Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Circ Res. 2015 Jul 31;117(4):333-45. doi: 10.1161/CIRCRESAHA.117.305875. Epub 2015 Jun 1.

Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.

Author information

1
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.).
2
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.

Abstract

RATIONALE:

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.

METHODS AND 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.

KEYWORDS:

aging; endothelial function; endothelial nitric oxide synthase; endothelial progenitor cell; longevity; vascular reactivity

PMID:
26034043
PMCID:
PMC5496930
DOI:
10.1161/CIRCRESAHA.117.305875
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center