Introduction. The driving force of atherogenesis is the chronic inflammation which promote the development of a vulnerable plaque responsible of acute cardiovascular diseases. A vulnerable plaque is characterized by a lipid-rich core and a thin fibrous cap. Moreover, this plaque is infiltrated by macrophages which secrete MMPs, such as MMP-9, that degrade extracellular matrix causing plaque rupture. It is known that oxidized LDLs cause atherosclerosis by accumulating in the arterial intima where they act as stimulators of inflammatory and immune response. In the light of these facts, our studies focus on contribution of oxysterols, derivatives of LDL-cholesterol oxidation, and 4-hydroxynonenal (HNE), an aldehyde generated by breakdown of PUFA, in inflammation and plaque instability. Methods. Proinflammatory molecules and MMP-9 levels were analyzed by qRT-PCR, western blotting, immunofluorescence and colorimetric tecniques. Results. In U937 cells, both 27-hydroxycholesterol (27OH) and HNE induced the expression of several cytokines and MMP-9 through TLR4 activation. Moreover, they sustained inflammation by upregulating COX-2 and mPGES-1levels, as well as iNOS and NO. Of note, inhibition of inflammatory molecule formation decrease MMP-9 release by macrophages, underlying the crucial role of inflammatory response in MMP-9 overexpression. We are now investigating whether an oxysterols mixture could modulate the expression of the proprotein convertase PCSK6, a new marker of plaque vulnerability. Our preliminary results indicate that oxysterols upregulate PCSK6 in U937 cells and SMCs. We are also investigating the possible link between PCSK6 and MMP-9 activation. Conclusion. Our results suggest that oxidized lipids promote plaque vulnerability by enhancing inflammation and MMP-9 upregulation.

Markers of plaque vulnerability induced by oxidized lipids.

GARGIULO, Simona;ROSSIN, DANIELA;STAURENGHI, ERICA;TESTA, GABRIELLA;GAMBA, Paola Francesca;POLI, Giuseppe;LEONARDUZZI, Gabriella Marisa
2016-01-01

Abstract

Introduction. The driving force of atherogenesis is the chronic inflammation which promote the development of a vulnerable plaque responsible of acute cardiovascular diseases. A vulnerable plaque is characterized by a lipid-rich core and a thin fibrous cap. Moreover, this plaque is infiltrated by macrophages which secrete MMPs, such as MMP-9, that degrade extracellular matrix causing plaque rupture. It is known that oxidized LDLs cause atherosclerosis by accumulating in the arterial intima where they act as stimulators of inflammatory and immune response. In the light of these facts, our studies focus on contribution of oxysterols, derivatives of LDL-cholesterol oxidation, and 4-hydroxynonenal (HNE), an aldehyde generated by breakdown of PUFA, in inflammation and plaque instability. Methods. Proinflammatory molecules and MMP-9 levels were analyzed by qRT-PCR, western blotting, immunofluorescence and colorimetric tecniques. Results. In U937 cells, both 27-hydroxycholesterol (27OH) and HNE induced the expression of several cytokines and MMP-9 through TLR4 activation. Moreover, they sustained inflammation by upregulating COX-2 and mPGES-1levels, as well as iNOS and NO. Of note, inhibition of inflammatory molecule formation decrease MMP-9 release by macrophages, underlying the crucial role of inflammatory response in MMP-9 overexpression. We are now investigating whether an oxysterols mixture could modulate the expression of the proprotein convertase PCSK6, a new marker of plaque vulnerability. Our preliminary results indicate that oxysterols upregulate PCSK6 in U937 cells and SMCs. We are also investigating the possible link between PCSK6 and MMP-9 activation. Conclusion. Our results suggest that oxidized lipids promote plaque vulnerability by enhancing inflammation and MMP-9 upregulation.
3rd Joint Meeting of Pathology and Laboratory Medicine
Montesilvano, Italia
4-6 ottobre 2016
Vol 186, A4
52
52
Gargiulo, S; Rossin, D; Staurenghi, E; Testa, G; Gamba, P; Poli, G; Leonarduzzi, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1644207
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