A large body of evidence has pointed to matrix metalloproteinases (MMPs) as major mediators of plaque vulnerability. In late stages MMPs can degrade the fibrous cap and lead to plaque rupture and thrombosis, causing acute coronary syndromes. Macrophages play a crucial role in chronic inflammation that characterizes atherogenesis and they co-localize with and release active MMPs, including MMP-9. As a part of atheroma inflammation, macrophage COX-2-dependent PGE2 production is involved in plaque growth and instability, through a variety of processes. Among them, PGE2 is able to induce MMP-9 and MMP-2. It has also been demonstrated that lipids play a crucial role in atherosclerosis. Among them, 27-hydroxycholesterol (27OH) and 4-hydroxynonenal (HNE), the major products deriving from LDL oxidation, are consistently present in inflamed and atherosclerotic arteries. Aims: Since chronic inflammation and matrix degradation might play a key role in plaque vulnerability, we investigated the effect of 27OH and HNE on various inflammatory molecules and MMP-9 expression in promonocytic U937 cells. Results: These oxidized lipids induced inflammation through the increment of COX-2 and mPGES-1 levels, enzymes that cooperate to catalyze the conversion of arachidonic acid to PGE2, as well as of iNOS and NO levels, which in turn could stimulate COX-2. Furthermore, 27OH and HNE enhanced IL-8, IL-1, TNF- levels, underlying the proinflammatory effect of these compounds and the possible consequent amplification of COX/PGES expression induced by cytokines themselves. This inflammatory loop was supported by the reduction of cytokine levels following COX inhibition. 27OH and HNE also induced MMP-9 expression. Using NS-398, a specific COX-2 inhibitor, or epigallocatechin gallate, a polyphenolic compound with anti-inflammatory properties, levels of MMP-9 were significantly decreased. Our results suggest that 27OH and HNE contribute to the plaque vulnerability by enhancing the inflammatory response involving COX-2 activation which can contribute to matrix degradation by MMP-9 upregulation.
Role of 27-hydroxycholesterol and 4-hydroxylnonenal in atherosclerotic plaque vulnerability.
GARGIULO, Simona;ROSSIN, DANIELA;GAMBA, Paola Francesca;TESTA, GABRIELLA;POLI, Giuseppe;LEONARDUZZI, Gabriella Marisa
2016-01-01
Abstract
A large body of evidence has pointed to matrix metalloproteinases (MMPs) as major mediators of plaque vulnerability. In late stages MMPs can degrade the fibrous cap and lead to plaque rupture and thrombosis, causing acute coronary syndromes. Macrophages play a crucial role in chronic inflammation that characterizes atherogenesis and they co-localize with and release active MMPs, including MMP-9. As a part of atheroma inflammation, macrophage COX-2-dependent PGE2 production is involved in plaque growth and instability, through a variety of processes. Among them, PGE2 is able to induce MMP-9 and MMP-2. It has also been demonstrated that lipids play a crucial role in atherosclerosis. Among them, 27-hydroxycholesterol (27OH) and 4-hydroxynonenal (HNE), the major products deriving from LDL oxidation, are consistently present in inflamed and atherosclerotic arteries. Aims: Since chronic inflammation and matrix degradation might play a key role in plaque vulnerability, we investigated the effect of 27OH and HNE on various inflammatory molecules and MMP-9 expression in promonocytic U937 cells. Results: These oxidized lipids induced inflammation through the increment of COX-2 and mPGES-1 levels, enzymes that cooperate to catalyze the conversion of arachidonic acid to PGE2, as well as of iNOS and NO levels, which in turn could stimulate COX-2. Furthermore, 27OH and HNE enhanced IL-8, IL-1, TNF- levels, underlying the proinflammatory effect of these compounds and the possible consequent amplification of COX/PGES expression induced by cytokines themselves. This inflammatory loop was supported by the reduction of cytokine levels following COX inhibition. 27OH and HNE also induced MMP-9 expression. Using NS-398, a specific COX-2 inhibitor, or epigallocatechin gallate, a polyphenolic compound with anti-inflammatory properties, levels of MMP-9 were significantly decreased. Our results suggest that 27OH and HNE contribute to the plaque vulnerability by enhancing the inflammatory response involving COX-2 activation which can contribute to matrix degradation by MMP-9 upregulation.
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