| Autor: |
Fernando, Sanuja, Schwarz, Nisha, Sandeman, Lauren, Skoumbourdis, Thalia, Zareh, Jonar, Williamson, Anna, Di Bartolo, Belinda, Tan, Joanne T, Bursill, Christina A, Nicholls, Stephen, Proud, Christopher, Psaltis, Peter J |
| Zdroj: |
Circulation (Ovid); November 2019, Vol. 140 Issue: Supplement 1 pA14114-A14114, 1p |
| Abstrakt: |
Eukaryotic elongation factor 2 kinase (eEF2k) is a unique enzyme that controls protein synthesis and promotes cell survival under stress conditions. Previous studies suggest a role for eEF2k in formation of atherosclerotic plaques, yet the cellular mechanisms remain unclear. Here we investigated the effects of eEF2k inhibition and deficiency on macrophage (M?) biology with a focus on foam cell formation. We hypothesised that eEF2K controls M?-derived foam cell formation by modifying the expression and/or function of cholesterol scavenger receptors. In vitro, bone marrow-derived M?s (BMDMs) were prepared from eEF2k knockout (Eef2k-/-) and wild type (WT) mice and exposed to atherogenic stimuli, including oxidised low-density lipoprotein cholesterol (oxLDL). In parallel, BMDMs from C57BL mice and human peripheral blood monocyte-derived M?s (MDMs) were treated with a highly selective eEF2k inhibitor, JAN-384. In vivo, Eef2k-LdlrDKOand WT-LdlrKOmice were fed an atherogenic diet to induce atherosclerosis. Eef2k-/-BMDMs produced fewer oil red O+foam cells when incubated with oxLDL compared to WT BMDMs (12.5?2.3% vs 32.3?2.0%, p<0.01, n=8). Similarly, JAN-384 treatment reduced foam cell formation from both C57BL BMDMs and human MDMs (p<0.05). eEF2K deficiency resulted in a 70% reduction in surface expression of CD36 on BMDMs but had no effect on other scavenger receptors. Pharmacological eEF2K inhibition reduced total CD36 protein in BMDMs by 25% (p<0.01) and surface expression by 17% (p<0.01), without altering Cd36mRNA levels. Interestingly, eEF2k deficiency/inhibition increased total cholesterol efflux capacity in foam cells (p<0.01), without increasing gene or protein expression of cholesterol efflux receptors. Eef2k-LdlrDKOmice showed lower CD36 surface expression on circulating monocytes and M?s after 4 and 16 wk of atherogenic diet compared to WT-LdlrKOmice (p<0.01), with marked reduction in their capacity to form foam cells from harvested peritoneal M?s and ex vivocultured BMDMs (p<0.01). eEF2k regulates M? foam cell formation most likely through post transcriptional effects on CD36 scavenger receptor. Further studies are needed to determine whether its therapeutic targeting will result in anti-atherosclerotic effects. |
| Databáze: |
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