Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran.
Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran.
Sci Rep. 2021 Sep 27;11(1):19091. doi: 10.1038/s41598-021-98276-2.
It has been well documented that chronic stress can induce atherosclerotic changes, however, the underlying mechanisms is yet to be established. In this regard, this study aimed to elucidate the relation between hypothalamic-pituitary adrenal-axis (HPA-axis), toll-like receptors (TLRs), as well as M1/M2 macrophage ratio and pre-atherosclerotic changes in social isolation stress (SIS) in mice. We used small interfering RNA against the glucocorticoid receptor (GR) to evaluate the relation between HPA-axis and TLRs. C57BL/6J mice were subjected to SIS and RT-PCR, ELISA, flow cytometry, and immunohistochemistry were used to assess the relations between pre-atherosclerotic changes and TLRs, macrophage polarization, pro-inflammatory cytokines, and cell adhesion molecules in aortic tissue. We used TAK-242 (0.3 mg/kg, intraperitoneally), a selective antagonist of TLR4, as a possible prophylactic treatment for atherosclerotic changes induced by SIS. We observed that isolated animals had higher serum concentration of corticosterone and higher body weight in comparison to normal animals. In isolated animals, results of in vitro study showed that knocking-down of the GR in bone marrow-derived monocytes significantly decreased the expression of TLR4. In vivo study suggested higher expression of TLR4 on circulating monocytes and higher M1/M2 ratio in aortic samples. Pathological study showed a mild pre-atherosclerotic change in isolated animals. Finally, we observed that treating animals with TAK-242 could significantly inhibit the pre-atherosclerotic changes. SIS can possibly increase the risk of atherosclerosis through inducing abnormal HPA-axis activity and subsequently lead to TLR4 up-regulation, vascular inflammation, high M1/M2 ratio in intima. Thus, TLR4 inhibitors might be a novel treatment to decrease the risk of atherosclerosis induced by chronic stress.
已有大量文献证实慢性应激可诱导动脉粥样硬化病变，但其中的潜在机制仍有待阐明。有鉴于此，本研究旨在阐明下丘脑-垂体-肾上腺轴（HPA 轴）、Toll 样受体（TLR）以及 M1/M2 巨噬细胞比值与社交隔离应激（SIS）中小鼠发生动脉粥样硬化前病变之间的关系。我们使用针对糖皮质激素受体（GR）的小干扰 RNA 来评估 HPA 轴与 TLR 之间的关系。将 C57BL/6J 小鼠置于 SIS 环境中，采用 RT-PCR、ELISA、流式细胞术和免疫组织化学等方法评估 TLRs、巨噬细胞极化、促炎细胞因子和细胞黏附分子与主动脉组织中动脉粥样硬化前病变之间的关系。我们使用 TLR4 的选择性拮抗剂 TAK-242（0.3mg/kg，腹腔内注射）作为 SIS 诱导的动脉粥样硬化变化的可能预防性治疗。我们发现，与正常动物相比，孤立动物的血清皮质酮浓度更高，体重也更高。在体外研究中，孤立动物的结果表明，在骨髓来源的单核细胞中敲低 GR 可显著降低 TLR4 的表达。体内研究表明，循环单核细胞上 TLR4 的表达更高，主动脉样本中的 M1/M2 比值更高。病理研究显示，孤立动物存在轻度的动脉粥样硬化前病变。最后，我们发现用 TAK-242 治疗动物可显著抑制动脉粥样硬化前病变。SIS 可能通过诱导异常的 HPA 轴活动增加动脉粥样硬化的风险，进而导致 TLR4 上调、血管炎症、内膜中 M1/M2 比值升高。因此，TLR4 抑制剂可能是一种降低慢性应激引起的动脉粥样硬化风险的新治疗方法。
