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

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 CattaneoRaffaele Izzo, Valentina Trimarco, Francesco Montella, Francesco Versaci, Alberto Auricchio, Giacomo Frati, Sebastiano Sciarretta, Paolo Madeddu, Elena Ciaglia, Carmine Vecchione

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Pages (from-to)2487-2497
Number of pages11
JournalEuropean Heart Journal
Volume41
Issue number26
Early online date10 Jul 2019
DOIs
Publication statusPublished - 7 Jul 2020

Keywords

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

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