Table 1.
Compounds used to stabilize atherosclerotic plaques via modulation of cell death
| Compound | Remarks | Reference |
|---|---|---|
| Pharmacological inhibition of cell death | ||
| Caspase inhibitors | ||
| Pancaspase inhibitors (e.g. z-VAD-fmk) | Inhibits apoptosis, but may induce autophagy and necrotic cell death; macrophages treated with z-VAD-fmk secrete pro-inflammatory cytokines | (Martinet et al., 2006; Sarai et al., 2007) |
| Antioxidants | ||
| Antioxidant vitamins (e.g. vitamin C and E) | Prevent oxidative injury; In vivo effectiveness is questionable; Analogues targeted at the mitochondria might be more effective | (Madamanchi et al., 2005; Victor et al., 2009) |
| Polyphenols (e.g. resveratrol) | May act as pro-apoptotic and anti-apoptotic agents, depending on their concentration | (Das and Das, 2007) |
| ER stress inhibitors | ||
| Chemical chaperones (e.g. PBA, TUDCA) | Alleviates lipid-induced ER stress and suppresses lesion development | (Erbay et al., 2009; Dong et al., 2010) |
| Antioxidants (e.g. N-acetylcysteine, Tempol) | Reduces oxidant stress-mediated ER stress | (Tabas, 2010) |
| Cytokine blocking agents | ||
| Anti-TNFα (e.g. infliximab) | Inhibits the pro-inflammatory effects of TNFα; Treatment may be associated with serious side effects, including worsening of atherosclerosis | (Di Micco et al., 2009; Murdaca et al., 2009) |
| Interleukin-1 receptor antagonist | Inhibits IL-1 actions by binding to the type 1 IL-1 receptor | (Elhage et al., 1998; Crossman et al., 2008) |
| Lipid lowering drugs | ||
| HMG-CoA reductase inhibitors (statins) | Hydrophilic statins are anti-apoptotic, although hydrophobic statins promote apoptosis | (Katsiki et al., 2010) |
| Efferocytosis stimulating drugs | ||
| Thiazolidinediones (e.g. pioglitazone) | Selectively improve phagocytosis of apoptotic cells, at least in vitro, but enhance macrophage apoptosis in atherosclerotic plaques | (Thorp et al., 2007) |
| Fish oil | Increases ω-3 fatty acids, which are thought to be important factors contributing to efficient phagocytosis of apoptotic cells | (Li et al., 2009) |
| Pharmacological stimulation of cell death | ||
| Pro-apoptotic drugs | ||
| TRAIL | Induces selective macrophage apoptosis; stimulates smooth muscle cell migration; CD14+ monocytes are resistant to TRAIL-induced apoptosis | (Secchiero et al., 2006) |
| Protein synthesis inhibitors | ||
| mTOR inhibitors (e.g. everolimus) | Induces selective macrophage autophagy | (Verheye et al., 2007) |
| Cycloheximide, anisomycin | Induces selective macrophage apoptosis | (Croons et al., 2007, 2009) |
| NO donors | ||
| Molsidomine | Induces selective macrophage apoptosis, possibly through induction of ER stress | (De Meyer et al., 2003; Martinet et al., 2007) |
| Liposomes with cytotoxic drugs | ||
| Clodronate-containing liposomes | Intracellular delivery of cytotoxic drugs via phagocytosis; selective induction of macrophage apoptosis; nonphagocytic cells are resistant to the treatment | (van Rooijen and Hendrikx, 2010) |
ER, endoplasmic reticulum; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; mTOR, mammalian target of rapamycin; NO, nitric oxide; PBA, 4-phenyl butyric acid; TRAIL, TNF-related apoptosis inducing ligand; TUDCA, tauroursodeoxycholic acid.