Macrophages play a key role in atherosclerotic plaque destabilization and rupture, whereas smooth muscle cells (SMCs) contribute to plaque stability. Therefore, selective depletion of macrophages from plaques may be a promising strategy to stabilize the structure of the plaque. Lithium chloride (LiCl) has been shown to induce cell death of cultured macrophages. Here, we investigated whether LiCl could induce macrophage death without affecting the viability of SMCs.

In vitro studies showed that 30 mM LiCl led to cell death of cultured J774A.1 macrophages, whereas SMCs were highly resistant. Cell death was characterized by externalization of phosphatidylserine, caspase-3 cleaving and DNA fragmentation, all indicative of apoptosis. Although LiCl can exert osmotic effects, this was only seen from 100 mM onward, similar to 100 mM NaCl. Subsequently, we investigated whether LiCl-induced apoptosis was mediated via inhibition of inositol monophosphatase (IMPase). LiCl reduced myo-inositol-1,4,5-triphosphate (IP₃) levels in macrophages. Moreover, the specific IMPase inhibitor
L-690,330 as well as IMPase gene silencing induced apoptosis of macrophages, similar to LiCl. These findings strongly indicate that LiCl-induced cell death was mediated by IMPase inhibition. In vitro treatment of atherosclerotic rabbit carotid artery rings with 30 mM LiCl resulted in induction of macrophage death, whereas SMC viability was unaffected. Local in vivo administration of LiCl via osmotic minipumps to collared rabbit atherosclerotic carotid arteries reduced the macrophage content in the plaques through apoptosis, as shown by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Vascular reactivity studies showed that LiCl did not affect the functionality of SMCs and endothelium.

In conclusion, LiCl selectively decreased the macrophage load in rabbit atherosclerotic plaques without affecting SMC viability.