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Publication - Professor Paolo Madeddu

    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

    Citation

    Puca, AA, Carrizzo, A, Spinelli, CC, Damato, A, Ambrosio, M, Villa, F, Ferrario, A, Maciąg, A, Fornai, F, Lenzi, P, Valenti, V, Nonno, Fd, Accarino, G, Madonna, M, Forte, M, Calì, G, Baragetti, A, Norata, GD, Catapano, AL, Cattaneo, M, Izzo, R, Trimarco, V, Montella, F, Versaci, F, Auricchio, A, Frati, G, Sciarretta, S, Madeddu, P, Ciaglia, E & Vecchione, C, 2019, ‘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’. European Heart Journal.

    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.

    Full details in the University publications repository