| Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques. | |
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MedLine Citation:
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PMID: 21138421 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Lithium chloride (LiCl) inhibits inositol monophosphatase (IMPase) at therapeutic concentrations. Given that LiCl induces death in cultured macrophages and that macrophages play an active role in atherosclerotic plaque destabilization, we investigated whether LiCl would induce selective macrophage death to stabilize the structure of the plaque. EXPERIMENTAL APPROACH: The effect of LiCl was assessed on macrophages and smooth muscle cells (SMCs) in culture, in isolated atherosclerotic carotid arteries from rabbits and after local in vivo treatment via osmotic minipumps to rabbits with collared atherosclerotic carotid arteries. In addition, in vitro experiments were performed to elucidate the mechanism of LiCl-induced macrophage death. KEY RESULTS: In vitro, whereas SMCs were highly resistant, LiCl induced macrophage death characterized by externalization of phosphatidylserine, caspase-3 cleavage and DNA fragmentation, all indicative of apoptosis. LiCl reduced inositol-1,4,5-trisphosphate levels in macrophages. Moreover, the IMPase inhibitor L-690 330 as well as IMPase gene silencing induced macrophage apoptosis. Both in vitro treatment of rabbit atherosclerotic carotid arteries with LiCl and local in vivo administration of LiCl to the plaques decreased plaque macrophages through apoptosis, as shown by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL), without affecting SMCs. Vasomotor studies in vitro showed that LiCl did not affect the functionality of SMCs and endothelial cells. CONCLUSIONS AND IMPLICATIONS: LiCl selectively decreased the macrophage load in rabbit atherosclerotic plaques via IMPase inhibition without affecting the viability or functionality of SMCs and endothelial cells. These data provide evidence for local administration of an IMPase inhibitor to stabilize atherosclerotic plaques. |
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Authors:
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Inge De Meyer; Wim Martinet; Cor E Van Hove; Dorien M Schrijvers; Vicky Y Hoymans; Luc Van Vaeck; Paul Fransen; Hidde Bult; Guido R Y De Meyer |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 162 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-23 Completed Date: 2011-09-06 Revised Date: 2012-03-01 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1410-23 Citation Subset: IM |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Division of Pharmacology, University of Antwerp, Antwerp, Belgium. inge.demeyer@ua.ac.be |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta Apoptosis* Carotid Arteries / drug effects* Cell Survival Enzyme Inhibitors / pharmacology* Gene Silencing Glycogen Synthase Kinase 3 / antagonists & inhibitors, metabolism Lithium Chloride / pharmacology* Macrophages / cytology, drug effects* Mice Myocytes, Smooth Muscle / drug effects*, physiology Phosphoric Monoester Hydrolases / antagonists & inhibitors*, genetics, metabolism Plaque, Atherosclerotic / pathology* Rabbits |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 7447-41-8/Lithium Chloride; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.25/myo-inositol-1 (or 4)-monophosphatase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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