{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:20:13Z","timestamp":1782433213501,"version":"3.54.5"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"26","license":[{"start":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T00:00:00Z","timestamp":1562716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002803","name":"Cariplo Foundation","doi-asserted-by":"publisher","award":["n.2016-0874"],"award-info":[{"award-number":["n.2016-0874"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Cariplo Foundation","doi-asserted-by":"publisher","award":["PRIN-20157ATSLF_009"],"award-info":[{"award-number":["PRIN-20157ATSLF_009"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","award":["RF-2016-02364864"],"award-info":[{"award-number":["RF-2016-02364864"]}],"id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"publisher","award":["FUV 2017cod.1072"],"award-info":[{"award-number":["FUV 2017cod.1072"]}],"id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"publisher","award":["FUV 2018cod.2153"],"award-info":[{"award-number":["FUV 2018cod.2153"]}],"id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"publisher","award":["FUV 2019cod.2198"],"award-info":[{"award-number":["FUV 2019cod.2198"]}],"id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>ApoE knockout mice (ApoE\u2212\/\u2212) fed a high-fat diet were randomly allocated to receive LAV-BPIFB4, wild-type (WT)-BPIFB4, or empty vector via adeno-associated viral vector injection. The primary endpoints of the study were to assess (i) vascular reactivity and (ii) atherosclerotic disease severity, by Echo-Doppler imaging, histology and ultrastructural analysis. Moreover, we assessed the capacity of the LAV-BPIFB4 protein to shift monocyte-derived macrophages of atherosclerotic mice and patients towards an anti-inflammatory phenotype. LAV-BPIFB4 gene therapy rescued endothelial function of mesenteric and femoral arteries from ApoE\u2212\/\u2212 mice; this effect was blunted by AMD3100, a CXC chemokine receptor type 4 (CXCR4) inhibitor. LAV-BPIFB4-treated mice showed a CXCR4-mediated shift in the balance between Ly6Chigh\/Ly6Clow monocytes and M2\/M1 macrophages, along with decreased T cell proliferation and elevated circulating levels of interleukins IL-23 and IL-27. In vitro conditioning with LAV-BPIFB4 protein of macrophages from atherosclerotic patients resulted in a CXCR4-dependent M2 polarization phenotype. Furthermore, LAV-BPIFB4 treatment of arteries explanted from atherosclerotic patients increased the release of atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1\u03b2, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (&amp;gt;25%) and intima media thickness &amp;gt;2\u2009mm.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Transfer of the LAV of BPIFB4 reduces the atherogenic process and skews macrophages towards an M2-resolving phenotype through modulation of CXCR4, thus opening up novel therapeutic possibilities in cardiovascular disease.<\/jats:p>\n                  <jats:p\/>\n               <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehz459","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T14:40:47Z","timestamp":1561473647000},"page":"2487-2497","source":"Crossref","is-referenced-by-count":64,"title":["Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism"],"prefix":"10.1093","volume":"41","author":[{"given":"Annibale Alessandro","family":"Puca","sequence":"first","affiliation":[{"name":"Ageing Unit, IRCCS MultiMedica , Via G. Fantoli 16\/15, 20138 Milan, Italy"},{"name":"Department of Medicine, Surgery and Dentistry, \u201cScuola Medica Salernitana\u201d University of Salerno , Via S. Allende, 84081 Baronissi (SA), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albino","family":"Carrizzo","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed , Loc. Camerelle, 86077 Pozzilli (IS), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Ageing Unit, IRCCS MultiMedica , Via G. Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Damato","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed , Loc. Camerelle, 86077 Pozzilli (IS), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariateresa","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed , Loc. Camerelle, 86077 Pozzilli (IS), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1696-6657","authenticated-orcid":false,"given":"Francesco","family":"Villa","sequence":"additional","affiliation":[{"name":"Ageing Unit, IRCCS MultiMedica , Via G. Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ferrario","sequence":"additional","affiliation":[{"name":"Ageing Unit, IRCCS MultiMedica , Via G. Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-5640","authenticated-orcid":false,"given":"Anna","family":"Maciag","sequence":"additional","affiliation":[{"name":"Ageing Unit, IRCCS MultiMedica , Via G. Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Fornai","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed , Loc. Camerelle, 86077 Pozzilli (IS), Italy"},{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa , via Roma 55, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4734-8798","authenticated-orcid":false,"given":"Paola","family":"Lenzi","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa , via Roma 55, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Valenti","sequence":"additional","affiliation":[{"name":"UOC Cardiologia Ospedale Santa Maria Goretti , 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"di Nonno","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed , Loc. 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Camerelle, 86077 Pozzilli (IS), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Cal\u00ec","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Experimental Oncology Institute , CNR, Via Sergio Pansini, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6216-1999","authenticated-orcid":false,"given":"Andrea","family":"Baragetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 Degli Studi di Milano , via Vanvitelli 32, 20129 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6081-1257","authenticated-orcid":false,"given":"Giuseppe Danilo","family":"Norata","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 Degli Studi di Milano , via Vanvitelli 32, 20129 Milan, Italy"},{"name":"Societ\u00e0 Italiana per lo Studio della Arteriosclerosi (SISA) Centro Aterosclerosi, Bassini Hospital , Cinisello Balsamo, 20092 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberico Luigi","family":"Catapano","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 Degli Studi di Milano , via Vanvitelli 32, 20129 Milan, Italy"},{"name":"IRCCS Multimedica Hospital , 20099 Sesto San Giovanni Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Ageing Unit, IRCCS MultiMedica , Via G. 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