{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:20Z","timestamp":1790189960222,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Clonal hematopoiesis driven by somatic mutations is an emerging cardiovascular risk factor, and the DNA damage response gene\n                      <jats:italic toggle=\"yes\">PPM1D<\/jats:italic>\n                      is among the most frequently mutated genes. Mutations in\n                      <jats:italic toggle=\"yes\">PPM1D<\/jats:italic>\n                      are enriched in cancer patients and survivors, where cytotoxic therapies promote the expansion of mutant clones, a condition termed therapy-related clonal hematopoiesis. Although\n                      <jats:italic toggle=\"yes\">PPM1D<\/jats:italic>\n                      -mutant clonal hematopoiesis has been associated with increased risk and poorer prognosis of atherosclerotic cardiovascular disease in humans, it remains unclear whether these mutations, or their expansion under cytotoxic stress, causally contribute to atherosclerosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We modeled\n                      <jats:italic toggle=\"yes\">PPM1D<\/jats:italic>\n                      -mutant clonal hematopoiesis in\n                      <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice through bone marrow transplantation strategies. Conventional transplantation approaches were used to generate mice with complete or partial hematopoietic reconstitution by cells carrying monoallelic or biallelic gain-of-function\n                      <jats:italic toggle=\"yes\">Ppm1d<\/jats:italic>\n                      <jats:sup>R451X<\/jats:sup>\n                      mutations. To mimic therapy-related clonal hematopoiesis, we used a nonconditioned adoptive transfer model in which a small fraction of mutant hematopoietic cells was introduced into recipients, followed by fractionated low-dose \u03b3-radiation to promote clonal expansion. All mice were fed a Western diet to induce atherosclerosis. Clonal dynamics, plaque size and characteristics, and macrophage functions were evaluated using flow cytometry, histopathology, and in vitro assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Ppm1d<\/jats:italic>\n                      -mutant cells expanded in blood and bone marrow after low-dose radiation, but not in nonirradiated mice. Across all transplantation strategies,\n                      <jats:italic toggle=\"yes\">Ppm1d<\/jats:italic>\n                      mutations did not affect plasma cholesterol, atherosclerotic plaque size, or composition. In vitro, mutant macrophages showed no alterations in proliferation, cytokine expression, or cholesterol handling, although apoptosis in response to genotoxic stress was modestly reduced (\u224820%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Ppm1d<\/jats:italic>\n                      -mutant hematopoietic cells expand predominantly under genotoxic stress and do not promote atherosclerosis in mice under the conditions tested. These findings raise the possibility that the association of\n                      <jats:italic toggle=\"yes\">PPM1D<\/jats:italic>\n                      mutations with atherosclerotic cardiovascular disease may, at least in part, reflect exposure to DNA damage response\u2013activating stressors that independently promote clonal expansion and atherosclerosis, rather than direct causality.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323734","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T09:00:29Z","timestamp":1779958829000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["No Effect of\n                    <i>Ppm1d<\/i>\n                    -Mutant Clonal Hematopoiesis on Atherosclerosis Development in Mice"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0025-0731","authenticated-orcid":true,"given":"Marta","family":"Amor\u00f3s-P\u00e9rez","sequence":"first","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid. Spain (M.A.-P., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda A.","family":"Zuriaga","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Zorita","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz L.","family":"Ramos-Neble","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Matesanz","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2030-6308","authenticated-orcid":true,"given":"Clara","family":"Pl\u00f6tner","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."},{"name":"Now with Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Germany (C.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Di Carli","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9481-5946","authenticated-orcid":true,"given":"Eline L.C.","family":"Mol","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."},{"name":"Now with Department of Anatomy &amp; Embryology and Cardiology, Leiden University Medical Center (LUMC), the Netherlands (E.L.C.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Moro","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Cuevas","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0125-7209","authenticated-orcid":true,"given":"Vicente","family":"Andr\u00e9s","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid. Spain (M.A.-P., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5970-629X","authenticated-orcid":true,"given":"Jos\u00e9 J.","family":"Fuster","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.A.-P., M.A.Z., V.Z., B.L.R.-N., N.M., C.P., M.D.C., E.L.C.M., R.M., D.C., V.A., J.J.F.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid. Spain (M.A.-P., V.A., J.J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-025-01148-9"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.122.318181"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-021-00015-3"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2020.02.008"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03213-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00206-6"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2023.5095"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.062126"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag1381"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00326-7"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-024-00579-w"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03341-5"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf602"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.12.6048"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.2741\/3999"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.07.010"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.10.004"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2819-2"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701719"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-850339"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00710-0"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023020331"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02296-x"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2025028417"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024025023"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108326"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.124.322893"},{"key":"e_1_3_3_31_2","first-page":"11","article-title":"Principles of bone marrow transplantation (BMT): providing optimal veterinary and husbandry care to irradiated mice in BMT studies.","volume":"48","author":"Duran-Struuck R","year":"2009","unstructured":"Duran-Struuck R, Dysko RC. Principles of bone marrow transplantation (BMT): providing optimal veterinary and husbandry care to irradiated mice in BMT studies. J Am Assoc Lab Anim Sci. 2009;48:11\u201322.","journal-title":"J Am Assoc Lab Anim Sci"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-700336"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.12.001"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.120.003003"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319314"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)37148-0"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1357-2725(98)00123-x"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2021.108854"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae546"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.218966"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvac080"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000251281.00845.18"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-023-01082-6"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.06.001"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112317108"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2010.03.002"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2008.11.006"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.003"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.125.323734","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:00:45Z","timestamp":1790186445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.125.323734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1161\/ATVBAHA.125.323734"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.125.323734","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"2025-09-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}