Exendin-4 intervention attenuates atherosclerosis severity by modulating myeloid-derived suppressor cells and inflammatory cytokines in ApoE-/- mice

Objective: To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE^-/- mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs.

Methods: Thirty male ApoE^-/- mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors.

Results: Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-β were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-β (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-β levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-β levels in the spleen and peripheral blood.

Conclusion: Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE^-/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids.

Atherosclerosis; Exendin-4; Inflammatory factors; Myeloid-derived suppressor cells.