Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques.
OBJECTIVE
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.


METHODS
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.


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
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.
Division of Pharmacology, University of Antwerp, Antwerp, Belgium. inge.demeyer@ua.ac.be
Inge
I
De Meyer
Wim
W
Martinet
Cor E
CE
Van Hove
Dorien M
DM
Schrijvers
Vicky Y
VY
Hoymans
Luc
L
Van Vaeck
Paul
P
Fransen
Hidde
H
Bult
Guido R Y
GR
De Meyer
D000818:Animals; D001011:Aorta; D017209:Apoptosis; D002339:Carotid Arteries / Q000187:drug effects*; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D011817:Rabbits
D004791:Enzyme Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D018021:Lithium Chloride