Prothymosin Alpha: A Novel Contributor to Estradiol Receptor Alpha–Mediated CD8+ T-Cell Pathogenic Responses and Recognition of Type 1 Collagen in Rheumatic Heart Valve Disease
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. Proteomics analysis of human h...
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| Published in: | Circulation (New York, N.Y.) Vol. 145; no. 7; pp. 531 - 548 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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Lippincott Williams & Wilkins
15-02-2022
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| Abstract | 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.
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 ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. 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
proteomes were used to identify mimic epitopes.
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 ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8
T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8
T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8
T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8
T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and
proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8
T-cell activation in vitro.
ProTα-dependent CD8
T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8
T cells, suggesting mechanisms provoking autoimmunity. |
|---|---|
| AbstractList | 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.
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 ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. 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
proteomes were used to identify mimic epitopes.
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 ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8
T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8
T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8
T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8
T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and
proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8
T-cell activation in vitro.
ProTα-dependent CD8
T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8
T cells, suggesting mechanisms provoking autoimmunity. BACKGROUNDRheumatic 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. METHODSProteomics 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 ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. 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 Streptococcuspyogenes proteomes were used to identify mimic epitopes. RESULTSA 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 ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8+ T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8+ T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8+ T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8+ T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and Spyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8+ T-cell activation in vitro. CONCLUSIONSProTα-dependent CD8+ T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8+ T cells, suggesting mechanisms provoking autoimmunity. |
| Author | Becker-Greene, Dakota Singh, Sasha A. Jha, Prabhash K. Blaser, Mark C. Dutra, Walderez O. Nunes, Maria C.P. Aikawa, Elena Levine, Robert A. Sukhova, Galina K. Libby, Peter Passos, Livia S.A. Romero, Dayanna Lupieri, Adrien Aikawa, Masanori |
| AuthorAffiliation | 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’s Hospital, Harvard Medical School, Boston, MA 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’s Hospital, Harvard Medical School, Boston, MA Departamento de Morfologia, Instituto de Ciências Biológicas (W.O.D.), Federal University of Minas Gerais, Belo Horizonte, Brazil Hospital das Clinicas, School of Medicine (M.C.P.N.), Federal University of Minas Gerais, Belo Horizonte, Brazil Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston (R.A.L.) |
| AuthorAffiliation_xml | – name: Hospital das Clinicas, School of Medicine (M.C.P.N.), Federal University of Minas Gerais, Belo Horizonte, Brazil – name: Departamento de Morfologia, Instituto de Ciências Biológicas (W.O.D.), Federal University of Minas Gerais, Belo Horizonte, Brazil – 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’s Hospital, Harvard Medical School, Boston, MA – name: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston (R.A.L.) – 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’s Hospital, Harvard Medical School, Boston, MA – name: 2 Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA – name: 3 Departamento de Morfologia, Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil – name: 1 Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA – name: 4 Department of Human Pathology, Sechenov First Moscow State Medical University, Moscow 119992, Russia – name: 5 Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA – name: 6 Hospital das Clinicas, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil |
| Author_xml | – sequence: 1 givenname: Livia S.A. surname: Passos fullname: Passos, Livia S.A. organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 2 givenname: Prabhash K. surname: Jha fullname: Jha, Prabhash K. organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 3 givenname: Dakota surname: Becker-Greene fullname: Becker-Greene, Dakota organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 4 givenname: Mark C. surname: Blaser fullname: Blaser, Mark C. organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 5 givenname: Dayanna surname: Romero fullname: Romero, Dayanna organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 6 givenname: Adrien surname: Lupieri fullname: Lupieri, Adrien organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 7 givenname: Galina K. surname: Sukhova fullname: Sukhova, Galina K. organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 8 givenname: Peter surname: Libby fullname: Libby, Peter organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 9 givenname: Sasha A. surname: Singh fullname: Singh, Sasha A. organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 10 givenname: Walderez O. surname: Dutra fullname: Dutra, Walderez O. organization: Departamento de Morfologia, Instituto de Ciências Biológicas (W.O.D.), Federal University of Minas Gerais, Belo Horizonte, Brazil – sequence: 11 givenname: Masanori surname: Aikawa fullname: Aikawa, Masanori organization: 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’s Hospital, Harvard Medical School, Boston, MA – sequence: 12 givenname: Robert A. surname: Levine fullname: Levine, Robert A. organization: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston (R.A.L.) – sequence: 13 givenname: Maria C.P. surname: Nunes fullname: Nunes, Maria C.P. organization: Hospital das Clinicas, School of Medicine (M.C.P.N.), Federal University of Minas Gerais, Belo Horizonte, Brazil – sequence: 14 givenname: Elena surname: Aikawa fullname: Aikawa, Elena organization: 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’s Hospital, Harvard Medical School, Boston, MA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35157519$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: Conceptualization, L.S.A.P., and E.A.; Methodology, L.S.A.P., S.A.S., M.C.B., P.K.J., G.S., W.D., M.C.N., M.A. and E.A.; Investigation, L.S.A.P., P.K.J., D.R., A.L., D.B.G. and M.B.; Writing – Original Draft, L.S.A.P; Writing – Review and Editing, E.A., M.A., P.L., S.A.S., R.A.L., M.C.P, W.O.D. and M.C.B.; Funding, E.A. and R.A.L. |
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| Snippet | Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The... BACKGROUNDRheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women.... |
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| SubjectTerms | Amino Acid Sequence CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Collagen Type I - chemistry Collagen Type I - metabolism Computational Biology - methods Disease Susceptibility Epitopes, T-Lymphocyte - immunology Estrogen Receptor alpha - metabolism Heart Valve Diseases - diagnosis Heart Valve Diseases - etiology Heart Valve Diseases - metabolism Histocompatibility Antigens Class I - chemistry Histocompatibility Antigens Class I - genetics Histocompatibility Antigens Class I - immunology Humans Leukocytes, Mononuclear - immunology Leukocytes, Mononuclear - metabolism Models, Biological Models, Molecular Protein Binding Protein Precursors - chemistry Protein Precursors - genetics Protein Precursors - metabolism Proteome Proteomics - methods Rheumatic Heart Disease - diagnosis Rheumatic Heart Disease - etiology Rheumatic Heart Disease - metabolism Structure-Activity Relationship Thymosin - analogs & derivatives Thymosin - chemistry Thymosin - genetics Thymosin - metabolism |
| Title | Prothymosin Alpha: A Novel Contributor to Estradiol Receptor Alpha–Mediated CD8+ T-Cell Pathogenic Responses and Recognition of Type 1 Collagen in Rheumatic Heart Valve Disease |
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