Acute psychological stress accelerates the progression of atherosclerosis
Final Report Abstract
Acute mental stress strongly associates with cardiovascular disease, but the underlying mechanisms remain largely elusive. We sought to close this gap in understanding and explored how acute mental stress precipitates disease. We first looked into the human situation and assessed blood leukocyte levels in healthy individuals that were exposed to an acute stressor. Individuals watched an exciting sporting event in which they were emotionally involved. To our surprise, we found that total blood leukocyte levels – particularly the inflammatory blood monocyte subset – decreased during stress exposure. To followed-up on this observation, we next moved in to an animal model of acute stress. We reproduced our observation from stressed individuals and found that blood leukocyte levels decreased during stress. We next explored the fate of these vanishing blood leukocytes and performed celltracking experiments which revealed that stress promoted leukocyte recruitment into distinct tissues. When we repeated these experiments using mice with pre-existing atherosclerosis, we found that stress exposure also promoted uptake of inflammatory blood leukocyte into atherosclerotic plaques. This resulted in a rapid expansion of inflammatory plaque leukocytes which, in turn, promoted vascular inflammation and plaque rupture. We next addressed how stress promotes influx of blood leukocytes into plaques. Here, we first tested the possibility whether stress alleviates leukocyte recruitment through modulation of plaque endothelial cells. Plaque endothelial cells indeed underwent phenotypic changes upon stress and upregulated leukocyte adhesion molecules. Further, we found that chemokines CCL7 (chemokine (C-C motif) ligand 7) and CXCL1 (chemokine (C-X-C motif) ligand 1) – both strong chemoattracts for monocytes and neutrophils – rose in the plasma. We next probed how stress elevated endothelial leukocyte adhesion molecule expression and chemokine release. We found that stress elevated levels of norepinephrine – the neurotransmitter of the sympathetic nervous system – locally in the vessel wall. Further, levels of the stress hormones epinephrine and glucocorticoids rose systemically in the plasma. Cell culture experiments revealed that only norepinephrine, but not epinephrine and glucocorticoids, modulated endothelial cells similarly to what we found in endothelial cells in vivo. Specifically, our experiments revealed that norepinephrine elevated leukocyte adhesion molecule levels and promoted adhesion of neutrophils and monocytes to norepinephrine-primed endothelial cells. This effect was mediated via alpha- but not beta-adrenoreceptors. We next depleted norepinephrine signaling using both a chemical and surgical approach and found reduced recruitment of blood leukocyte to plaques in norepinephrine depleted mice. Next, we explored the source of CCL7 and CXCL1 and found that both endothelial cells and macrophages release these chemokines in a norepinephrine-dependent manner. Systemic CCL7 and CXCL1 depletion using neutralizing antibodies dampened recruitment of blood leukocyte into plaques and hence prevented stress-induced accumulation of plaque leukocytes. In summary, stress is a crucial risk factor for atherosclerosis and is comparably associated with the occurrence of cardiovascular disease as other classical risk factors. Despite this impact on public health, we do not yet fully understand the underlying biological basis. Our study provides novel mechanistic insights into precisely how acute mental stress precipitates progression of atherosclerosis leading to plaque rupture. We show that acute stress promotes leukocyte influx to tissues, particularly atherosclerotic plaques, through norepinephrine-dependent activation of endothelial cells and macrophages. Consequently, acute stress promotes rapid accumulation of inflammatory plaque leukocytes, known drivers of vascular inflammation and plaque vulnerability.
Publications
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Functional investigation of the coronary artery disease gene SVEP1. Basic Res Cardiol. 2020 Nov 13;115(6):67
Winkler MJ, Müller P, Sharifi AM, Wobst J, Winter H, Mokry M, Ma L, van der Laan SW, Pang S, Miritsch B, Hinterdobler J, Werner J, Stiller B, Güldener U, Webb TR, Asselbergs FW, Björkegren JLM, Maegdefessel L, Schunkert H, Sager HB, Kessler T
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Hospital Admissions with Acute Coronary Syndromes During the COVID-19 Pandemic in German Cardiac Care Units. Cardiovasc Res. 2020 Jul 8
Kessler T, Graf T, Hilgendorf I, Rizas K, Martens E, Mühlen CVZ, Kraemer P, Meyer-Saraei R, Neumann FJ, Bode C, Laugwitz KL, Massberg S, Schunkert H, Weil J, Kastrati A, Sager HB
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Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis. Eur Heart J. 2021
J. Hinterdobler, S. Schott, H. Jin, A. Meesmann, A.-L. Steinsiek, A.-S. Zimmermann, J. Wobst, P. Müller, C. Mauersberger, B. Vilne, A. Baecklund, C.-S. Chen, A. Moggio, Q. Braster, M. Molitor, M. Krane, W. E. Kempf, K.-H. Ladwig, M. Hristov, M. Hulsmans, I. Hilgendorf, C. Weber, P. Wenzel, C. Scheiermann, L. Maegdefessel, O. Soehnlein, P. Libby, M. Nahrendorf, H. Schunkert, T. Kessler, H. B. Sager
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Immune cell-based cardiovascular risk assessment: spotlight on the neutrophillymphocyte ratio. Eur Heart J. 2021 Jan 9
Sager HB, Koenig W
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Inflammation-Related Risk Loci in Genome-Wide Association Studies of Coronary Artery Disease. Cells 2021, 10(2), 440
Mauersberger C, Schunkert H, and Sager HB
