Fisetin Clears Senescent Cells Through the Pi3k-Akt-Bcl-2/Bcl-xl Pathway to Alleviate Diabetic Aortic Aging. Phytother Res 2025. [PMID: 40259678 DOI: 10.1002/ptr.8507] [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: 12/10/2024] [Revised: 03/18/2025] [Accepted: 03/29/2025] [Indexed: 04/23/2025]
Abstract
Vascular aging is a major contributor to age-related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) induced early arterial aging and excessive senescent cells (SCs) burden in vessels. Inhibiting cellular senescence or eliminating SCs could effectively improve aging-related CVDs. Fisetin, a flavonoid extracted from cotinus coggygria scop, has shown potential in alleviating aging by clearing SCs. This study investigated the unexplored mechanisms and efficacy of fisetin in alleviating T2DM-related aortic aging. The T2DM mouse model was induced using a high-fat diet and low-dose streptozotocin injection. Chronic fisetin treatment's protective effects against aortic aging were assessed via senescence-associated beta-galactosidase (SA-β-Gal) staining, histopathology, and vasomotor function. RNA-sequencing and western blotting identified relevant signaling pathways and protein expression. Fisetin's effects on SCs and senescence-associated secretory phenotype (SASP) factors were evaluated through cell viability, apoptosis, and co-culture assays. Docking simulations suggested fisetin as a potential Phosphoinositide 3-kinase (Pi3k) inhibitor. In vivo, chronic fisetin treatment reduced aortic SCs burden, alleviating T2DM-related and natural aortic aging. In vitro, fisetin selectively induced apoptosis of senescent endothelial cells via regulating the Pi3k-Protein Kinase B (Akt)-B-cell lymphoma (Bcl)-2/Bcl-xl pathway and suppressed SASP and its detrimental effects. Furthermore, fisetin combined with metformin therapy showed superior anti-aging effects on T2DM-related aortic aging compared to metformin monotherapy. In conclusion, chronic fisetin treatment alleviates T2DM-related aortic aging via clearing the SCs burden and abrogating the SASP factors. Fisetin combined with metformin therapy might be a potential therapeutic strategy for T2DM-related CVDs.
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Affiliation(s)
- Xiao-Man Ji
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xin-Xin Dong
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jia-Peng Li
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Guang-Jie Tai
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shu Qiu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wei Wei
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ceaser Wankumbu Silumbwe
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Davaadagva Damdinjav
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Joseph Nicolao Otieno
- Institute of Traditional Medicine, Muhimbili University of Health and Allied Sciencea, Dar es Salaam, Tanzania
| | - Xiao-Xue Li
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ming Xu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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González I, Maldonado-Agurto R. The role of cellular senescence in endothelial dysfunction and vascular remodelling in arteriovenous fistula maturation. J Physiol 2025. [PMID: 39977444 DOI: 10.1113/jp287387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 01/29/2025] [Indexed: 02/22/2025] Open
Abstract
Haemodialysis (HD) is often required for patients with end-stage renal disease. Arteriovenous fistulas (AVFs), a surgical procedure connecting an artery to a vein, are the preferred vascular access for HD due to their durability and lower complication rates. The aim of AVFs is to promote vein remodelling to accommodate increased blood flow needed for dialysis. However, many AVFs fail to mature properly, making them unsuitable for dialysis. Successful maturation requires remodelling, resulting in an increased luminal diameter and thickened walls to support the increased blood flow. After AVF creation, haemodynamic changes due to increased blood flow on the venous side of the AVF initiate a cascade of events that, when successful, lead to the proper maturation of the AVF, making it suitable for cannulation. In this process, endothelial cells play a crucial role since they are in direct contact with the frictional forces exerted by the blood, known as shear stress. Patients requiring HD often have other conditions that increase the burden of senescent cells, such as ageing, diabetes and hypertension. These senescent cells are characterized by irreversible growth arrest and the secretion of pro-inflammatory and pro-thrombotic factors, collectively known as the senescence-associated secretory phenotype (SASP). This accumulation can impair vascular function by promoting inflammation, reducing vasodilatation, and increasing thrombosis risk, thus hindering proper AVF maturation and function. This review explores the contribution of senescent endothelial cells to AVF maturation and explores potential therapeutic strategies to alleviate the effects of senescent cell accumulation, aiming to improve AVF maturation rates.
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Affiliation(s)
- Ignacia González
- Center for Biomedical Research (CIBMED), Faculty of Medicine, Universidad Finis Terrae, Santiago, Chile
| | - Rodrigo Maldonado-Agurto
- Center for Biomedical Research (CIBMED), Faculty of Medicine, Universidad Finis Terrae, Santiago, Chile
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Zheng H, Li T, Hu Z, Zheng Q, Wang J. The potential of flavonoids to mitigate cellular senescence in cardiovascular disease. Biogerontology 2024; 25:985-1010. [PMID: 39325277 DOI: 10.1007/s10522-024-10141-7] [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: 06/28/2024] [Accepted: 09/13/2024] [Indexed: 09/27/2024]
Abstract
Aging is one of the most significant factors affecting cardiovascular health, with cellular senescence being a central hallmark. Senescent cells (SCs) secrete a specific set of signaling molecules known as the senescence-associated secretory phenotype (SASP). The SASP has a remarkable impact on age-associated diseases, particularly cardiovascular diseases (CVD). Targeting SCs through anti-aging therapies represents a novel strategy to effectively retard senescence and attenuate disease progression. Accumulating evidence demonstrates that the flavonoids, widely presented in fruits and vegetables worldwide, can delay or treat CVD via selectively eliminating SCs (senolytics) and modulating SASPs (senomorphics). Nevertheless, only sporadic research has illustrated the application of flavonoids in targeting SCs for CVD, which requires further exploration. This review recapitulates the hallmarks and key molecular mechanisms involved in cellular senescence, then summarizes senescence of different types of cardiac cells and describes the mechanisms by which cellular senescence affects CVD development. The discussion culminates with the potential use of flavonoids via exerting their biological effects on cellular senescence to reduce CVD incidence. This summary will provide valuable insights for cardiovascular drug design, development and clinical applications leveraging flavonoids.
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Affiliation(s)
- Huimin Zheng
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, Jiangsu, People's Republic of China
| | - Tiantian Li
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, Jiangsu, People's Republic of China
| | - Ziyun Hu
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, Jiangsu, People's Republic of China
| | - Qi Zheng
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, Jiangsu, People's Republic of China
| | - Junsong Wang
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, Jiangsu, People's Republic of China.
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Sim HH, Shiwakoti S, Lee JH, Lee IY, Ok Y, Lim HK, Ko JY, Oak MH. 2,7-Phloroglucinol-6,6'-bieckol from Ecklonia cava ameliorates nanoplastics-induced premature endothelial senescence and dysfunction. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 949:175007. [PMID: 39053557 DOI: 10.1016/j.scitotenv.2024.175007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/26/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024]
Abstract
Nanoplastics (NPs), plastic particles ranging from 1 to 100 nm are ubiquitous environmental pollutants infiltrating ecosystems. Their small size and widespread use in various products raise concerns for human health, particularly their association with cardiovascular diseases (CVD). NPs can enter the human body through multiple routes, causing oxidative stress, and leading to the senescence and dysfunction of endothelial cells (ECs). Although there are potential natural compounds for treating CVD, there is limited research on preventing CVD induced by NPs. This study investigates the efficacy of Ecklonia cava extract (ECE) in preventing NPs-induced premature vascular senescence and dysfunction. Exposure of porcine coronary arteries (PCAs) and porcine coronary ECs to NPs, either alone or in combination with ECE, demonstrated that ECE mitigates senescence-associated β-galactosidase (SA-β-gal) activity induced by NPs, thus preventing premature endothelial senescence. ECE also improved NPs-induced vascular dysfunction. The identified active ingredient in Ecklonia cava, 2,7'-Phloroglucinol-6,6'-bieckol (PHB), a phlorotannin, proved to be pivotal in these protective effects. PHB treatment ameliorated SA-β-gal activity, reduced oxidative stress, restored cell proliferation, and decreased the expression of cell cycle regulatory proteins such as p53, p21, p16, and angiotensin type 1 receptor (AT1), well known triggers for EC senescence. Moreover, PHB also improved NPs-induced vascular dysfunction by upregulating endothelial nitric oxide synthase (eNOS) expression and restoring endothelium-dependent vasorelaxation. In conclusion, Ecklonia cava and its active ingredient, PHB, exhibit potential as therapeutic agents against NPs-induced premature EC senescence and dysfunction, indicating a protective effect against environmental pollutants-induced CVDs associated with vascular dysfunction.
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Affiliation(s)
- Hwan-Hee Sim
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea
| | - Saugat Shiwakoti
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea
| | - Ji-Hyeok Lee
- Division of Commercialization Support, Honam National Institute of Biological Resources, Mokpo 58762, Republic of Korea
| | - In-Young Lee
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea
| | - Yejoo Ok
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea
| | - Han-Kyu Lim
- Department of Marine and Fisheries Resources, Mokpo National University, Muan 58554, Republic of Korea
| | - Ju-Young Ko
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea.
| | - Min-Ho Oak
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan 58554, Republic of Korea.
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Shafqat A, Masters MC, Tripathi U, Tchkonia T, Kirkland JL, Hashmi SK. Long COVID as a disease of accelerated biological aging: An opportunity to translate geroscience interventions. Ageing Res Rev 2024; 99:102400. [PMID: 38945306 DOI: 10.1016/j.arr.2024.102400] [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: 04/21/2024] [Revised: 06/12/2024] [Accepted: 06/27/2024] [Indexed: 07/02/2024]
Abstract
It has been four years since long COVID-the protracted consequences that survivors of COVID-19 face-was first described. Yet, this entity continues to devastate the quality of life of an increasing number of COVID-19 survivors without any approved therapy and a paucity of clinical trials addressing its biological root causes. Notably, many of the symptoms of long COVID are typically seen with advancing age. Leveraging this similarity, we posit that Geroscience-which aims to target the biological drivers of aging to prevent age-associated conditions as a group-could offer promising therapeutic avenues for long COVID. Bearing this in mind, this review presents a translational framework for studying long COVID as a state of effectively accelerated biological aging, identifying research gaps and offering recommendations for future preclinical and clinical studies.
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Affiliation(s)
- Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
| | - Mary Clare Masters
- Division of Infectious Diseases, Northwestern University, Chicago, IL, USA
| | - Utkarsh Tripathi
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Tamara Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Shahrukh K Hashmi
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Research and Innovation Center, Department of Health, Abu Dhabi, UAE; College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
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Yan H, Miranda EAD, Jin S, Wilson F, An K, Godbee B, Zheng X, Brau-Rodríguez AR, Lei L. Primary oocytes with cellular senescence features are involved in ovarian aging in mice. Sci Rep 2024; 14:13606. [PMID: 38871781 PMCID: PMC11176158 DOI: 10.1038/s41598-024-64441-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024] Open
Abstract
In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP factors in the ovary, in addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
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Affiliation(s)
- Hao Yan
- Buck Institute for Research on Aging, Novato, CA, 94945, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Edgar Andres Diaz Miranda
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA
| | - Shiying Jin
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA
| | - Faith Wilson
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA
- Division of Biological Sciences, College of Arts and Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - Kang An
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA
| | - Brooke Godbee
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA
- College of Health Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - Xiaobin Zheng
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, 21218, USA
| | - Astrid Roshealy Brau-Rodríguez
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA
| | - Lei Lei
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, MO, 65211, USA.
- Division of Biological Sciences, College of Arts and Sciences, University of Missouri, Columbia, MO, 65211, USA.
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9
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Fossel M. Curing age-related disease, transforming global medicine. Expert Opin Ther Targets 2024; 28:481-485. [PMID: 37902505 DOI: 10.1080/14728222.2023.2277223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/26/2023] [Indexed: 10/31/2023]
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Feng Y, Huang Z, Ma X, Zong X, Tesic V, Ding B, Wu CYC, Lee RHC, Zhang Q. Photobiomodulation Inhibits Ischemia-Induced Brain Endothelial Senescence via Endothelial Nitric Oxide Synthase. Antioxidants (Basel) 2024; 13:633. [PMID: 38929072 PMCID: PMC11200452 DOI: 10.3390/antiox13060633] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/04/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Recent research suggests that photobiomodulation therapy (PBMT) positively impacts the vascular function associated with various cerebrovascular diseases. Nevertheless, the specific mechanisms by which PBMT improves vascular function remain ambiguous. Since endothelial nitric oxide synthase (eNOS) is crucial in regulating vascular function following cerebral ischemia, we investigated whether eNOS is a key element controlling cerebrovascular function and the senescence of vascular endothelial cells following PBMT treatment. Both rat photothrombotic (PT) stroke and in vitro oxygen-glucose deprivation (OGD)-induced vascular endothelial injury models were utilized. We demonstrated that treatment with PBMT (808 nm, 350 mW/cm2, 2 min/day) for 7 days significantly reduced PT-stroke-induced vascular permeability. Additionally, PBMT inhibited the levels of endothelial senescence markers (senescence green and p21) and antiangiogenic factor (endostatin), while increasing the phospho-eNOS (Ser1177) in the peri-infarct region following PT stroke. In vitro study further indicated that OGD increased p21, endostatin, and DNA damage (γH2AX) levels in the brain endothelial cell line, but they were reversed by PBMT. Intriguingly, the beneficial effects of PBMT were attenuated by a NOS inhibitor. In summary, these findings provide novel insights into the role of eNOS in PBMT-mediated protection against cerebrovascular senescence and endothelial dysfunction following ischemia. The use of PBMT as a therapeutic is a promising strategy to improve endothelial function in cerebrovascular disease.
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Affiliation(s)
- Yu Feng
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Zhihai Huang
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Xiaohui Ma
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Xuemei Zong
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Vesna Tesic
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Baojin Ding
- Department of Biochemistry & Molecular Biology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Celeste Yin-Chieh Wu
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Reggie Hui-Chao Lee
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
| | - Quanguang Zhang
- Institute for Cerebrovascular and Neuroregeneration Research, Shreveport, LA 71103, USA
- Department of Neurology, Louisiana State University Health, Shreveport, LA 71103, USA
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Balasubramanian P, Kiss T, Gulej R, Nyul Toth A, Tarantini S, Yabluchanskiy A, Ungvari Z, Csiszar A. Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence. Nutrients 2024; 16:952. [PMID: 38612986 PMCID: PMC11013792 DOI: 10.3390/nu16070952] [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: 11/22/2023] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
High-fat diets (HFDs) have pervaded modern dietary habits, characterized by their excessive saturated fat content and low nutritional value. Epidemiological studies have compellingly linked HFD consumption to obesity and the development of type 2 diabetes mellitus. Moreover, the synergistic interplay of HFD, obesity, and diabetes expedites the aging process and prematurely fosters age-related diseases. However, the underlying mechanisms driving these associations remain enigmatic. One of the most conspicuous hallmarks of aging is the accumulation of highly inflammatory senescent cells, with mounting evidence implicating increased cellular senescence in the pathogenesis of age-related diseases. Our hypothesis posits that HFD consumption amplifies senescence burden across multiple organs. To scrutinize this hypothesis, we subjected mice to a 6-month HFD regimen, assessing senescence biomarker expression in the liver, white adipose tissue, and the brain. Aging is intrinsically linked to impaired cellular stress resilience, driven by dysfunction in Nrf2-mediated cytoprotective pathways that safeguard cells against oxidative stress-induced senescence. To ascertain whether Nrf2-mediated pathways shield against senescence induction in response to HFD consumption, we explored senescence burden in a novel model of aging: Nrf2-deficient (Nrf2+/-) mice, emulating the aging phenotype. Our initial findings unveiled significant Nrf2 dysfunction in Nrf2+/- mice, mirroring aging-related alterations. HFD led to substantial obesity, hyperglycemia, and impaired insulin sensitivity in both Nrf2+/- and Nrf2+/+ mice. In control mice, HFD primarily heightened senescence burden in white adipose tissue, evidenced by increased Cdkn2a senescence biomarker expression. In Nrf2+/- mice, HFD elicited a significant surge in senescence burden across the liver, white adipose tissue, and the brain. We postulate that HFD-induced augmentation of senescence burden may be a pivotal contributor to accelerated organismal aging and the premature onset of age-related diseases.
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Affiliation(s)
- Priya Balasubramanian
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Tamas Kiss
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
- International Training Program in Geroscience, First Department of Pediatrics, Semmelweis University, 1089 Budapest, Hungary
| | - Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Adam Nyul Toth
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
| | - Stefano Tarantini
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
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12
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Ma S, Xie X, Yuan R, Xin Q, Miao Y, Leng SX, Chen K, Cong W. Vascular Aging and Atherosclerosis: A Perspective on Aging. Aging Dis 2024; 16:AD.2024.0201-1. [PMID: 38502584 PMCID: PMC11745439 DOI: 10.14336/ad.2024.0201-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/01/2024] [Indexed: 03/21/2024] Open
Abstract
Vascular aging (VA) is recognized as a pivotal factor in the development and progression of atherosclerosis (AS). Although various epidemiological and clinical research has demonstrated an intimate connection between aging and AS, the candidate mechanisms still require thorough examination. This review adopts an aging-centric perspective to deepen the comprehension of the intricate relationship between biological aging, vascular cell senescence, and AS. Various aging-related physiological factors influence the physical system's reactions, including oxygen radicals, inflammation, lipids, angiotensin II, mechanical forces, glucose levels, and insulin resistance. These factors cause endothelial dysfunction, barrier damage, sclerosis, and inflammation for VA and promote AS via distinct or shared pathways. Furthermore, the increase of senescent cells inside the vascular tissues, caused by genetic damage, dysregulation, secretome changes, and epigenetic modifications, might be the primary cause of VA.
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Affiliation(s)
- Shudong Ma
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xuena Xie
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Rong Yuan
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qiqi Xin
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Yu Miao
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Sean Xiao Leng
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
| | - Keji Chen
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Weihong Cong
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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13
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Lui KO, Ma Z, Dimmeler S. SARS-CoV-2 induced vascular endothelial dysfunction: direct or indirect effects? Cardiovasc Res 2024; 120:34-43. [PMID: 38159046 DOI: 10.1093/cvr/cvad191] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/18/2023] [Accepted: 11/03/2023] [Indexed: 01/03/2024] Open
Abstract
Clinical evidence reveals that manifestations of endothelial dysfunction are widely observed in COVID-19 and long-COVID patients. However, whether these detrimental effects are caused by direct infection of the endothelium or are indirectly mediated by systemic inflammation has been a matter of debate. It has been well acknowledged that endothelial cells (ECs) of the cardiovascular system ubiquitously express the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), yet accumulating evidence suggests that it is more predominantly expressed by pericytes and vascular smooth muscle cells of the mammalian blood vessel. Besides, replicative infection of ECs by SARS-CoV-2 has yet to be demonstrated both in vitro and in vivo. In this study, we review latest research on endothelial ACE2 expression in different vascular beds, and the heterogeneity in various EC subsets with differential ACE2 expression in response to SARS-CoV-2. We also discuss ACE2-independent alternative mechanisms underlying endothelial activation in COVID-19, and the clinical manifestations of SARS-CoV-2-induced endothelial dysfunction. Altogether, understanding ACE2-dependent and ACE2-independent mechanisms driving SARS-CoV-2-induced vascular dysfunction would shed light on strategies of more effective therapies targeting cardiovascular complications associated with COVID-19.
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Affiliation(s)
- Kathy O Lui
- Department of Chemical Pathology, and Li Ka Shing Institute of Health Science, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Sha Tin, New Territories, 999077 Hong Kong, China
| | - Zhangjing Ma
- Department of Chemical Pathology, and Li Ka Shing Institute of Health Science, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Sha Tin, New Territories, 999077 Hong Kong, China
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, and Faculty of Biological Sciences, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany
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14
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Akagi R, Nanba F, Saito S, Maruo T, Toda T, Yamashita Y, Ashida H, Suzuki T. Black Soybean Seed Coat Extract Improves Endothelial Function and Upregulates Oxidative Stress Marker Expression in Healthy Volunteers by Stimulating Nitric Oxide Production in Endothelial Cells. J Med Food 2024; 27:134-144. [PMID: 38294791 DOI: 10.1089/jmf.2023.k.0149] [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] [Indexed: 02/01/2024] Open
Abstract
Black soybean seed coat extract (BE) contains multiple bioactive polyphenols, including flavan-3-ols and anthocyanins. BE improves endothelial function; however, it is unclear whether BE protects endothelial cells from senescence. In this study, we examined the effects of BE on endothelial cell senescence and vascular function in healthy individuals. High concentrations of glucose were used to induce senescence in bovine aortic endothelial cells incubated with BE. Senescence, vascular function, and oxidative stress markers were measured. Incubation with BE remarkably inhibited senescence-associated β-galactosidase and lactate dehydrogenase activities and dose dependently reduced intracellular reactive oxygen species levels in bovine aortic endothelial cells. BE treatment increased the levels of endothelial nitric oxide synthase (eNOS) mRNA and endothelial nitric oxide (NO) metabolites and increased the mRNA expression of klotho, a gene associated with an antiaging phenotype. To examine the effects of BE in humans, we conducted a clinical study using the second derivative of the fingertip photoplethysmogram to investigate vascular function and aging in 24 healthy volunteers. The participants consumed BE supplements (100 mg/day) or a placebo for 2 weeks. When compared with the placebo group, the BE group showed considerably improved vascular function, NO metabolite levels, and oxidative stress. These results suggest that BE supplementation improves endothelial function, possibly through antioxidant activity and NO production, and may consequently reduce the cardiovascular risk associated with aging. BE supplementation may be an effective and safe approach to reduce the risk of atherosclerosis and cardiovascular disease; however, additional studies investigating chronic vascular inflammation are needed.
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Affiliation(s)
- Ryota Akagi
- Research and Development Department, Fujicco Co. Ltd., Kobe, Japan
| | - Fumio Nanba
- Research and Development Department, Fujicco Co. Ltd., Kobe, Japan
| | - Shizuka Saito
- Research and Development Department, Fujicco Co. Ltd., Kobe, Japan
| | - Toshinari Maruo
- Research and Development Department, Fujicco Co. Ltd., Kobe, Japan
| | - Toshiya Toda
- Research and Development Department, Fujicco Co. Ltd., Kobe, Japan
- Department of Innovative Food Sciences, School of Food Sciences and Nutrition, Mukogawa Women's University, Nishinomiya, Japan
| | - Yoko Yamashita
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan
| | - Hitoshi Ashida
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan
| | - Toshio Suzuki
- Research and Development Department, Fujicco Co. Ltd., Kobe, Japan
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15
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Yan H, Miranda EAD, Jin S, Wilson F, An K, Godbee B, Zheng X, Brau-Rodríguez AR, Lei L. Primary oocytes with cellular senescence features are involved in ovarian aging in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574768. [PMID: 38260383 PMCID: PMC10802418 DOI: 10.1101/2024.01.08.574768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 months to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP cytokines in the ovary. In addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation and female fertility. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
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Affiliation(s)
- Hao Yan
- Buck Institute for Research on Aging, Novato, California, 94945
- Carnegie Institution for Science, Department of Embryology, Baltimore, Maryland, 21218
| | - Edgar Andres Diaz Miranda
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
| | - Shiying Jin
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
| | - Faith Wilson
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
- Division of Biological Sciences, College of Arts and Sciences, University of Missouri, Columbia, Missouri, 65211
| | - Kang An
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
| | - Brooke Godbee
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
- College of Health Sciences, University of Missouri, Columbia, Missouri, 65211
| | - Xiaobin Zheng
- Carnegie Institution for Science, Department of Embryology, Baltimore, Maryland, 21218
| | - Astrid Roshealy Brau-Rodríguez
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
| | - Lei Lei
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, Missouri, 65211
- Division of Biological Sciences, College of Arts and Sciences, University of Missouri, Columbia, Missouri, 65211
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16
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Maurer GS, Clayton ZS. Anthracycline chemotherapy, vascular dysfunction and cognitive impairment: burgeoning topics and future directions. Future Cardiol 2023; 19:547-566. [PMID: 36354315 PMCID: PMC10599408 DOI: 10.2217/fca-2022-0086] [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: 09/09/2022] [Accepted: 10/17/2022] [Indexed: 11/12/2022] Open
Abstract
Anthracyclines, chemotherapeutic agents used to treat common forms of cancer, increase cardiovascular (CV) complications, thereby necessitating research regarding interventions to improve the health of cancer survivors. Vascular dysfunction, which is induced by anthracycline chemotherapy, is an established antecedent to overt CV diseases. Potential treatment options for ameliorating vascular dysfunction have largely been understudied. Furthermore, patients treated with anthracyclines have impaired cognitive function and vascular dysfunction is an independent risk factor for the development of mild cognitive impairment. Here, we will focus on: anthracycline chemotherapy associated CV diseases risk; how targeting mechanisms underlying vascular dysfunction may be a means to improve both CV and cognitive health; and research gaps and potential future directions for the field of cardio-oncology.
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Affiliation(s)
- Grace S Maurer
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Zachary S Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
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17
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Culley MK, Rao RJ, Mehta M, Zhao J, El Khoury W, Harvey LD, Perk D, Tai YY, Tang Y, Shiva S, Rabinovitch M, Gu M, Bertero T, Chan SY. Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function. Vascul Pharmacol 2023; 151:107181. [PMID: 37164245 PMCID: PMC10524929 DOI: 10.1016/j.vph.2023.107181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 04/19/2023] [Accepted: 05/07/2023] [Indexed: 05/12/2023]
Abstract
Deficiency of iron‑sulfur (FeS) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of FeS biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreich's ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, we aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells had increased vasoconstrictor production (EDN1) and decreased nitric oxide synthase expression (NOS3). These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.
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Affiliation(s)
- Miranda K Culley
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rashmi J Rao
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Monica Mehta
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jingsi Zhao
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Wadih El Khoury
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Lloyd D Harvey
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Dror Perk
- Medical Scientist Training Program, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yi Yin Tai
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ying Tang
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sruti Shiva
- Department of Pharmacology and Chemical Biology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, USA
| | - Marlene Rabinovitch
- Stanford Children's Health Betty Irene Moore Children's Heart Center, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Mingxia Gu
- Perinatal Institute, Division of Pulmonary Biology Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Thomas Bertero
- Université Côte d'Azur, CNRS, UMR7275, IPMC, Valbonne, France
| | - Stephen Y Chan
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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18
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Corkery AT, Miller KB, Loeper CA, Tetri LH, Pearson AG, Loggie NA, Howery AJ, Eldridge MW, Barnes JN. Association between serum prostacyclin and cerebrovascular reactivity in healthy young and older adults. Exp Physiol 2023; 108:1047-1056. [PMID: 37170828 PMCID: PMC10524213 DOI: 10.1113/ep090903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/17/2023] [Indexed: 05/13/2023]
Abstract
NEW FINDINGS What is the central question of this study? What is the relationship between prostacyclin and cerebrovascular reactivity to hypercapnia before and after administration of a cyclooxygenase inhibitor, indomethacin, in healthy young and older adults? What is the main finding and importance? Serum prostacyclin was not related to cerebrovascular reactivity to hypercapnia before or after administration of indomethacin. However, in older adults, serum prostacyclin was related to the magnitude of change in cerebrovascular reactivity from before to after indomethacin administration. This suggests that older adults with higher serum prostacyclin may rely more on cyclooxygenase products to mediate cerebrovascular reactivity. ABSTRACT Platelet activation may contribute to age-related cerebrovascular dysfunction by interacting with the endothelial cells that regulate the response to vasodilatory stimuli. This study evaluated the relationship between a platelet inhibitor, prostacyclin, and cerebrovascular reactivity (CVR) in healthy young (n = 35; 25 ± 4 years; 17 women, 18 men) and older (n = 12; 62 ± 2 years; 8 women, 4 men) adults, who were not daily aspirin users, before and after cyclooxygenase inhibition. Prostacyclin was determined by levels of 6-keto-prostaglandin F1α (6-keto PGF1α) in the blood. CVR was assessed by measuring the middle cerebral artery blood velocity response to hypercapnia using transcranial Doppler ultrasound before (CON) and 90 min after cyclooxygenase inhibition with indomethacin (INDO). In young adults, there were no associations between prostacyclin and middle cerebral artery CVR during CON (r = -0.14, P = 0.415) or INDO (r = 0.27, P = 0.118). In older adults, associations between prostacyclin and middle cerebral artery CVR during CON (r = 0.53, P = 0.075) or INDO (r = -0.45, P = 0.136) did not reach the threshold for significance. We also evaluated the relationship between prostacyclin and the change in CVR between conditions (ΔCVR). We found no association between ΔCVR and prostacyclin in young adults (r = 0.27, P = 0.110); however, in older adults, those with higher baseline prostacyclin levels demonstrated significantly greater ΔCVR (r = -0.74, P = 0.005). In conclusion, older adults with higher serum prostacyclin, a platelet inhibitor, may rely more on cyclooxygenase products for cerebrovascular reactivity to hypercapnia.
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Affiliation(s)
- Adam T Corkery
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
| | - Kathleen B Miller
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
| | - Carissa A Loeper
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
| | - Laura H Tetri
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Andrew G Pearson
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
| | - Nicole A Loggie
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
| | - Anna J Howery
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
| | - Marlowe W Eldridge
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jill N Barnes
- Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin Madison, Madison, WI, USA
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19
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Zhang J, Li C, Zhang Y, Wu J, Huang Z. Therapeutic potential of nitric oxide in vascular aging due to the promotion of angiogenesis. Chem Biol Drug Des 2023; 102:395-407. [PMID: 37062588 DOI: 10.1111/cbdd.14248] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/20/2023] [Accepted: 04/04/2023] [Indexed: 04/18/2023]
Abstract
The decrease in angiogenesis that occurs with aging significantly contributes to the higher incidence and mortality of cardiovascular diseases among the elderly. This decline in angiogenesis becomes more pronounced with increasing age and is closely linked to abnormal function and senescence of endothelial cells. Enhancing angiogenesis in aging and targeting senescent endothelial cells have gained considerable attention. Nitric oxide (NO) has been thoroughly investigated for its function in regulating angiogenesis and is an important factor that can counteract endothelial cell senescence. This review summarizes the mechanisms of reduced angiogenesis during aging and therapeutic strategies targeting senescent cells. We also discuss the potential of combining the current approaches with NO in promoting angiogenesis in aging vessels.
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Affiliation(s)
- Jiaming Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Cunrui Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Yihua Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Jianbing Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Zhangjian Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
- School of Pharmacy, Xinjiang Medical University, China
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20
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Uruski P, Matuszewska J, Leśniewska A, Rychlewski D, Niklas A, Mikuła-Pietrasik J, Tykarski A, Książek K. An integrative review of nonobvious puzzles of cellular and molecular cardiooncology. Cell Mol Biol Lett 2023; 28:44. [PMID: 37221467 DOI: 10.1186/s11658-023-00451-y] [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: 02/22/2023] [Accepted: 04/17/2023] [Indexed: 05/25/2023] Open
Abstract
Oncologic patients are subjected to four major treatment types: surgery, radiotherapy, chemotherapy, and immunotherapy. All nonsurgical forms of cancer management are known to potentially violate the structural and functional integrity of the cardiovascular system. The prevalence and severity of cardiotoxicity and vascular abnormalities led to the emergence of a clinical subdiscipline, called cardiooncology. This relatively new, but rapidly expanding area of knowledge, primarily focuses on clinical observations linking the adverse effects of cancer therapy with deteriorated quality of life of cancer survivors and their increased morbidity and mortality. Cellular and molecular determinants of these relations are far less understood, mainly because of several unsolved paths and contradicting findings in the literature. In this article, we provide a comprehensive view of the cellular and molecular etiology of cardiooncology. We pay particular attention to various intracellular processes that arise in cardiomyocytes, vascular endothelial cells, and smooth muscle cells treated in experimentally-controlled conditions in vitro and in vivo with ionizing radiation and drugs representing diverse modes of anti-cancer activity.
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Affiliation(s)
- Paweł Uruski
- Department of Hypertensiology, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Julia Matuszewska
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Aleksandra Leśniewska
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Daniel Rychlewski
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Arkadiusz Niklas
- Department of Hypertensiology, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Justyna Mikuła-Pietrasik
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Andrzej Tykarski
- Department of Hypertensiology, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Krzysztof Książek
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland.
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21
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Zhao X, Zhou S, Liu Y, Gong C, Xiang L, Li S, Wang P, Wang Y, Sun L, Zhang Q, Yang Y. Parishin alleviates vascular ageing in mice by upregulation of Klotho. J Cell Mol Med 2023; 27:1398-1409. [PMID: 37032511 PMCID: PMC10183705 DOI: 10.1111/jcmm.17740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 04/11/2023] Open
Abstract
Senescence of vascular endothelial cells is the major risk of vascular dysfunction and disease among elderly people. Parishin, which is a phenolic glucoside derived from Gastrodia elata, significantly prolonged yeast lifespan. However, the action of parishin in vascular ageing remains poorly understood. Here, we treated human coronary artery endothelial cells (HCAEC) and naturally aged mice by parishin. Parishin alleviated HCAEC senescence and general age-related features in vascular tissue in naturally aged mice. Network pharmacology approach was applied to determine the compound-target networks of parishin. Our analysis indicated that parishin had a strong binding affinity for Klotho. Expression of Klotho, a protein of age-related declines, was upregulated by parishin in serum and vascular tissue in naturally aged mice. Furthermore, FoxO1, on Klotho/FoxO1 signalling pathway, was increased in the parishin-intervened group, accompanied by the downregulated phosphorylated FoxO1. Taken together, parishin can increase Klotho expression to alleviate vascular endothelial cell senescence and vascular ageing.
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Affiliation(s)
- Xinxiu Zhao
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Shixian Zhou
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Yang Liu
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Caixia Gong
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Lan Xiang
- College of Pharmaceutical SciencesZhejiang University866 Yu Hang Tang RoadHangzhouChina
| | - Shumin Li
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Peixia Wang
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Yuejun Wang
- Zhejiang Aged Care HospitalHangzhou Normal UniversityHangzhouZhejiangChina
| | - Linlin Sun
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Qin Zhang
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Yunmei Yang
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
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22
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Sakamuri A, Ogola BO. The intersection between senescence-mediated vascular dysfunction and cognitive impairment in female mice. Am J Physiol Heart Circ Physiol 2023; 324:H411-H413. [PMID: 36800510 PMCID: PMC9988518 DOI: 10.1152/ajpheart.00076.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Affiliation(s)
- Anil Sakamuri
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Bernard Ojwang Ogola
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
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23
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Sweeney M, Cook SA, Gil J. Therapeutic opportunities for senolysis in cardiovascular disease. FEBS J 2023; 290:1235-1255. [PMID: 35015342 PMCID: PMC10952275 DOI: 10.1111/febs.16351] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/20/2021] [Accepted: 01/10/2022] [Indexed: 12/19/2022]
Abstract
Cellular senescence within the cardiovascular system has, until recently, been understudied and unappreciated as a factor in the development of age-related cardiovascular diseases such as heart failure, myocardial infarction and atherosclerosis. This is in part due to challenges with defining senescence within post-mitotic cells such as cardiomyocytes. However, recent evidence has demonstrated senescent-like changes, including a senescence-associated secretory phenotype (SASP), in cardiomyocytes in response to ageing and cell stress. Other replicating cells, including fibroblasts and vascular smooth muscle cells, within the cardiovascular system have also been shown to undergo senescence and contribute to disease pathogenesis. These findings coupled with the emergence of senolytic therapies, to target and eliminate senescent cells, have provided fascinating new avenues for management of several age-related cardiovascular diseases with high prevalence. In this review, we discuss the role of senescent cells within the cardiovascular system and highlight the contribution of senescence cells to common cardiovascular diseases. We discuss the emerging role for senolytics in cardiovascular disease management while highlighting important aspects of senescence biology which must be clarified before the potential of senolytics can be fully realized.
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Affiliation(s)
- Mark Sweeney
- MRC London Institute of Medical Sciences (LMS)LondonUK
- Institute of Clinical Sciences (ICS)Faculty of MedicineImperial College LondonUK
- Wellcome Trust / National Institute of Health Research 4i Clinical Research FellowLondonUK
| | - Stuart A. Cook
- MRC London Institute of Medical Sciences (LMS)LondonUK
- Institute of Clinical Sciences (ICS)Faculty of MedicineImperial College LondonUK
| | - Jesús Gil
- MRC London Institute of Medical Sciences (LMS)LondonUK
- Institute of Clinical Sciences (ICS)Faculty of MedicineImperial College LondonUK
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24
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Di Pietrantonio N, Di Tomo P, Mandatori D, Formoso G, Pandolfi A. Diabetes and Its Cardiovascular Complications: Potential Role of the Acetyltransferase p300. Cells 2023; 12:431. [PMID: 36766773 PMCID: PMC9914144 DOI: 10.3390/cells12030431] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised that the acetyltransferase, p300, may contribute to establishing an early vascular senescent phenotype, playing a relevant role in diabetes-associated inflammation and oxidative stress, which drive endothelial dysfunction. Specifically, p300 can modulate vascular inflammation through epigenetic mechanisms and transcription factors acetylation. Indeed, it regulates the inflammatory pathway by interacting with nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) or by inducing its acetylation, suggesting a crucial role of p300 as a bridge between NF-κB p65 and the transcriptional machinery. Additionally, p300-mediated epigenetic modifications could be upstream of the activation of inflammatory cytokines, and they may induce oxidative stress by affecting the production of reactive oxygen species (ROS). Because several in vitro and in vivo studies shed light on the potential use of acetyltransferase inhibitors, a better understanding of the mechanisms underlying the role of p300 in diabetic vascular dysfunction could help in finding new strategies for the clinical management of CV diseases related to diabetes.
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Affiliation(s)
- Nadia Di Pietrantonio
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Pamela Di Tomo
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Domitilla Mandatori
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Gloria Formoso
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
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25
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Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics. Exp Mol Med 2023; 55:1-12. [PMID: 36599934 PMCID: PMC9898542 DOI: 10.1038/s12276-022-00906-w] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/25/2022] [Accepted: 10/31/2022] [Indexed: 01/05/2023] Open
Abstract
Senescence compromises the essential role that the endothelium plays in maintaining vascular homeostasis, so promoting endothelial dysfunction and the development of age-related vascular diseases. Their biological and clinical significance calls for strategies for identifying and therapeutically targeting senescent endothelial cells. While senescence and endothelial dysfunction have been studied extensively, distinguishing what is distinctly endothelial senescence remains a barrier to overcome for an effective approach to addressing it. Here, we review the mechanisms underlying endothelial senescence and the evidence for its clinical importance. Furthermore, we discuss the current state and the limitations in the approaches for the detection and therapeutic intervention of target cells, suggesting potential directions for future research.
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26
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Association between atherogenic risk-modulating proteins and endothelium-dependent flow-mediated dilation in coronary artery disease patients. Eur J Appl Physiol 2023; 123:367-380. [PMID: 36305972 PMCID: PMC9894982 DOI: 10.1007/s00421-022-05040-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 09/04/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE Endothelial dysfunction is an early and integral event in the development of atherosclerosis and coronary artery disease (CAD). Reduced NO bioavailability, oxidative stress, vasoconstriction, inflammation and senescence are all implicated in endothelial dysfunction. However, there are limited data examining associations between these pathways and direct in vivo bioassay measures of endothelial function in CAD patients. This study aimed to examine the relationships between in vivo measures of vascular function and the expression of atherogenic risk-modulating proteins in endothelial cells (ECs) isolated from the radial artery of CAD patients. METHODS Fifty-six patients with established CAD underwent trans-radial catheterization. Prior to catheterization, radial artery vascular function was assessed using a) flow-mediated dilation (FMD), and b) exercise-induced dilation in response to handgrip (HE%). Freshly isolated ECs were obtained from the radial artery during catheterization and protein content of eNOS, NAD(P)H oxidase subunit NOX2, NFκB, ET-1 and the senescence markers p53, p21 and p16 were evaluated alongside nitrotyrosine abundance and eNOS Ser1177 phosphorylation. RESULTS FMD was positively associated with eNOS Ser1177 phosphorylation (r = 0.290, P = 0.037), and protein content of p21 (r = 0.307, P = 0.027) and p16 (r = 0.426, P = 0.002). No associations were found between FMD and markers of oxidative stress, vasoconstriction or inflammation. In contrast to FMD, HE% was not associated with any of the EC proteins. CONCLUSION These data revealed a difference in the regulation of endothelium-dependent vasodilation measured in vivo between patients with CAD compared to previously reported data in subjects without a clinical diagnosis, suggesting that eNOS Ser1177 phosphorylation may be the key to maintain vasodilation in CAD patients.
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27
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Bloom SI, Islam MT, Lesniewski LA, Donato AJ. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol 2023; 20:38-51. [PMID: 35853997 PMCID: PMC10026597 DOI: 10.1038/s41569-022-00739-0] [Citation(s) in RCA: 198] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2022] [Indexed: 12/15/2022]
Abstract
Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic physiological function. The vascular endothelium is particularly susceptible to pathogenic stimuli that activate tumour suppressor pathways leading to cellular senescence. We now understand that senescent endothelial cells are highly active, secretory and pro-inflammatory, and have an aberrant morphological phenotype. Moreover, endothelial senescence has been identified as an important contributor to various cardiovascular and metabolic diseases. In this Review, we discuss the consequences of endothelial cell exposure to damaging stimuli (haemodynamic forces and circulating and endothelial-derived factors) and the cellular and molecular mechanisms that induce endothelial cell senescence. We also discuss how endothelial cell senescence causes arterial dysfunction and contributes to clinical cardiovascular diseases and metabolic disorders. Finally, we summarize the latest evidence on the effect of eliminating senescent endothelial cells (senolysis) and identify important remaining questions to be addressed in future studies.
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Affiliation(s)
- Samuel I Bloom
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Md Torikul Islam
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Lisa A Lesniewski
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, USA
- Veterans Affairs Medical Center-Salt Lake City, Geriatric Research Education and Clinical Center, Salt Lake City, UT, USA
| | - Anthony J Donato
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, USA.
- Veterans Affairs Medical Center-Salt Lake City, Geriatric Research Education and Clinical Center, Salt Lake City, UT, USA.
- Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
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28
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Fossel M, Bean J, Khera N, Kolonin MG. A Unified Model of Age-Related Cardiovascular Disease. BIOLOGY 2022; 11:1768. [PMID: 36552277 PMCID: PMC9775230 DOI: 10.3390/biology11121768] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/18/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022]
Abstract
Despite progress in biomedical technologies, cardiovascular disease remains the main cause of mortality. This is at least in part because current clinical interventions do not adequately take into account aging as a driver and are hence aimed at suboptimal targets. To achieve progress, consideration needs to be given to the role of cell aging in disease pathogenesis. We propose a model unifying the fundamental processes underlying most age-associated cardiovascular pathologies. According to this model, cell aging, leading to cell senescence, is responsible for tissue changes leading to age-related cardiovascular disease. This process, occurring due to telomerase inactivation and telomere attrition, affects all components of the cardiovascular system, including cardiomyocytes, vascular endothelial cells, smooth muscle cells, cardiac fibroblasts, and immune cells. The unified model offers insights into the relationship between upstream risk factors and downstream clinical outcomes and explains why interventions aimed at either of these components have limited success. Potential therapeutic approaches are considered based on this model. Because telomerase activity can prevent and reverse cell senescence, telomerase gene therapy is discussed as a promising intervention. Telomerase gene therapy and similar systems interventions based on the unified model are expected to be transformational in cardiovascular medicine.
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Affiliation(s)
| | - Joe Bean
- University of Missouri School of Medicine, Kansas City, MO 65211, USA
| | - Nina Khera
- Buckingham Browne and Nichols School, Wellesley, MA 02138, USA
| | - Mikhail G. Kolonin
- University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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29
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Changes in Arterial Stiffness in Response to Various Types of Exercise Modalities: A Narrative Review on Physiological and Endothelial Senescence Perspectives. Cells 2022; 11:cells11223544. [PMID: 36428973 PMCID: PMC9688701 DOI: 10.3390/cells11223544] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 11/12/2022] Open
Abstract
Arterial stiffness is a reliable independent predictor of cardiovascular events. Exercise training might enhance arterial compliance through improved metabolic health status. Different modes of exercise may have different effects on arterial stiffness. However, the interactions among different modes of exercise on endothelial senescence, the development of arterial vascular stiffness, and the associated molecular mechanisms are not completely understood. In this narrative review, we evaluate the current evidence focusing on the effects of various exercise modes on arterial stiffness and vascular health, and the known underlying physiological mechanisms are discussed as well. Here, we discuss the most recent evidence of aerobic exercise, high-intensity interval training (HIIT), and resistance exercise (RE) on arterial stiffness and endothelial senescence in physiological and cellular studies. Indeed, aerobic, HIIT, and progression RE-induced arterial compliance may reduce arterial stiffness by effectively promoting nitric oxide (NO) bioavailability and reducing endothelial senescence. However, the transient increase in inflammation and sympathetic activation may contribute to the temporary elevation in arterial stiffness following whole-body high-intensity acute resistance exercise.
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30
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Age-Related Changes in Skeletal Muscle Oxygen Utilization. J Funct Morphol Kinesiol 2022; 7:jfmk7040087. [PMID: 36278748 PMCID: PMC9590092 DOI: 10.3390/jfmk7040087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 11/17/2022] Open
Abstract
The cardiovascular and skeletal muscle systems are intrinsically interconnected, sharing the goal of delivering oxygen to metabolically active tissue. Deficiencies within those systems that affect oxygen delivery to working tissues are a hallmark of advancing age. Oxygen delivery and utilization are reflected as muscle oxygen saturation (SmO2) and are assessed using near-infrared resonance spectroscopy (NIRS). SmO2 has been observed to be reduced by ~38% at rest, ~24% during submaximal exercise, and ~59% during maximal exercise with aging (>65 y). Furthermore, aging prolongs restoration of SmO2 back to baseline by >50% after intense exercise. Regulatory factors that contribute to reduced SmO2 with age include blood flow, capillarization, endothelial cells, nitric oxide, and mitochondrial function. These mechanisms are governed by reactive oxygen species (ROS) at the cellular level. However, mishandling of ROS with age ultimately leads to alterations in structure and function of the regulatory factors tasked with maintaining SmO2. The purpose of this review is to provide an update on the current state of the literature regarding age-related effects in SmO2. Furthermore, we attempt to bridge the gap between SmO2 and associated underlying mechanisms affected by aging.
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31
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Ogłuszka M, Lipiński P, Starzyński RR. Effect of Omega-3 Fatty Acids on Telomeres-Are They the Elixir of Youth? Nutrients 2022; 14:nu14183723. [PMID: 36145097 PMCID: PMC9504755 DOI: 10.3390/nu14183723] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022] Open
Abstract
Telomeres are complexes consisting of tandem repeat DNA combined with associated proteins that play a key role in protecting the ends of chromosomes and maintaining genome stability. They are considered a biological clock, as they shorten in parallel with aging. Furthermore, short telomeres are associated with several age-related diseases. However, the variability in telomere shortening independent of chronological age suggests that it is a modifiable factor. In fact, it is regulated inter alia by genetic damage, cell division, aging, oxidative stress, and inflammation. A key question remains: how can we prevent accelerated telomere attrition and subsequent premature replicative senescence? A number of studies have explored the possible impact of omega-3 fatty acids on telomere shortening. This review summarizes published cross-sectional studies, randomized controlled trials, and rodent studies investigating the role of omega-3 fatty acids in telomere biology. It also covers a broad overview of the mechanism, currently favored in the field, that explains the impact of omega-3 fatty acids on telomeres—the food compound’s ability to modulate oxidative stress and inflammation. Although the results of the studies performed to date are not consistent, the vast majority indicate a beneficial effect of omega-3 fatty acids on telomere length.
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Affiliation(s)
- Magdalena Ogłuszka
- Department of Genomics, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Paweł Lipiński
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Rafał R. Starzyński
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
- Correspondence:
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32
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Revisiting Epithelial Carcinogenesis. Int J Mol Sci 2022; 23:ijms23137437. [PMID: 35806442 PMCID: PMC9267463 DOI: 10.3390/ijms23137437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/22/2022] [Accepted: 06/22/2022] [Indexed: 12/04/2022] Open
Abstract
The origin of cancer remains one of the most important enigmas in modern biology. This paper presents a hypothesis for the origin of carcinomas in which cellular aging and inflammation enable the recovery of cellular plasticity, which may ultimately result in cancer. The hypothesis describes carcinogenesis as the result of the dedifferentiation undergone by epithelial cells in hyperplasia due to replicative senescence towards a mesenchymal cell state with potentially cancerous behavior. In support of this hypothesis, the molecular, cellular, and histopathological evidence was critically reviewed and reinterpreted when necessary to postulate a plausible generic series of mechanisms for the origin and progression of carcinomas. In addition, the implications of this theoretical framework for the current strategies of cancer treatment are discussed considering recent evidence of the molecular events underlying the epigenetic switches involved in the resistance of breast carcinomas. The hypothesis also proposes an epigenetic landscape for their progression and a potential mechanism for restraining the degree of dedifferentiation and malignant behavior. In addition, the manuscript revisits the gradual degeneration of the nonalcoholic fatty liver disease to propose an integrative generalized mechanistic explanation for the involution and carcinogenesis of tissues associated with aging. The presented hypothesis might serve to understand and structure new findings into a more encompassing view of the genesis of degenerative diseases and may inspire novel approaches for their study and therapy.
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33
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Shiwakoti S, Ko JY, Gong D, Dhakal B, Lee JH, Adhikari R, Gwak Y, Park SH, Jun Choi I, Schini-Kerth VB, Kang KW, Oak MH. Effects of polystyrene nanoplastics on endothelium senescence and its underlying mechanism. ENVIRONMENT INTERNATIONAL 2022; 164:107248. [PMID: 35461096 DOI: 10.1016/j.envint.2022.107248] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 04/03/2022] [Accepted: 04/13/2022] [Indexed: 06/14/2023]
Abstract
Global plastic use has increased rapidly, and environmental pollution associated with nanoplastics (NPs) has been a growing concern recently. However, the impact and biological mechanism of NPs on the cardiovascular system are not well characterized. This study aimed to assess the possibility that NPs exposure promotes premature endothelial cell (EC) senescence in porcine coronary artery ECs and, if so, to elucidate the underlying mechanism. Treatment of ECs with NPs promoted the acquisition of senescence markers, senescence-associated β-galactosidase activity, and p53, p21, and p16 protein expression, resulting in the inhibition of proliferation. In addition, NPs impaired endothelium-dependent vasorelaxation associated with decreased endothelial nitric oxide synthase (eNOS) expression. NPs enhanced reactive oxygen species formation in ECs, and increased oxidative stress levels were associated with the induction of NADPH oxidases expression, followed by the subsequent downregulation of Sirt1 expression. The characteristics of EC senescence and dysfunction caused by NPs are prevented by an antioxidant (N-acetylcysteine), an NADPH oxidase inhibitor (apocynin), and a Sirt1 activator (resveratrol). These findings indicate that NPs induced premature EC senescence, at least in part, through the redox-sensitive eNOS/Sirt1 signaling pathway. This study suggested the effects and underlying mechanism of NPs on the cardiovascular system, which may provide pharmacological targets to prevent NPs-associated cardiovascular diseases.
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Affiliation(s)
- Saugat Shiwakoti
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Ju-Young Ko
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Dalseong Gong
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea; Regenerative Nanomedicine, Faculty of Pharmacy, UMR 1260 INSERM (French National Institute of Health and Medical Research), University of Strasbourg, Strasbourg, France
| | - Bikalpa Dhakal
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Jeong-Hye Lee
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Radhika Adhikari
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Yeonhyang Gwak
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Sin-Hee Park
- Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ik Jun Choi
- Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Valérie B Schini-Kerth
- Regenerative Nanomedicine, Faculty of Pharmacy, UMR 1260 INSERM (French National Institute of Health and Medical Research), University of Strasbourg, Strasbourg, France
| | - Ki-Woon Kang
- Division of Cardiology, Cardiovascular and Arrhythmia Center, Chung-Ang University, Seoul, Republic of Korea
| | - Min-Ho Oak
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea.
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34
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Mehdizadeh M, Aguilar M, Thorin E, Ferbeyre G, Nattel S. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol 2022; 19:250-264. [PMID: 34667279 DOI: 10.1038/s41569-021-00624-2] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/06/2021] [Indexed: 12/11/2022]
Abstract
Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. Clinical evidence and experimental studies link cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiac pathologies such as heart failure, myocardial ischaemia and infarction, and cancer chemotherapy-related cardiotoxicity. However, the precise role of senescent cells in these conditions is unclear and, in some instances, both detrimental and beneficial effects have been reported. The involvement of cellular senescence in other important entities, such as cardiac arrhythmias and remodelling, is poorly understood. In this Review, we summarize the basic biology of cellular senescence and discuss what is known about the role of cellular senescence and the SASP in heart disease. We then consider the various approaches that are being developed to prevent the accumulation of senescent cells and their consequences. Many of these strategies are applicable in vivo and some are being investigated for non-cardiac indications in clinical trials. We end by considering important knowledge gaps, directions for future research and the potential implications for improving the management of patients with heart disease.
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Affiliation(s)
- Mozhdeh Mehdizadeh
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | - Martin Aguilar
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.,Department of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Eric Thorin
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.,Department of Surgery, Université de Montréal, Montreal, QC, Canada
| | - Gerardo Ferbeyre
- Department of Biochemistry, Université de Montréal and CRCHUM, Montreal, QC, Canada
| | - Stanley Nattel
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada. .,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada. .,Department of Medicine, Université de Montréal, Montreal, QC, Canada. .,Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. .,Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany. .,IHU LIRYC and Fondation Bordeaux, Université Bordeaux, Bordeaux, France.
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35
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Jiang D, Sun W, Wu T, Zou M, Vasamsetti SB, Zhang X, Zhao Y, Phillippi JA, Sawalha AH, Tavakoli S, Dutta P, Florentin J, Chan SY, Tollison TS, Di Wu, Cui J, Huntress I, Peng X, Finkel T, Li G. Post-GWAS functional analysis identifies CUX1 as a regulator of p16 INK4a and cellular senescence. NATURE AGING 2022; 2:140-154. [PMID: 37117763 PMCID: PMC10154215 DOI: 10.1038/s43587-022-00177-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 12/21/2021] [Indexed: 04/30/2023]
Abstract
Accumulation of senescent cells with age is an important driver of aging and age-related diseases. However, the mechanisms and signaling pathways that regulate senescence remain elusive. In this report, we performed post-genome-wide association studies (GWAS) functional studies on the CDKN2A/B locus, a locus known to be associated with multiple age-related diseases and overall human lifespan. We demonstrate that transcription factor CUX1 (Cut-Like Homeobox 1) specifically binds to an atherosclerosis-associated functional single-nucleotide polymorphism (fSNP) (rs1537371) within the locus and regulates the CDKN2A/B-encoded proteins p14ARF, p15INK4b and p16INK4a and the antisense noncoding RNA in the CDK4 (INK4) locus (ANRIL) in endothelial cells (ECs). Endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced senescence via activation of p16INK4a expression. Thus, our studies identify CUX1 as a regulator of p16INK4a-dependent endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.
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Affiliation(s)
- Danli Jiang
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wei Sun
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ting Wu
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Meijuan Zou
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Sathish Babu Vasamsetti
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Xiaoyu Zhang
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yihan Zhao
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julie A Phillippi
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amr H Sawalha
- Departments of Pediatrics Medicine, and Immunology & Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sina Tavakoli
- Departments of Radiology and Medicine, University of Pittsburgh, UPMC Presbyterian Hospital, Pittsburg, PA, USA
| | - Partha Dutta
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jonathan Florentin
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Stephen Y Chan
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Tammy S Tollison
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA
| | - Di Wu
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Oral and Craniofacial Health Sciences, Adam School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jing Cui
- Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, MA, USA
| | - Ian Huntress
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA
- Bioinformatics Graduate Program, North Carolina State University, Raleigh, NC, USA
| | - Xinxia Peng
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - Toren Finkel
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Gang Li
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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36
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Roger I, Milara J, Belhadj N, Cortijo J. Senescence Alterations in Pulmonary Hypertension. Cells 2021; 10:3456. [PMID: 34943963 PMCID: PMC8700581 DOI: 10.3390/cells10123456] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is the arrest of normal cell division and is commonly associated with aging. The interest in the role of cellular senescence in lung diseases derives from the observation of markers of senescence in chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (IPF), and pulmonary hypertension (PH). Accumulation of senescent cells and the senescence-associated secretory phenotype in the lung of aged patients may lead to mild persistent inflammation, which results in tissue damage. Oxidative stress due to environmental exposures such as cigarette smoke also promotes cellular senescence, together with additional forms of cellular stress such as mitochondrial dysfunction and endoplasmic reticulum stress. Growing recent evidence indicate that senescent cell phenotypes are observed in pulmonary artery smooth muscle cells and endothelial cells of patients with PH, contributing to pulmonary artery remodeling and PH development. In this review, we analyze the role of different senescence cell phenotypes contributing to the pulmonary artery remodeling process in different PH clinical entities. Different molecular pathway activation and cellular functions derived from senescence activation will be analyzed and discussed as promising targets to develop future senotherapies as promising treatments to attenuate pulmonary artery remodeling in PH.
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Affiliation(s)
- Inés Roger
- Centro de Investigación en Red Enfermedades Respiratorias CIBERES, Health Institute Carlos III, 28029 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Javier Milara
- Centro de Investigación en Red Enfermedades Respiratorias CIBERES, Health Institute Carlos III, 28029 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
- Pharmacy Unit, University General Hospital Consortium of Valencia, 46014 Valencia, Spain
| | - Nada Belhadj
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Julio Cortijo
- Centro de Investigación en Red Enfermedades Respiratorias CIBERES, Health Institute Carlos III, 28029 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
- Research and Teaching Unit, University General Hospital Consortium, 46014 Valencia, Spain
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37
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Mojiri A, Walther BK, Jiang C, Matrone G, Holgate R, Xu Q, Morales E, Wang G, Gu J, Wang R, Cooke JP. Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice. Eur Heart J 2021; 42:4352-4369. [PMID: 34389865 PMCID: PMC8603239 DOI: 10.1093/eurheartj/ehab547] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/29/2021] [Accepted: 08/12/2021] [Indexed: 12/28/2022] Open
Abstract
AIMS Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing. METHODS AND RESULTS We generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice. CONCLUSION Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases.
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Affiliation(s)
- Anahita Mojiri
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Brandon K Walther
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St., College Station, TX 77840, USA
| | - Chongming Jiang
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Gianfranco Matrone
- British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Rhonda Holgate
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Qiu Xu
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Elisa Morales
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Guangyu Wang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Jianhua Gu
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Rongfu Wang
- Department of Medicine, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - John P Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
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38
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Gagat M, Zielińska W, Mikołajczyk K, Zabrzyński J, Krajewski A, Klimaszewska-Wiśniewska A, Grzanka D, Grzanka A. CRISPR-Based Activation of Endogenous Expression of TPM1 Inhibits Inflammatory Response of Primary Human Coronary Artery Endothelial and Smooth Muscle Cells Induced by Recombinant Human Tumor Necrosis Factor α. Front Cell Dev Biol 2021; 9:668032. [PMID: 34604206 PMCID: PMC8484921 DOI: 10.3389/fcell.2021.668032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 08/25/2021] [Indexed: 12/19/2022] Open
Abstract
Tumor necrosis factor α (TNFα) is one of the most important proinflammatory cytokines, which affects many processes associated with the growth and characteristics of endothelial, smooth muscle, and immune system cells. However, there is no correlation between most in vivo and in vitro studies on its role in endothelial cell proliferation and migration. In this study, we examined the effect of recombinant human (rh) TNFα produced in HEK293 cells on primary human coronary artery endothelial cells (pHCAECs) in the context of F-actin organization and such processes as migration and adhesion. Furthermore, we evaluated the possibility of the inhibition of the endothelial inflammatory response by the CRISPR-based regulation of TPM1 gene expression. We showed that TNFα-induced activation of pHCAECs was related to the reorganization of the actin cytoskeleton into parallel-arranged stress fibers running along the longer axis of pHCAECs. It allowed for the directed and parallel motion of the cells during coordinated migration. This change in F-actin organization promoted strong but discontinuous cell–cell contacts involved in signalization between migrating cells. Moreover, this form of intercellular connections together with locally increased adhesion was related to the formation of migrasomes and further migracytosis. Stabilization of the actin cytoskeleton through the CRISPR-based activation of endogenous expression of TPM1 resulted in the inhibition of the inflammatory response of pHCAECs following treatment with rh TNFα and stabilization of cell–cell junctions through reduced cleavage of vascular endothelial cadherin (VE-cadherin) and maintenance of the stable levels of α- and β-catenins. We also showed that CRISPR-based activation of TPM1 reduced inflammatory activation, proliferation, and migration of primary human coronary artery smooth muscle cells. Therefore, products of the TPM1 gene may be a potential therapeutic target for the treatment of proinflammatory vascular disorders.
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Affiliation(s)
- Maciej Gagat
- Department of Histology and Embryology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Wioletta Zielińska
- Department of Histology and Embryology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Klaudia Mikołajczyk
- Department of Histology and Embryology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Jan Zabrzyński
- Department of Clinical Pathomorphology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland.,Department of General Orthopaedics, Musculoskeletal Oncology and Trauma Surgery, University of Medical Sciences, Poznań, Poland
| | - Adrian Krajewski
- Department of Histology and Embryology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Anna Klimaszewska-Wiśniewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Alina Grzanka
- Department of Histology and Embryology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
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Kraler S, Libby P, Evans PC, Akhmedov A, Schmiady MO, Reinehr M, Camici GG, Lüscher TF. Resilience of the Internal Mammary Artery to Atherogenesis: Shifting From Risk to Resistance to Address Unmet Needs. Arterioscler Thromb Vasc Biol 2021; 41:2237-2251. [PMID: 34107731 PMCID: PMC8299999 DOI: 10.1161/atvbaha.121.316256] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.
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Affiliation(s)
- Simon Kraler
- Center for Molecular Cardiology, University of Zürich, 8952 Schlieren, Switzerland
| | - Peter Libby
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
| | - Paul C. Evans
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
| | - Alexander Akhmedov
- Center for Molecular Cardiology, University of Zürich, 8952 Schlieren, Switzerland
| | - Martin O. Schmiady
- Clinic for Cardiac Surgery, University Heart Centre, University Hospital Zurich, Zurich, Switzerland
| | - Michael Reinehr
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Giovanni G. Camici
- Center for Molecular Cardiology, University of Zürich, 8952 Schlieren, Switzerland
- University Heart Center, Department of Cardiology, University Hospital, Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Thomas F. Lüscher
- Center for Molecular Cardiology, University of Zürich, 8952 Schlieren, Switzerland
- Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom
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40
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Guo G, Watterson S, Zhang SD, Bjourson A, McGilligan V, Peace A, Rai TS. The role of senescence in the pathogenesis of atrial fibrillation: A target process for health improvement and drug development. Ageing Res Rev 2021; 69:101363. [PMID: 34023420 DOI: 10.1016/j.arr.2021.101363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 01/24/2021] [Accepted: 05/12/2021] [Indexed: 12/11/2022]
Abstract
Cellular senescence is a state of growth arrest that occurs after cells encounter various stresses. Senescence contributes to tumour suppression, embryonic development, and wound healing. It impacts on the pathology of various diseases by secreting inflammatory chemokines, immune modulators and other bioactive factors. These secretory biosignatures ultimately cause inflammation, tissue fibrosis, immunosenescence and many ageing-related diseases such as atrial fibrillation (AF). Because the molecular mechanisms underpinning AF development remain unclear, current treatments are suboptimal and have serious side effects. In this review, we summarize recent results describing the role of senescence in AF. We propose that senescence factors induce AF and have a causative role. Hence, targeting senescence and its secretory phenotype may attenuate AF.
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41
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Aberdeen H, Battles K, Taylor A, Garner-Donald J, Davis-Wilson A, Rogers BT, Cavalier C, Williams ED. The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor. J Cardiovasc Dev Dis 2021; 8:58. [PMID: 34067715 PMCID: PMC8156687 DOI: 10.3390/jcdd8050058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/16/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hypoglycemia remain unclear and the subject of much debate. In this review, the molecular basis of the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular lesions and injury are discussed. Further, we review the potential role of the serum response factor (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins.
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Affiliation(s)
- Hazel Aberdeen
- Department of Biomedical Sciences, Baptist Health Sciences University, Memphis, TN 38103, USA; or
| | - Kaela Battles
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
| | - Ariana Taylor
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
| | - Jeranae Garner-Donald
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
| | - Ana Davis-Wilson
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
| | - Bryan T. Rogers
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
| | - Candice Cavalier
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
| | - Emmanuel D. Williams
- Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; (K.B.); (A.T.); (J.G.-D.); (A.D.-W.); (B.T.R.); (C.C.)
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Rojas-Vázquez S, Blasco-Chamarro L, López-Fabuel I, Martínez-Máñez R, Fariñas I. Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline. Front Neurosci 2021; 15:666881. [PMID: 33958987 PMCID: PMC8093510 DOI: 10.3389/fnins.2021.666881] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/25/2021] [Indexed: 01/25/2023] Open
Abstract
The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.
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Affiliation(s)
- Sara Rojas-Vázquez
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València-Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Valencia, Spain.,Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain
| | - Laura Blasco-Chamarro
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain.,Instituto de Biotecnología y Biomedicina (BioTecMed), Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Irene López-Fabuel
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain.,Instituto de Biotecnología y Biomedicina (BioTecMed), Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Ramón Martínez-Máñez
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València-Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Valencia, Spain.,Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, Valencia, Spain.,Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe, Valencia, Spain
| | - Isabel Fariñas
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain.,Instituto de Biotecnología y Biomedicina (BioTecMed), Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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43
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Chanda PK, Sukhovershin R, Cooke JP. mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration. Cells 2021; 10:187. [PMID: 33477787 PMCID: PMC7832270 DOI: 10.3390/cells10010187] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/11/2021] [Accepted: 01/16/2021] [Indexed: 12/13/2022] Open
Abstract
mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target "undruggable" diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration.
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Affiliation(s)
| | | | - John P. Cooke
- RNA Therapeutics Program, Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; (P.K.C.); (R.S.)
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44
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Kim TH, Kim JY, Bae J, Kim YM, Won MH, Ha KS, Kwon YG, Kim YM. Korean Red ginseng prevents endothelial senescence by downregulating the HO-1/NF-κB/miRNA-155-5p/eNOS pathway. J Ginseng Res 2020; 45:344-353. [PMID: 33841015 PMCID: PMC8020293 DOI: 10.1016/j.jgr.2020.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 07/05/2020] [Accepted: 08/10/2020] [Indexed: 11/30/2022] Open
Abstract
Background Korean Red ginseng extract (KRGE) has beneficial effects on the cardiovascular system by improving endothelial cell function. However, its pharmacological effect on endothelial cell senescence has not been clearly elucidated. Therefore, we examined the effect and molecular mechanism of KRGE on the senescence of human umbilical vein endothelial cells (HUVECs). Methods HUVECs were grown in normal or KRGE-supplemented medium. Furthermore, they were transfected with heme oxygenase-1 (HO-1) gene or treated with its inhibitor, a NF-κB inhibitor, and a miR-155-5p mimic or inhibitor. Senescence-associated characteristics of endothelial cells were determined by biochemical and immunohistochemical analyses. Results Treatment of HUVECs with KRGE resulted in delayed onset and progression of senescence-associated characteristics, such as increased lysosomal acidic β-galactosidase and decreased telomerase activity, angiogenic dysfunction, and abnormal cell morphology. KRGE preserved the levels of anti-senescent factors, such as eNOS-derived NO, MnSOD, and cyclins D and A: however, it decreased the levels of senescence-promoting factors, such as ROS, activated NF-κB, endothelial cell inflammation, and p21 expression. The beneficial effects of KRGE were due to the induction of HO-1 and the inhibition of NF-κB-dependent biogenesis of miR-155-5p that led to the downregulation of eNOS. Moreover, treatment with inhibitors of HO-1, NF-κB, and miR-155-5p abolished the anti-senescence effects of KRGE. Conclusion KRGE delayed or prevented HUVEC senescence through a signaling cascade involving the induction of HO-1, the inhibition of NF-κB-dependent miR-155-5p biogenesis, and the maintenance of the eNOS/NO axis activity, suggesting that it may protect against vascular diseases associated with endothelial senescence.
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Affiliation(s)
- Tae-Hoon Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea
| | - Ji-Yoon Kim
- Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul, 04763, South Korea
| | - Jieun Bae
- Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul, 04763, South Korea
| | - Young-Mi Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea
| | - Moo-Ho Won
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea
| | - Kwon-Soo Ha
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea
| | - Young-Guen Kwon
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea
| | - Young-Myeong Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea
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45
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Kim DE, Dollé MET, Vermeij WP, Gyenis A, Vogel K, Hoeijmakers JHJ, Wiley CD, Davalos AR, Hasty P, Desprez P, Campisi J. Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin. Aging Cell 2020; 19:e13072. [PMID: 31737985 PMCID: PMC7059167 DOI: 10.1111/acel.13072] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/07/2019] [Accepted: 10/30/2019] [Indexed: 12/11/2022] Open
Abstract
ERCC1 (excision repair cross complementing‐group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross‐link repair. Ercc1−/Δ mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1−/Δ mice display combined features of human progeroid and cancer‐prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1−/Δ mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1−/Δ mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1−/Δ mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence‐associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor‐suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1‐deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1−/Δ mouse skin, where the apoptotic cells are localized, compared to age‐matched wild‐type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1‐depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health‐ or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.
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Affiliation(s)
- Dong Eun Kim
- Buck Institute for Research on Aging Novato CA USA
| | - Martijn E. T. Dollé
- Centre for Health Protection Research National Institute of Public Health and the Environment (RIVM) Bilthoven The Netherlands
| | - Wilbert P. Vermeij
- Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands
- Princess Máxima Center for Pediatric Oncology ONCODE Institute Utrecht The Netherlands
| | | | | | - Jan H. J. Hoeijmakers
- Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands
- Princess Máxima Center for Pediatric Oncology ONCODE Institute Utrecht The Netherlands
- CECAD Forschungszentrum Köln Germany
| | | | | | - Paul Hasty
- Department of Molecular Medicine Sam and Ann Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center San Antonio TX USA
| | | | - Judith Campisi
- Buck Institute for Research on Aging Novato CA USA
- Lawrence Berkeley National Laboratory Berkeley CA USA
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Mensegue MF, Burgueño AL, Tellechea ML. Perinatal taurine exerts a hypotensive effect in male spontaneously hypertensive rats and down-regulates endothelial oxide nitric synthase in the aortic arch. Clin Exp Pharmacol Physiol 2020; 47:780-789. [PMID: 31958174 DOI: 10.1111/1440-1681.13260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 12/17/2019] [Accepted: 01/13/2020] [Indexed: 12/25/2022]
Abstract
Essential hypertension is considered to be a result of the interaction between genetic and environmental factors, including perinatal factors. Different advantageous perinatal factors proved to have beneficial long-lasting effects against an abnormal genetic background. Taurine is a ubiquitous sulphur-containing amino acid present in foods such as seafood. The antihypertensive effects of taurine have been reported in experimental studies and in human hypertension. We aimed to investigate the effects of perinatal treatment with taurine in spontaneously hypertensive rats (SHR), a known model of genetic hypertension. Female SHR were administered with taurine (3 g/L) during gestation and lactation (SHR-TAU). Untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. Long-lasting effects in offspring were investigated. Addition of taurine to the mother's drinking water reduced blood pressure in adult offspring. No differences were observed in cardiac hypertrophy. Findings on morphometric evaluations suggest that perinatal treatment with taurine would be partially effective in improving structural alterations of the aorta. Modifications in gene expression of Bcl-2 family members and upregulation of endothelial nitric oxide synthase in the aorta of 22-week-old male offspring were found. No differences were observed on relative telomere length in different cardiovascular tissues between SHR and SHR-TAU. Altogether results suggest that taurine programming, albeit sex specific, is associated with gene expression changes which ultimately may lead to improvement of aortic remodelling and enhanced endothelial function because of augmented nitric oxide (NO) production.
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Affiliation(s)
- Melisa F Mensegue
- Institute of Medical Research A. Lanari, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Adriana L Burgueño
- Instituto de Investigaciones Biomédicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Pontificia Universidad Católica Argentina, Ciudad Autónoma de Buenos Aires, Argentina
| | - Mariana L Tellechea
- Institute of Medical Research A. Lanari, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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Hofmann P, Sommer J, Theodorou K, Kirchhof L, Fischer A, Li Y, Perisic L, Hedin U, Maegdefessel L, Dimmeler S, Boon RA. Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling. Cardiovasc Res 2020; 115:230-242. [PMID: 30107531 PMCID: PMC6302267 DOI: 10.1093/cvr/cvy206] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022] Open
Abstract
Aims Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19. Methods and results H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation. Conclusion These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.
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Affiliation(s)
- Patrick Hofmann
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany.,German Center for Cardiovascular Research DZHK, Partner Site Frankfurt Rhine-Main, Berlin, Germany
| | - Janina Sommer
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany
| | - Kosta Theodorou
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany
| | - Luisa Kirchhof
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany
| | - Ariane Fischer
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany
| | - Yuhuang Li
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany.,German Center for Cardiovascular Research DZHK, Partner Site Munich, Berlin, Germany
| | - Ljubica Perisic
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Ulf Hedin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Lars Maegdefessel
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany.,German Center for Cardiovascular Research DZHK, Partner Site Munich, Berlin, Germany.,Department of Medicine, Karolinska Institute, Stockholm, Sweden; and
| | - Stefanie Dimmeler
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany.,German Center for Cardiovascular Research DZHK, Partner Site Frankfurt Rhine-Main, Berlin, Germany
| | - Reinier A Boon
- Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany.,German Center for Cardiovascular Research DZHK, Partner Site Frankfurt Rhine-Main, Berlin, Germany.,Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands
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Fossel M. A unified model of dementias and age-related neurodegeneration. Alzheimers Dement 2020; 16:365-383. [PMID: 31943780 DOI: 10.1002/alz.12012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/09/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022]
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Noncoding RNAs in Vascular Aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7914957. [PMID: 31998442 PMCID: PMC6969641 DOI: 10.1155/2020/7914957] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/20/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023]
Abstract
Increases in age are accompanied by vascular aging, which can lead to a variety of chronic diseases, including atherosclerosis and hypertension. Noncoding RNAs (ncRNAs) have become a research hotspot in different fields of life sciences in recent years. For example, these molecules have been found to have regulatory roles in many physiological and pathological processes. Many studies have shown that microRNAs (miRNAs) and long ncRNAs (lncRNAs) also play a regulatory role in vascular aging. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are important components of blood vessels, and the senescence of both cell types promotes the occurrence of vascular aging. This review provides a contemporary update on the molecular mechanisms underlying the senescence of ECs and VSMCs and the regulatory role of miRNAs and lncRNAs in this process.
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50
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Cheng G, Wang L, Dai M, Wei F, Xu D. Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension. Int J Med Sci 2020; 17:2180-2186. [PMID: 32922179 PMCID: PMC7484671 DOI: 10.7150/ijms.48456] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/27/2020] [Indexed: 12/29/2022] Open
Abstract
Background: The essential hypertension (EH) pathophysiology remains poorly understood. Many studies indicate that reduced leukocyte telomere length (LTL) is involved in the EH pathogenesis, however, the direct analysis of arterial telomere length (ATL) from EH patients and normotensive individuals did not show a difference. To address these discrepant observations between LTL and ATL, we performed comprehensive analyses of LTL, telomerase gene expression and their genetic variants in healthy normotensive controls and EH patients. Methods: Sex-matched 206 EH patients and equal numbers of healthy controls were recruited. LTL, and the expression of two key telomerase components, telomerase reverse transcriptase (TERT) and internal RNA template (TERC) were determined using qPCR. Genetic variants of rs2736100 at the TERT and rs12696304 at the TERC loci were determined using TaqMan genotyping kits. Results: LTL was significantly shorter in EH patients than in their normotensive controls (0.96 ± 0.52 vs 1.19 ± 0.58, P = 0.001). Moreover, TERT and TERC expression in patients' leukocytes were substantially lower compare to that in healthy controls (TERT, 0.98 ± 0.98 vs 1.76 ± 1.75, P = 0.003; TERC, 1.26 ± 1.62 vs 4.69 ± 3.61, P < 0.001). However, there were no differences in the genetic variants of rs2736100 and rs12696304 between patient and control groups. Conclusions: EH patients have significantly shorter LTL, which may result from defective TERT and TERC expression in leukocytes. Collectively, lower telomerase expression contributes to shorter LTL observed in EH patients, and telomerase activators may be considered for EH therapy.
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Affiliation(s)
- Guanghui Cheng
- Central Research Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, PR China
| | - Lina Wang
- Central Research Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, PR China
| | - Mingkai Dai
- Central Research Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, PR China
| | - Fengtao Wei
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, PR China
| | - Dawei Xu
- Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, SE-171 76 Solna, Sweden
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