{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:09:25Z","timestamp":1792843765952,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,2,21]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We investigated senescence (p16, p21) and DNA damage (\u03b3-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16\n              <jats:sup>LUC\/+<\/jats:sup>\n              ) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter\u2013driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16\n              <jats:sup>LUC\/LUC<\/jats:sup>\n              mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT\n              <jats:sup>+<\/jats:sup>\n              ), and rats given monocrotaline.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and \u03b3-H2AX protein levels, with abundant vascular cells costained for p16, \u03b3-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16\n              <jats:sup>LUC\/+<\/jats:sup>\n              mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen\u2013stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16\n              <jats:sup>LUC\/LUC<\/jats:sup>\n              mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT\n              <jats:sup>+<\/jats:sup>\n              mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.122.058794","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T10:00:28Z","timestamp":1671012028000},"page":"650-666","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":147,"title":["Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression"],"prefix":"10.1161","volume":"147","author":[{"given":"Emmanuelle","family":"Born","sequence":"first","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7998-8378","authenticated-orcid":true,"given":"Larissa","family":"Lipskaia","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Breau","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Houssaini","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0258-747X","authenticated-orcid":true,"given":"Delphine","family":"Beaulieu","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid)."},{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon, UMR INSERM U1052\/CNRS 5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, France (D.B., J.-M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Marcos","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. 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Adnot, S. Abid)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry V.","family":"Bulavin","sequence":"additional","affiliation":[{"name":"Institute for Research on Cancer and Aging, Nice (IRCAN), France (D.V.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-9809","authenticated-orcid":true,"given":"Marion","family":"Delcroix","sequence":"additional","affiliation":[{"name":"Clinical Department of Respiratory Diseases, University Hospitals and Laboratory of Respiratory Diseases &amp; Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven-University of Leuven, Belgium (M.D., R.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8293-6261","authenticated-orcid":true,"given":"Rozenn","family":"Quarck","sequence":"additional","affiliation":[{"name":"Clinical Department of Respiratory Diseases, University Hospitals and Laboratory of Respiratory Diseases &amp; Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven-University of Leuven, Belgium (M.D., R.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virinder","family":"Reen","sequence":"additional","affiliation":[{"name":"MRC London Institute of Medical Sciences (LMS), United Kingdom (V.R., J.G.)."},{"name":"Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, United Kingdom (V.R., J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-6260","authenticated-orcid":true,"given":"Jesus","family":"Gil","sequence":"additional","affiliation":[{"name":"MRC London Institute of Medical Sciences (LMS), United Kingdom (V.R., J.G.)."},{"name":"Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, United Kingdom (V.R., J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-2074","authenticated-orcid":true,"given":"David","family":"Bernard","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon, UMR INSERM U1052\/CNRS 5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, France (D.B., J.-M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Flaman","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon, UMR INSERM U1052\/CNRS 5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, France (D.B., J.-M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5666-3063","authenticated-orcid":true,"given":"Serge","family":"Adnot","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid)."},{"name":"Institute for Lung Health, Justus Liebig University, Giessen, Germany (S. Adnot)."},{"name":"Medical Research Center, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan (S. Abid)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shariq","family":"Abid","sequence":"additional","affiliation":[{"name":"INSERM U955 and D\u00e9partement de Physiologie, H\u00f4pital Henri Mondor, FHU SENEC, AP-HP, Cr\u00e9teil, France; Universit\u00e9 Paris-Est Cr\u00e9teil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. 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