{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T02:50:45Z","timestamp":1772851845278,"version":"3.50.1"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":2081,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T00:00:00Z","timestamp":1588896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["Longevity-associated BPIFB4 gene therapy for treatment of ischemic disease (PG\/15\/54\/31559)"],"award-info":[{"award-number":["Longevity-associated BPIFB4 gene therapy for treatment of ischemic disease (PG\/15\/54\/31559)"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BHF Centre for Regenerative Medicine Award (II) - \u201cCentre for Vascular Regeneration\u201d","award":["RM\/17\/3\/33381"],"award-info":[{"award-number":["RM\/17\/3\/33381"]}]},{"name":"Italian Ministry of Health Ricerca Corrente for IRCCS Multimedica"},{"name":"Young Investigator grant from the Italian Ministry of Health","award":["GR-2013-02358692"],"award-info":[{"award-number":["GR-2013-02358692"]}]},{"name":"Cariplo Foundation grant \u2018BPIFB4 isoforms: possible genetic risk factor and therapeutic tool for human frailty\u2019"},{"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"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["Longevity\u2010associated BPIFB4 gene therapy for treatment of ischemic disease (PG\/15\/54\/31559)"],"award-info":[{"award-number":["Longevity\u2010associated BPIFB4 gene therapy for treatment of ischemic disease (PG\/15\/54\/31559)"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"publisher","award":["GR\u20102013\u201002358692"],"award-info":[{"award-number":["GR\u20102013\u201002358692"]}],"id":[{"id":"10.13039\/501100003196","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":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Homozygosity for a four-missense single-nucleotide polymorphism haplotype of the human BPIFB4 gene is enriched in long-living individuals. Delivery of this longevity-associated variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell-derived factor-1 (SDF-1). Here, we investigated if delivery of the LAV-BPIFB4 gene may attenuate the progression of diabetic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Compared with age-matched lean controls, diabetic db\/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV-BPIFB4 gene therapy using an adeno-associated viral vector serotype 9 (AAV9). In contrast, AAV9 wild-type-BPIFB4 exerted no benefit. Interestingly, LAV-BPIFB4-treated mice showed increased SDF-1 levels in peripheral blood and myocardium and up-regulation of the cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF-1 up-regulation was instrumental to LAV-BPIFB4-induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF-1 CXCR4 receptor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In mice with type-2 diabetes, LAV-BPIFB4 gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes-induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1840","type":"journal-article","created":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T11:02:52Z","timestamp":1588935772000},"page":"1568-1581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Transfer of a Human Gene Variant Associated with Exceptional Longevity Improves Cardiac Function in Obese Type 2 Diabetic Mice Through Induction of the SDF-1\/CXCR4 Signalling Pathway"],"prefix":"10.1093","volume":"22","author":[{"given":"Zexu","family":"Dang","sequence":"first","affiliation":[{"name":"Translational Health Sciences, Bristol Medical School, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Avolio","sequence":"additional","affiliation":[{"name":"Translational Health Sciences, Bristol Medical School, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita C.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Translational Health Sciences, Bristol Medical School, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashton","family":"Faulkner","sequence":"additional","affiliation":[{"name":"Translational Health Sciences, Bristol Medical School, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio P.","family":"Beltrami","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine , Udine ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celeste","family":"Cervellin","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine , Udine ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albino","family":"Carrizzo","sequence":"additional","affiliation":[{"name":"Vascular Pathophysiology Unit, IRCCS Neuromed , Pozzilli ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Maciag","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, IRCCS Multimedica , Milan ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Gu","sequence":"additional","affiliation":[{"name":"Translational Health Sciences, Bristol Medical School, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Ciaglia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, \u201cScuola Medica Salernitana\u201d, University of Salerno , Baronissi (SA) ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoletta","family":"Finato","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine , Udine ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Damato","sequence":"additional","affiliation":[{"name":"Vascular Pathophysiology Unit, IRCCS Neuromed , Pozzilli ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaia","family":"Spinetti","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, IRCCS Multimedica , Milan 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