P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels

Abstract In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1β) release that may influence MMP9 generation, thus thei...

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Autores principales:	Maria Lombardi, Maria Elena Mantione, Domenico Baccellieri, David Ferrara, Renata Castellano, Roberto Chiesa, Ottavio Alfieri, Chiara Foglieni
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1d61b32b9d41497dbcd510eb4700511b
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spelling	oai:doaj.org-article:1d61b32b9d41497dbcd510eb4700511b2021-12-02T11:53:10ZP2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels10.1038/s41598-017-05137-y2045-2322https://doaj.org/article/1d61b32b9d41497dbcd510eb4700511b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05137-yhttps://doaj.org/toc/2045-2322Abstract In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1β) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were studied in ex-vivo tissue cultures of human PL’s vs. non-atherosclerotic internal mammary artery (IMA) by using molecular biology, immune-biochemical and microscopy methodologies. We highlighted atherosclerosis-related differences between PLs and IMAs molecular patterns, and their responsivity to P2X7 antagonism. High IL-1β tissue content was associated with PLs morphology and instability/vulnerability. We demonstrated that A740003, but not KN62, decreased IL-1β and MMP9 independently from NLR family pyrin domain containing 3, but in relationship with patient’s smoking status. Acting downstream P2X7 by MMPs inhibitors, diminished IL-1β mRNA without transcriptional effect at MMP9, possibly because the assumption of statin by patients. These data firstly demonstrated A740003 suitability as a specific tool to decrease inflammatory status in human vessels and might support the design of studies applying P2X7 antagonists for the local targeting and tailored therapy of atherosclerosis.Maria LombardiMaria Elena MantioneDomenico BaccellieriDavid FerraraRenata CastellanoRoberto ChiesaOttavio AlfieriChiara FoglieniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria Lombardi Maria Elena Mantione Domenico Baccellieri David Ferrara Renata Castellano Roberto Chiesa Ottavio Alfieri Chiara Foglieni P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels
description	Abstract In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1β) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were studied in ex-vivo tissue cultures of human PL’s vs. non-atherosclerotic internal mammary artery (IMA) by using molecular biology, immune-biochemical and microscopy methodologies. We highlighted atherosclerosis-related differences between PLs and IMAs molecular patterns, and their responsivity to P2X7 antagonism. High IL-1β tissue content was associated with PLs morphology and instability/vulnerability. We demonstrated that A740003, but not KN62, decreased IL-1β and MMP9 independently from NLR family pyrin domain containing 3, but in relationship with patient’s smoking status. Acting downstream P2X7 by MMPs inhibitors, diminished IL-1β mRNA without transcriptional effect at MMP9, possibly because the assumption of statin by patients. These data firstly demonstrated A740003 suitability as a specific tool to decrease inflammatory status in human vessels and might support the design of studies applying P2X7 antagonists for the local targeting and tailored therapy of atherosclerosis.
format	article
author	Maria Lombardi Maria Elena Mantione Domenico Baccellieri David Ferrara Renata Castellano Roberto Chiesa Ottavio Alfieri Chiara Foglieni
author_facet	Maria Lombardi Maria Elena Mantione Domenico Baccellieri David Ferrara Renata Castellano Roberto Chiesa Ottavio Alfieri Chiara Foglieni
author_sort	Maria Lombardi
title	P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels
title_short	P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels
title_full	P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels
title_fullStr	P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels
title_full_unstemmed	P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels
title_sort	p2x7 receptor antagonism modulates il-1β and mmp9 in human atherosclerotic vessels
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1d61b32b9d41497dbcd510eb4700511b
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_version_	1718394853944983552

P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels

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