ArticleCirculation research2015
Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.
Open access · bronzeAbstract readMulticenter Study
In one paragraph
Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed
3.9field-weighted citation impact, top 6% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
55 citing papers in PubMed, 88 citations in OpenAlex.
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Corrections and comments
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Authors and funding
25 authors at 3 institutions in 2 countries.
Francesco VillaFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Albino CarrizzoFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Chiara C SpinelliFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Anna FerrarioFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Alberto MaloviniFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Anna MaciągFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Antonio DamatoFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Alberto AuricchioFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Gaia SpinettiFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Elena SangalliFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Zexu DangFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Michele MadonnaFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Mariateresa AmbrosioFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Leopoldo SitiaFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Paolo BiginiFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Gaetano CalìFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Stefan SchreiberFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Thomas PerlsFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Sergio FucileFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Francesca MulasFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Almut NebelFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Riccardo BellazziFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Paolo MadedduFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Carmine VecchioneFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.).
Annibale A PucaFrom the National Research Council, Institute for Biomedical Technologies, Segrate (MI), Italy (F.V., C.C.S., A.F.); IRCCS Neuromed, Department of Vascular Physiopathology, Pozzilli (IS), Italy (A.C., A.D., M.M., M.A., S.F., C.V.); Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy (A. Malovini, F.M., R.B.); IRCCS Multimedica, Cardiovascular Department, Milan, Italy (A. Maciąg, G.S., E.S., A.A.P.); Department of Translational Medicine, "Federico II" University, Naples, Italy (A.A.); TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy (A.A.); Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (Z.D., P.M.); Department of Biochemistry and Molecular Pharmacology IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (L.S., P.B.); National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy (G.C.); Institute of Clinical Molecular Biology, Christian-Albrechts University and the Schleswig-Holstein University Hospital, Kiel, Germany (S.S., A.N.); Geriatrics Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA (T.P.); Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, Rome, Italy (S.F.); and Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, 84081 Baronissi (SA), Italy (C.V., A.A.P.). apuca@unisa.it cvecchione@unisa.it.
Kiel University · DEMario Negri Institute for Pharmacological Research · ITConsorzio Roma Ricerche · IT
Funding
Systems BiologyU19AG023122 · NIA · TRANSLATIONAL GENOMICS RESEARCH INST · PI Thomas Girke, NICHOLAS Joseph SCHORK · 2004 to 2026
$102.6MMedical Research Council MR/J002593/1NIA NIH HHS U19 AG023122
Abstract
rationaleLong living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury.
objectiveExploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease. METHODS AND
resultsWe show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34(+) cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle.
conclusionsLongevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.
Indexed as
Neovascularization, Physiologic14-3-3 ProteinsAgedAged, 80 and overAge FactorsAnimalsBlood PressureCell MovementDisease Models, AnimaleIF-2 KinaseEndothelial Progenitor CellsEuropeFemaleGenetic Association StudiesGenetic TherapyGenotype14-3-3 ProteinsBPIFB4 protein, humaneIF-2 KinaseHSP90 Heat-Shock ProteinsIntercellular Signaling Peptides and ProteinsNitric Oxide Synthase Type IIINOS3 protein, humanNos3 protein, ratPhosphoproteinsagingendothelial functionendothelial nitric oxide synthaseendothelial progenitor celllongevityvascular reactivity
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