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Published on: December 9, 2022
Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.
Francesco Villa1, Albino Carrizzo1, Chiara C Spinelli1
1From 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.).
A specific variant of bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) is linked to exceptional longevity. This variant improves cardiovascular health and promotes tissue repair, offering potential therapeutic benefits.
Area of Science:
- Cardiovascular Biology
- Genetics of Aging
- Molecular Medicine
Background:
- Aging is associated with cardiovascular homeostasis loss, reduced endothelial nitric oxide synthase activity, and impaired tissue repair.
- Long-living individuals often exhibit delayed aging processes, suggesting underlying genetic and molecular mechanisms.
Purpose of the Study:
- To identify master molecular regulators of physiological aging through genetic analysis of long-living individuals.
- To discover novel therapeutic targets for cardiovascular disease treatment.
Main Methods:
- Genetic analysis of three independent populations to identify longevity-associated genetic variants.
- Investigated the role of bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) in cellular and vascular homeostasis.
- Utilized gene transfer in hypertensive rats and old mice, and studied BPIFB4 function in endothelial progenitor cells and a murine ischemia model.
Main Results:
- A specific variant (rs2070325, Ile229Val) in BPIFB4 was associated with exceptional longevity across populations.
- BPIFB4 regulates protein synthesis, maintains vascular homeostasis, and is crucial for endothelium-dependent vasorelaxation.
- Gene transfer of the longevity-associated BPIFB4 variant restored endothelial function, reduced blood pressure, and promoted vascular repair in animal models.
- BPIFB4 expression in CD34+ cells is linked to longevity and is essential for endothelial progenitor cell migration and vascular repair after ischemia.
Conclusions:
- The longevity-associated BPIFB4 variant demonstrates potential as a therapeutic agent.
- BPIFB4 may serve as a novel therapeutic tool to combat endothelial dysfunction and enhance vascular repair processes.
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