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

M Lombardi, ME Mantione, D Baccellieri, David Ferrara, R Castellano, R Chiesa, O Alfieri, C Foglieni

Research output: Contribution to journalArticle

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.
Original languageEnglish
Article number4872
JournalScientific Reports
Volume7
Issue number7
DOIs
Publication statusPublished - 2017

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Purinergic P2X Receptors
(N-(1-(((cyanoimino)(5-quinolinylamino) methyl) amino)-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide)
Interleukin-1beta
Purinergic P2X Receptor Antagonists
Metalloproteases
Atherosclerosis
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mammary Arteries
Molecular Biology
Rupture
Microscopy
Smoking
Messenger RNA

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P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels. / Lombardi, M; Mantione, ME; Baccellieri, D; Ferrara, David; Castellano, R; Chiesa, R; Alfieri, O; Foglieni, C.

In: Scientific Reports, Vol. 7, No. 7, 4872, 2017.

Research output: Contribution to journalArticle

Lombardi, M ; Mantione, ME ; Baccellieri, D ; Ferrara, David ; Castellano, R ; Chiesa, R ; Alfieri, O ; Foglieni, C. / P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels. In: Scientific Reports. 2017 ; Vol. 7, No. 7.
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AU - Lombardi, M

AU - Mantione, ME

AU - Baccellieri, D

AU - Ferrara, David

AU - Castellano, R

AU - Chiesa, R

AU - Alfieri, O

AU - Foglieni, C

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AB - 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.

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