Abstract
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.
Highlights
It has been well documented that chronic stress can induce atherosclerotic changes, the underlying mechanisms is yet to be established
We evaluated that the body weight before and after four weeks of experiment in both socially isolated and normal animals
Our results demonstrated that the proportion of low-density lipoprotein (LDL) to highdensity lipoprotein levels (HDL) was significantly higher in both isolation conditioned (2.82 ± 0.31) and isolation conditioned animals treated with TAK-242 (3.12 ± 0.56) in comparison to social conditioned mice (1.39 ± 0.22, P < 0.001)
Summary
It has been well documented that chronic stress can induce atherosclerotic changes, 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. Pathological study showed a mild pre-atherosclerotic change in isolated animals. 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. Since glucocorticoid receptors (GR) agonists such as dexamethasone could suppress inflammation through inhibiting the nuclear factor-κB (NF-κB)[12,13], current study hypothesized that HPA-axis might be the linkage between SIS, innate immune system, and atherosclerosis. The polarization of macrophages into M1 or M2 phenotypes has been associated with inflammation and toll-like receptors (TLRs) 2 and 4 signaling p athway[19,20,21]
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