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 Spinelli, Antonio Damato, Mariateresa Ambrosio, Francesco Villa, Anna Ferrario, Anna Maciag, Francesco Fornai, Paola Lenzi, Valentina Valenti, Flavio di Nonno, Giulio Accarino, Michele Madonna, Maurizio Forte, Gaetano Calì, Andrea Baragetti, Giuseppe Danilo Norata, Alberico Luigi 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

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. LAV-BPIFB4 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 atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1β, 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.

CONCLUSION: 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.

Original languageEnglish
JournalEuropean Heart Journal
DOIs
Publication statusE-pub ahead of print - Jul 10 2019

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CXCR4 Receptors
Apolipoproteins E
Knockout Mice
Atherosclerosis
Inflammation
Genes
Macrophages
Interleukin-23
Phenotype
Genetic Therapy
Interleukin-27
Mesenteric Arteries
Nitric Oxide Synthase Type III
Carotid Stenosis
High Fat Diet
Therapeutic Uses
Femoral Artery
Interleukin-1
Blood Vessels
Monocytes

Cite this

@article{dc7d11561fb04d9bb205ff4363879376,
title = "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",
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. LAV-BPIFB4 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 atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1β, 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.CONCLUSION: 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.",
author = "Puca, {Annibale Alessandro} and Albino Carrizzo and Chiara Spinelli and Antonio Damato and Mariateresa Ambrosio and Francesco Villa and Anna Ferrario and Anna Maciag and Francesco Fornai and Paola Lenzi and Valentina Valenti and {di Nonno}, Flavio and Giulio Accarino and Michele Madonna and Maurizio Forte and Gaetano Cal{\`i} and Andrea Baragetti and Norata, {Giuseppe Danilo} and Catapano, {Alberico Luigi} and Monica Cattaneo and Raffaele Izzo and Valentina Trimarco and Francesco Montella and Francesco Versaci and Alberto Auricchio and Giacomo Frati and Sebastiano Sciarretta and Paolo Madeddu and Elena Ciaglia and Carmine Vecchione",
note = "{\circledC} The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.",
year = "2019",
month = "7",
day = "10",
doi = "10.1093/eurheartj/ehz459",
language = "English",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",

}

TY - JOUR

T1 - 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

AU - Puca, Annibale Alessandro

AU - Carrizzo, Albino

AU - Spinelli, Chiara

AU - Damato, Antonio

AU - Ambrosio, Mariateresa

AU - Villa, Francesco

AU - Ferrario, Anna

AU - Maciag, Anna

AU - Fornai, Francesco

AU - Lenzi, Paola

AU - Valenti, Valentina

AU - di Nonno, Flavio

AU - Accarino, Giulio

AU - Madonna, Michele

AU - Forte, Maurizio

AU - Calì, Gaetano

AU - Baragetti, Andrea

AU - Norata, Giuseppe Danilo

AU - Catapano, Alberico Luigi

AU - Cattaneo, Monica

AU - Izzo, Raffaele

AU - Trimarco, Valentina

AU - Montella, Francesco

AU - Versaci, Francesco

AU - Auricchio, Alberto

AU - Frati, Giacomo

AU - Sciarretta, Sebastiano

AU - Madeddu, Paolo

AU - Ciaglia, Elena

AU - Vecchione, Carmine

N1 - © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2019/7/10

Y1 - 2019/7/10

N2 - 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. LAV-BPIFB4 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 atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1β, 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.CONCLUSION: 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.

AB - 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. LAV-BPIFB4 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 atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1β, 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.CONCLUSION: 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.

U2 - 10.1093/eurheartj/ehz459

DO - 10.1093/eurheartj/ehz459

M3 - Article

C2 - 31289820

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

ER -