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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

Research output: Contribution to journalArticle

  • Annibale Alessandro Puca
  • Albino Carrizzo
  • Chiara C Spinelli
  • Antonio Damato
  • Mariateresa Ambrosio
  • Francesco Villa
  • Anna Ferrario
  • Anna Maciąg
  • Francesco Fornai
  • Paola Lenzi
  • Valentina Valenti
  • Flavio di Nonno
  • Giulio Accarino
  • Michele Madonna
  • Maurizio Forte
  • Gaetano Calì
  • Andrea Baragetti
  • Giuseppe D. Norata
  • Alberico L. Catapano
  • Monica Cattaneo
  • Raffaele Izzo
  • Valentina Trimarco
  • Francesco Montella
  • Francesco Versaci
  • Alberto Auricchio
  • Giacomo Frati
  • Sebastiano Sciarretta
  • Paolo Madeddu
  • Elena Ciaglia
  • Carmine Vecchione
Original languageEnglish
Number of pages12
JournalEuropean Heart Journal
DOIs
DateAccepted/In press - 22 Jun 2019
DatePublished (current) - 10 Jul 2019

Abstract

Aims: Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. Methods and Results: ApoE knockout mice (ApoE−/−) 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. LAVBPIFB4 gene therapy rescued endothelial function of mesenteric and femoral arteries from ApoE−/−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 athero-protective IL-33 while inhibiting the release of pro-inflammatory IL-1, inducing eNOS phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and IMT >2 mm. Conclusions: Transfer of the longevity-associated variant 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.

    Research areas

  • Atherosclerosis, Low-density lipoprotein, vascular function, immune system

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via OUP at https://doi.org/10.1093/eurheartj/ehz459 . Please refer to any applicable terms of use of the publisher.

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    Licence: CC BY-NC

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