Leukocyte activation significantly contributes to the pathogenesis of inflammatory diseases, including atherosclerosis. Provided monocyte phenotypes in such environments are better understood, impaired human monocytes themselves could be addressed as therapeutic targets by new effective oxygenating drugs, such as Oxygen-Loaded Nanobubbles (OLNs). In the early stage of atherosclerosis, human monocytes invade into the subendothelium space, and matrix metalloproteinases (MMPs) appear to play a crucial role. Moreover, in inflamed tissues such as atherosclerotic plaques, monocytes chronically live under moderate hypoxia, and release significant amounts of 15-hydroxyeicosatetraenoic acid (15-HETE) as a result of increased 15-lipoxygenase activity. In the present work, the effects of 15-HETE on the secretion of gelatinases (MMP-2 and -9) from human monocytes cultured in normoxic or hypoxic conditions were studied; and the therapeutic potential of OLNs was evaluated. Untreated cells released basal levels of MMP-9 but did not secrete MMP-2. Hypoxia reduced basal MMP-9 release without affecting expression levels. 15-HETE enhanced MMP-9 expression and release, either in normoxia or hypoxia. OLNs - constituted by dextran shell and oxygen-storing decafluoropentane core, with sizes of about 500 nm and a negative surface charge, showing good capacity of O2 delivery, not accompanied by O3 generation after UV rays (346 nm) sterilization, and not displaying toxic effects on cells - abrogated 15-HETE-dependent increase of MMP-9 secretion, either in normoxia or hypoxia. These data suggest that OLNs can counteract 15-HETE-dependent upregulation of MMP-9 release through so far unknown mechanisms, thereby preventing monocyte invasion and subsequent inflammation in atherosclerotic plaques. OLNs can therefore constitute a potential therapeutic tool in atherosclerosis-related pathologies.
Oxygen-loaded dextran nanobubbles inhibit 15-HETE-dependent upregulation of MMP-9 release in human monocytes: new therapeutic perspectives for atherosclerosis
PRATO, Mauro;POLIMENI, Manuela;VALENTE, Elena;NOVELLO, Matteo;GIRIBALDI, Giuliana;GUIOT, Caterina
2012-01-01
Abstract
Leukocyte activation significantly contributes to the pathogenesis of inflammatory diseases, including atherosclerosis. Provided monocyte phenotypes in such environments are better understood, impaired human monocytes themselves could be addressed as therapeutic targets by new effective oxygenating drugs, such as Oxygen-Loaded Nanobubbles (OLNs). In the early stage of atherosclerosis, human monocytes invade into the subendothelium space, and matrix metalloproteinases (MMPs) appear to play a crucial role. Moreover, in inflamed tissues such as atherosclerotic plaques, monocytes chronically live under moderate hypoxia, and release significant amounts of 15-hydroxyeicosatetraenoic acid (15-HETE) as a result of increased 15-lipoxygenase activity. In the present work, the effects of 15-HETE on the secretion of gelatinases (MMP-2 and -9) from human monocytes cultured in normoxic or hypoxic conditions were studied; and the therapeutic potential of OLNs was evaluated. Untreated cells released basal levels of MMP-9 but did not secrete MMP-2. Hypoxia reduced basal MMP-9 release without affecting expression levels. 15-HETE enhanced MMP-9 expression and release, either in normoxia or hypoxia. OLNs - constituted by dextran shell and oxygen-storing decafluoropentane core, with sizes of about 500 nm and a negative surface charge, showing good capacity of O2 delivery, not accompanied by O3 generation after UV rays (346 nm) sterilization, and not displaying toxic effects on cells - abrogated 15-HETE-dependent increase of MMP-9 secretion, either in normoxia or hypoxia. These data suggest that OLNs can counteract 15-HETE-dependent upregulation of MMP-9 release through so far unknown mechanisms, thereby preventing monocyte invasion and subsequent inflammation in atherosclerotic plaques. OLNs can therefore constitute a potential therapeutic tool in atherosclerosis-related pathologies.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
