ArticleThe Journal of clinical investigation2021
Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.
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Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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52citing papers in PubMed, 1 pooled it
4.5field-weighted citation impact, top 4% of its field
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.
- Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.Science translational medicine · 2024Pooled it
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- Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.Nature communications · 2026Article
- Molecular biology of vascular bioenergetics rewiring: Mitochondrial protective mechanisms of Piper retrofractum in hypertension and oxidative injury.Molecular biology reports · 2026Review
- The right time, the right cell: the potential for precision senotherapy in pulmonary arterial hypertension.American journal of physiology. Lung cellular and molecular physiology · 2026Review
- Pulmonary Vascular Signaling in Pulmonary Hypertension: Potential Role of Endothelial CaArteriosclerosis, thrombosis, and vascular biology · 2026Review
- Advances in the pathogenesis and clinical management of pulmonary hypertension.Medical review (2021) · 2026Review
- Mitochondrial dysfunction in endothelial senescence: implications for vascular remodeling and therapeutic strategies.Archives of pharmacal research · 2026Review
- Astrocytic frataxin deficiency drives neurocognitive impairment in sickle cell mice.PNAS nexus · 2026Article
- NARFL Knockout Triggers Ferroptosis-Driven Vascular Endothelial Dysfunction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Endothelial ADAR1 Deficit Induces the NOCT-IRF7 Axis in Pulmonary Hypertension.Circulation research · 2026Article
- Aging and lung diseases: Unraveling mechanisms and therapeutic targets.Chinese medical journal pulmonary and critical care medicine · 2025Review
- Cellular senescence in adult pulmonary hypertension: current state and future challenges.European respiratory review : an official journal of the European Respiratory Society · 2025Review
- New Horizons in Myotonic Dystrophy Type 1: Cellular Senescence as a Therapeutic Target.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.Science (New York, N.Y.) · 2025Article
- Mechanisms of cellular senescence-induced vascular aging: evidence of senotherapeutic strategies.The journal of cardiovascular aging · 2025Article
- Cellular senescence in age-related cardiovascular disease: past and future.Frontiers in aging · 2025Review
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Authors and funding
31 authors at 15 institutions in 3 countries.
Miranda K CulleyCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Jingsi ZhaoCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Yi Yin TaiCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Ying TangCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Dror PerkCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Vinny NegiCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Qiujun YuCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Chen-Shan C WoodcockCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Adam HandenCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Gil SpeyerResearch Computing, Arizona State University, Tempe, Arizona, USA.
Seungchan KimCenter for Computational Systems Biology, Department of Electrical and Computer Engineering, College of Engineering, Prairie View A&M University, Prairie View, Texas, USA.
Yen-Chun LaiDivision of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Taijyu SatohCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Annie Mm WatsonCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Yassmin Al AarajCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
John SembratCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Mauricio RojasDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA.
Dmitry GoncharovLung Center, Pulmonary Vascular Disease Program, Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis School of Medicine, Davis, California, USA.
Elena A GoncharovaLung Center, Pulmonary Vascular Disease Program, Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis School of Medicine, Davis, California, USA.
Omar F KhanInstitute of Biomedical Engineering, Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Daniel G AndersonDepartment of Chemical Engineering, Institute of Medical Engineering and Science, Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
James E DahlmanWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.
Aditi U GurkarAging Institute, Division of Geriatric Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, GRECC VA, Pittsburgh, Pennsylvania, USA.
Robert LafyatisCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Ahmed U FayyazDepartment of Cardiovascular Medicine and.
Margaret M RedfieldDepartment of Cardiovascular Medicine and.
Mark T GladwinCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Marlene RabinovitchDepartment of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
Mingxia GuPerinatal 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, Ohio, USA.
Thomas BerteroUniversité Côte d'Azur, CNRS, UMR7275, IPMC, Valbonne, France.
Stephen Y ChanCenter for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood Vascular Medicine Institute, Divisions of Cardiology, Pulmonary, Allergy, and Critical Care Medicine and Rheumatology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
University of Pittsburgh · USUniversity of California, Davis · USArizona State University · USCentre National de la Recherche Scientifique · FRCincinnati Children's Hospital Medical Center · USGeorgia Institute of Technology · USHarvard–MIT Division of Health Sciences and Technology · USIndiana University School of MedicineMayo Clinic · USPrairie View A&M University · USStanford University · USThe Ohio State University · USUniversity of Iowa · USUniversity of Pittsburgh Medical Center · USUniversity of Toronto · CA
Funding
VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Jacqueline A. Lees · 1985 to 2026
$93.9MTranslational Pulmonary Vascular BiologyT32HL110849 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Sruti Shiva · 2012 to 2026
$5.0MDefining the Complex Biology of the miR-130/301 Family in Pulmonary HypertensionR01HL124021 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y · 2014 to 2025
$4.9MIron-Sulfur Deficiency as a Critical Pathogenic Cause of Pulmonary HypertensionR01HL122596 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y · 2015 to 2024
$4.5MHIPPO Signaling in Pulmonary Arterial HypertensionR01HL130261 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2016 to 2023
$3.5MTSC2 Signaling in Pulmonary Arterial HypertensionR01HL113178 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2012 to 2021
$3.1MGATA-6 in pulmonary arterial hypertensionR01HL150638 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI GONCHAROVA, ELENA, TROJANOWSKA, MARIA · 2020 to 2023
$2.6MMolecular Drivers of Vascular Stiffness and Metabolic Dysfunction in HIV-Induced Pulmonary Arterial HypertensionR01HL138437 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y, NORRIS, KAREN A · 2017 to 2020
$2.4MMapping Age-Related Changes in the LungU01HL145550 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BENOS, PANAGIOTIS V, FINKEL, TOREN · 2019 to 2022
$2.4MModulators of DNA damage associated nucleo-mitochondrial communication in agingR00AG049126 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GURKAR, ADITI U · 2017 to 2019
$835kUncovering compensatory mechanisms in family members with disease causing mutations of pulmonary hypertensionR00HL135258 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI GU, MINGXIA · 2020 to 2022
$747kComputational repurposing of chemotherapies for pulmonary hypertensionUH2TR002073 · NCATS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y · 2017 to 2018
$615kNCATS NIH HHS UH2 TR002073NCATS NIH HHS UH3 TR002073NCI NIH HHS P30 CA014051NHLBI NIH HHS F30 HL139017NHLBI NIH HHS K99 HL135258NHLBI NIH HHS R00 HL135258NHLBI NIH HHS R01 HL113178NHLBI NIH HHS R01 HL122596NHLBI NIH HHS R01 HL124021NHLBI NIH HHS R01 HL130261NHLBI NIH HHS R01 HL138437NHLBI NIH HHS R01 HL150638NHLBI NIH HHS T32 HL110849NHLBI NIH HHS U01 HL145550NIA NIH HHS R00 AG049126NIH HHS S10 OD023684
Abstract
The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S-containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell-derived endothelial cells from Friedreich's ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency-dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.
Indexed as
Friedreich AtaxiaHypertension, PulmonaryAnimalsCellular SenescenceEndothelial Progenitor CellsEndothelium, VascularFemaleFrataxinHumansIron-Binding ProteinsMaleMiceMice, KnockoutVascular RemodelingFrataxinIron-Binding ProteinsCardiovascular diseaseEndothelial cellsHypertensionPulmonologyVascular Biology
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