Role of hypothalamic-pituitary adrenal-axis, toll-like receptors, and macrophage polarization in pre-atherosclerotic changes induced by social isolation stress in mice

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.

Sibling Death in Childhood and Early Adulthood and Risk of Early-Onset Cardiovascular Disease

“…Our finding was consistent with those previous studies that the risks of AF, acute MI, hemorrhagic stroke, and heart failure were the highest immediately after the death of a child or a partner . The findings of a higher CVD risk shortly after sibling death may support the acute physiological mechanisms for posttraumatic stress on CVD, which included the activation of hypothalamic-pituitary-adrenal axis and short-term increased inflammatory activity . Additionally, our findings might support the roles of short-term lifestyle and behavior changes in the postbereavement period .…”

“… 8 , 9 , 10 , 11 , 15 , 23 , 24 The findings of a higher CVD risk shortly after sibling death may support the acute physiological mechanisms for posttraumatic stress on CVD, which included the activation of hypothalamic-pituitary-adrenal axis and short-term increased inflammatory activity. 38 , 44 Additionally, our findings might support the roles of short-term lifestyle and behavior changes in the postbereavement period. 45 In contrast, a Swedish study of individuals born in 1932 to 1962 found a stronger association between sibling death and mortality in the longer term than in the short term, 30 and a Danish study from 1980 to 1996 only observed an increased risk of MI after 6 years of follow-up in parents who lost a child.…”

“…Sibling Death in Childhood and Early Adulthood and Risk of Early-Onset CVD activity. 38,44 Additionally, our findings might support the roles of short-term lifestyle and behavior changes in the postbereavement period. 45 In contrast, a Swedish study of individuals born in 1932 to 1962 found a stronger association between sibling death and mortality in the longer term than in the short term, 30 and a Danish study from 1980 to 1996 only observed an increased risk of MI after 6 years of follow-up in parents who lost a child.…”

Maternal nicotine intoxication before pregnancy induces depressive‐ and anxiety‐like behaviors as well as cognitive deficits in male offspring and correlates with neurobiological changes

“…This axis controls hormone synthesis and release, making it crucial for the ability to deal with adversity. Most individuals with depression have a hyperactive HPA axis (Haj-Mirzaian et al, 2021;Pariante & Lightman, 2008). Corticosteroids have been shown to affect emotional behaviors and cognition in animals and humans in a complex manner (Bos et al, 2012).…”

Recent Progress of Chronic Stress in the Development of Atherosclerosis

“…The activated sympathetic adrenal system can increase the number of immune response cells expressing M receptor and inflammatory cytokines [ 32 , 33 ] and produce a large number of cytokines. After HPA axis changes caused by chronic stress, TLR4/NF- κ B pathway activates proinflammatory cytokines such as MCP-1 and IL-1 α and IL-6 and, at the same time, leads to the increase of intimal macrophage/monocyte ratio [ 17 , 34 ], so that under the interaction of inflammatory factors and cells, endothelial homeostasis changes and inflammation further progresses and forms a vicious circle [ 35 ]. Interestingly, recent studies have also demonstrated that TLR4/NF- κ B pathway also downregulates HMGB1 protein-mediated PPAR γ /LXR α .…”