title: Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.
abstract: BACKGROUND
  Long 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.
  
  
  OBJECTIVE
  Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.
authors.affiliation: From 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.).
authors.forename: Francesco
authors.initials: F
authors.lastname: Villa
authors.affiliation: From 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.).
authors.forename: Albino
authors.initials: A
authors.lastname: Carrizzo
authors.affiliation: From 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.).
authors.forename: Chiara C
authors.initials: CC
authors.lastname: Spinelli
authors.affiliation: From 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.).
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrario
authors.affiliation: From 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.).
authors.forename: Alberto
authors.initials: A
authors.lastname: Malovini
authors.affiliation: From 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.).
authors.forename: Anna
authors.initials: A
authors.lastname: Maciąg
authors.affiliation: From 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.).
authors.forename: Antonio
authors.initials: A
authors.lastname: Damato
authors.affiliation: From 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.).
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.affiliation: From 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.).
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.affiliation: From 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.).
authors.forename: Elena
authors.initials: E
authors.lastname: Sangalli
authors.affiliation: From 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.).
authors.forename: Zexu
authors.initials: Z
authors.lastname: Dang
authors.affiliation: From 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.).
authors.forename: Michele
authors.initials: M
authors.lastname: Madonna
authors.affiliation: From 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.).
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Ambrosio
authors.affiliation: From 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.).
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Sitia
authors.affiliation: From 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.).
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.affiliation: From 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.).
authors.forename: Gaetano
authors.initials: G
authors.lastname: Calì
authors.affiliation: From 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.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: From 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.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Perls
authors.affiliation: From 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.).
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.affiliation: From 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.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Mulas
authors.affiliation: From 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.).
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.affiliation: From 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.).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bellazzi
authors.affiliation: From 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.).
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
authors.affiliation: From 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.).
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.affiliation: From 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.
authors.forename: Annibale A
authors.initials: AA
authors.lastname: Puca
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001794:Blood Pressure; D002465:Cell Movement; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D005060:Europe; D005260:Female; D056726:Genetic Association Studies; D015316:Genetic Therapy; D005838:Genotype; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D008136:Longevity / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D011918:Rats, Inbred SHR; D015398:Signal Transduction; D013314:Stress, Mechanical; D014162:Transfection; D014481:United States; D014664:Vasodilation; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D018841:HSP90 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D052250:Nitric Oxide Synthase Type III; D010750:Phosphoproteins; D019892:eIF-2 Kinase; C000602462:BPIFB4 protein, human; C496314:NOS3 protein, human; C496316:Nos3 protein, rat
keywords: aging; endothelial function; endothelial nitric oxide synthase; endothelial progenitor cell; longevity; vascular reactivity