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.
journal_name
Eur Heart Jjournal_title
European heart journalauthors
Puca AA,Carrizzo A,Spinelli C,Damato A,Ambrosio M,Villa F,Ferrario A,Maciag A,Fornai F,Lenzi P,Valenti V,di Nonno F,Accarino G,Madonna M,Forte M,Calì G,Baragetti A,Norata GD,Catapano AL,Cattaneo M,Izzo R,Trimarcdoi
10.1093/eurheartj/ehz459subject
Has Abstractpub_date
2020-07-07 00:00:00pages
2487-2497issue
26eissn
0195-668Xissn
1522-9645pii
5530158journal_volume
41pub_type
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journal_title:European heart journal
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doi:
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abstract:AIM:Short-term psychological stress is associated with an immediate physiological response and may be associated with a transiently higher risk of cardiovascular events. The aim of this study was to determine whether brief episodes of anger trigger the onset of acute myocardial infarction (MI), acute coronary syndromes...
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doi:10.1093/oxfordjournals.eurheartj.a060402
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journal_title:European heart journal
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doi:10.1093/eurheartj/14.6.812
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journal_title:European heart journal
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doi:10.1093/eurheartj/12.suppl_d.108
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journal_title:European heart journal
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doi:10.1093/eurheartj/12.9.1006
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doi:10.1093/oxfordjournals.eurheartj.a060841
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doi:10.1093/eurheartj/ehq208
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pub_type: 临床试验,杂志文章
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