Editors' ChoiceAtherosclerosis

Stress (In)Flames Atherosclerosis

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Science Translational Medicine  06 Aug 2014:
Vol. 6, Issue 248, pp. 248ec134
DOI: 10.1126/scitranslmed.3010113

Stress can escalate cardiovascular complications. That’s common knowledge, but how does it work at the molecular level? A new study by Heidt et al. draws new mechanistic links between the central nervous system and atherosclerosis that involve stress-induced hematopoietic progenitor cell activity. The researchers sought to mechanistically explain their initial observations made in highly stressed, on-duty medical residents working in the intensive care unit. They reported that higher perceived stress in medical residents while on duty was associated with elevated leukocyte counts. They also noted that chronic stress in mice led to elevated leukocyte counts that could be explained by increased proliferation of hematopoietic stem cells (HSCs).

To provide a mechanism for these observations, the researchers focused on the sympathetic nervous system, which produces catecholamines such as norepinephrine in response to stress. They looked at the impact of norepinephrine on the HSC niche and found increased expression of norepinephrine and the limiting enzyme in norepinephrine production, tyrosine hydroxylase, in the bone marrow of the stressed mice. Moreover, the production of the chemokine CXCL12, which has a primary role in limiting HSC proliferation and is a target of norepinephrine, was suppressed in the bone marrow of the stressed mice. Next, the researchers discovered that β3-adrenergic receptors were highly expressed in the mesenchymal stromal cells of the bone marrow. Through an elaborate set of experiments involving a mouse model of genetic β3-adrenergic receptor deficiency and a selective β3-adrenoreceptor antogonist, the researchers demonstrated that production of stress-induced norepinephrine acts on HSC proliferation and CXCL12 suppression by selective engagement of the β3-adrenergic receptors in the HSC niche. These results should spark further interest in identifying the “stress sensor” in the hematopoietic progenitor cells that controls their differentiation into proinflammatory leukocytes.

The authors next investigated whether chronic stress promotes atherosclerosis by increasing the supply of inflammatory leukocytes to the atherosclerotic plaques through this new mechanism. Indeed, chronic stress in mice elevated plaque inflammation and the necrotic core size while thinning the fibrous cap (characteristics of vulnerable plaques), but surprisingly did so without altering plaque size. Furthermore, these stress-induced effects on plaque composition could be blocked by using β3-adrenoreceptor antogonists. These exciting findings warrant further investigation into the potential of selective β3-adrenergic receptor blockers for limiting cardiovascular events in humans.

T. Heidt et al., Chronic variable stress activates hematopoietic stem cells. Nat. Med. 10.1038/nm.3589 (2014). [Abstract]

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