Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. 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. LAV-BPIFB4 gene ther- apy 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 atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1b, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and intima media thickness >2 mm. 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.

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 / Puca, Annibale Alessandro; Carrizzo, Albino; Spinelli, Chiara; Damato, Antonio; Ambrosio, Mariateresa; Villa, Francesco; Ferrario, Anna; Maciag, Anna; Fornai, Francesco; Lenzi, Paola; Valenti, Valentina; di Nonno, Flavio; Accarino, Giulio; Madonna, Michele; Forte, Maurizio; Calì, Gaetano; Baragetti, Andrea; Norata, Giuseppe Danilo; Catapano, Alberico Luigi; Cattaneo, Monica; Izzo, Raffaele; Trimarco, Valentina; Montella, Francesco; Versaci, Francesco; Auricchio, Alberto; Frati, Giacomo; Sciarretta, Sebastiano; Madeddu, Paolo; Ciaglia, Elena; Vecchione, Carmine. - In: EUROPEAN HEART JOURNAL. - ISSN 1522-9645. - 41:26(2020), pp. 2487-2497. [10.1093/eurheartj/ehz459]

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

Valenti, Valentina;Frati, Giacomo;Sciarretta, Sebastiano;
2020

Abstract

Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. 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. LAV-BPIFB4 gene ther- apy 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 atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1b, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and intima media thickness >2 mm. 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.
2020
atherosclerosis; immune system; low-density lipoprotein; vascular function
01 Pubblicazione su rivista::01a Articolo in rivista
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 / Puca, Annibale Alessandro; Carrizzo, Albino; Spinelli, Chiara; Damato, Antonio; Ambrosio, Mariateresa; Villa, Francesco; Ferrario, Anna; Maciag, Anna; Fornai, Francesco; Lenzi, Paola; Valenti, Valentina; di Nonno, Flavio; Accarino, Giulio; Madonna, Michele; Forte, Maurizio; Calì, Gaetano; Baragetti, Andrea; Norata, Giuseppe Danilo; Catapano, Alberico Luigi; Cattaneo, Monica; Izzo, Raffaele; Trimarco, Valentina; Montella, Francesco; Versaci, Francesco; Auricchio, Alberto; Frati, Giacomo; Sciarretta, Sebastiano; Madeddu, Paolo; Ciaglia, Elena; Vecchione, Carmine. - In: EUROPEAN HEART JOURNAL. - ISSN 1522-9645. - 41:26(2020), pp. 2487-2497. [10.1093/eurheartj/ehz459]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1428909
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