Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques |
| |
Authors: | De Meyer Inge Martinet Wim Van Hove Cor E Schrijvers Dorien M Hoymans Vicky Y Van Vaeck Luc Fransen Paul Bult Hidde De Meyer Guido R Y |
| |
Institution: | 1Division of Pharmacology, University of Antwerp, Antwerp, Belgium;2Division of Chemistry, University of Antwerp, Antwerp, Belgium;3Laboratory for Cellular and Molecular Cardiology, Antwerp University Hospital, and Division of Cardiology, University of Antwerp, Antwerp, Belgium |
| |
Abstract: | BACKGROUND AND PURPOSELithium 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 APPROACHThe 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 RESULTSIn 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 IMPLICATIONSLiCl 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. |
| |
Keywords: | apoptosis atherosclerosis inositol monophosphatase lithium macrophage plaque stability |
本文献已被 PubMed 等数据库收录! |
|