Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques
Faculty of Sciences. Chemistry
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Medicine and Health Sciences
British journal of pharmacology. - London
, p. 1410-1423
University of Antwerp
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 destabilisation, we investigated whether LiCl would induce selective macrophage death to stabilise 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 characterised by externalisation 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 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 stabilise atherosclerotic plaques.