Stress facilitates plaques inflammation and disruption
Atherosclerosis is an inflammatory disease characterized by the “hardening” of the arteries. This is caused by the accumulation of deposits mainly composed of cell debris, fats, cholesterol, calcium, on the inner walls of arteries leading to vessels’ narrowing and decreased blood flow. These deposits are called plaques and they also contain platelets and immune cells (leukocytes), in particular inflammatory monocytes and macrophages. Enzymes produced by the immune cells can partially degrade the plaques causing their disruption and cause formation of blood clots that will occlude the vessels and block oxygen supply to different organs and tissues. If a clot occurs in vessels of the heart or the brain, it will elicit a heart attack or a stroke respectively.
Link between stress and atherosclerosis
There is evidence that chronic stress increases the risk of atherosclerosis, but no mechanism linking the two phenomena has been demonstrated so far. Since stressful emotional states can affect the function of the immune system, Heidt and colleagues of the Massachusetts General Hospital hypothesized that stress increases the activity of inflammatory cells in the plaques facilitating their rupture, as you can read in their recently published article.
To test this possibility the scientists measured the effects of various forms of stress (including isolation, damp bedding, overnight illumination) on the number of leukocytes in mice. They found that compared to the controls the stressed animals had significantly more circulating immune cells. This was the result of increased division of the hematopoietic stem cells (HSCs), which are the immature precursors of the immune cells, and subsequent increased production of leukocyte progenitors in their bone marrow.
But how does stress activate the HSCs?
The researchers found that stress also increased the levels of the neurotransmitter noradrenaline in the bone marrow. This chemical blocked the production of another molecule called CXCL12, which is known to inhibit HSC proliferation. Thus, by eliminating the inhibitor CXCL12, stress activates HSCs and the production of immune cells.
The scientists then wondered if this process is active also in atherosclerosis and can thus mediate the deleterious effects of stress on plaque stability. To examine this possibility, they repeated the experiments in the atherosclerosis-prone mice called Apoe -/-. They confirmed that stress caused an increase of leukocytes and that it significantly augmented the number of immune cells in the atherosclerotic plaques of the Apoe -/- animals. Accordingly, the levels of plaque-degrading enzymes were higher compared to those found in unstressed animals, and the plaques presented signs of fragility, such has a thin surface and a necrotic core.
Function of the nervous system
Since stress acts on the immune system through the nervous system, would it be possible to reduce plaque inflammation by modulating the activity of the nervous system? To find the answer, the researchers treated the stressed, atherosclerotic mice with a drug (β3-adrenergic receptor blocker) that opposes the activity of noradrenaline. They discovered that in fact the drug decreased the number of inflammatory immune cells in the atherosclerotic lesions and inhibited disease progression.
How does this study help us?
These observations have relevance for humans as well. When the authors examined medical residents working in intensive care units under significant stress, they reported that these subjects had higher numbers of leukocytes in their blood compared to those measured when they were not working, suggesting that the effects of stress on the human immune system are similar to those found in mice.
Even if a formal proof of a neuroimmune effect of stress and of its role in exacerbating atherosclerosis in humans is still missing, this study calls for investigations in this area and, importantly, suggests that specific noradrenaline receptor blockers may be useful in limiting atheroslcerosis progression in stressed individuals.
Photo: Flickr, kugel
Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A, von Zur Muhlen C, Bode C, Fricchione GL, Denninger J, Lin CP, Vinegoni C, Libby P, Swirski FK, Weissleder R, & Nahrendorf M (2014). Chronic variable stress activates hematopoietic stem cells. Nature medicine, 20 (7), 754-8 PMID: 24952646
enzymes, CXCL12, hematopoietic stem cells, HSCs, noradrenaline, atherosclerosis, stress, leukocytes, arteries, plaque,