{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:38:43Z","timestamp":1788338323821,"version":"build-2803163510"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,2,15]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProT\u03b1 (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProT\u03b1. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and\n                      <jats:italic>Streptococcus<\/jats:italic>\n                      <jats:italic>pyogenes<\/jats:italic>\n                      proteomes were used to identify mimic epitopes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProT\u03b1 common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProT\u03b1 plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProT\u03b1 colocalized with CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in RHVD. Expression of ProT\u03b1 and estrogen receptor alpha correlated strongly in circulating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from patients with RHVD. Recombinant ProT\u03b1 induced expression of the lytic proteins perforin and granzyme B by CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProT\u03b1 increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProT\u03b1. In silico analysis of RHVD and\n                      <jats:italic>S<\/jats:italic>\n                      <jats:italic>pyogenes<\/jats:italic>\n                      proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell activation in vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      ProT\u03b1-dependent CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProT\u03b1 as a potential regulator of sex predisposition in RHVD. ProT\u03b1 facilitated recognition of type 1 collagen mimic epitopes by CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, suggesting mechanisms provoking autoimmunity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.121.057301","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T14:00:58Z","timestamp":1644847258000},"page":"531-548","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Prothymosin Alpha: A Novel Contributor to Estradiol Receptor Alpha\u2013Mediated CD8\n                    <sup>+<\/sup>\n                    T-Cell Pathogenic Responses and Recognition of Type 1 Collagen in Rheumatic Heart Valve Disease"],"prefix":"10.1161","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5725-5691","authenticated-orcid":true,"given":"Livia S.A.","family":"Passos","sequence":"first","affiliation":[{"name":"Center for Excellence in Vascular Biology (L.S.A.P., P.K.J., D.B.-G., D.R., A.L., G.K.S., P.L., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhash K.","family":"Jha","sequence":"additional","affiliation":[{"name":"Center for Excellence in Vascular Biology (L.S.A.P., P.K.J., D.B.-G., D.R., A.L., G.K.S., P.L., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakota","family":"Becker-Greene","sequence":"additional","affiliation":[{"name":"Center for Excellence in Vascular Biology (L.S.A.P., P.K.J., D.B.-G., D.R., A.L., G.K.S., P.L., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3923-9786","authenticated-orcid":true,"given":"Mark C.","family":"Blaser","sequence":"additional","affiliation":[{"name":"Center for Interdisciplinary Cardiovascular Sciences (M.C.B., S.A.S., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayanna","family":"Romero","sequence":"additional","affiliation":[{"name":"Center for Excellence in Vascular Biology (L.S.A.P., P.K.J., D.B.-G., D.R., A.L., G.K.S., P.L., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9245-0169","authenticated-orcid":true,"given":"Adrien","family":"Lupieri","sequence":"additional","affiliation":[{"name":"Center for Excellence in Vascular Biology (L.S.A.P., P.K.J., D.B.-G., D.R., A.L., G.K.S., P.L., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1421-9455","authenticated-orcid":true,"given":"Galina K.","family":"Sukhova","sequence":"additional","affiliation":[{"name":"Center for Excellence in Vascular Biology (L.S.A.P., P.K.J., D.B.-G., D.R., A.L., G.K.S., P.L., M.A., E.A.), Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, 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