Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke

You don't want more atherosclerosis after your stroke, so DEMAND your doctor come up with a solution. Not doing anything at all should be grounds for firing.  Dead wood needs to be removed and we have to start someplace, your stroke hospital is not cleaning house of incompetent staff.
http://stm.sciencemag.org/content/10/432/eaao1313?utm_campaign=toc_stm_2018-03-14&et_rid=33952789&et_cid=1907187

1. Stefan Roth¹,²,
2. Vikramjeet Singh¹,²,
3. Steffen Tiedt¹,²,
4. Lisa Schindler¹,²,
5. Georg Huber³,
6. Arie Geerlof³,
7. Daniel J. Antoine⁴,
8. Antoine Anfray⁵,
9. Cyrille Orset⁵,
10. Maxime Gauberti⁵,
11. Antoine Fournier⁵,
12. Lesca M. Holdt⁶,
13. Helena Erlandsson Harris⁷,
14. Britta Engelhardt⁸,
15. Marco E. Bianchi⁹,
16. Denis Vivien⁵,
17. Christof Haffner¹,
18. Jürgen Bernhagen¹,²,
19. Martin Dichgans¹,² and
20. Arthur Liesz¹,²,*

1. ¹Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.
2. ²Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.
3. ³Institute of Structural Biology, Helmholtz Centre Munich, 85764 Munich, Germany.
4. ⁴Medical Research Council Center for Drug Safety Science, Department for Molecular and Clinical Pharmacology, University of Liverpool, L69 3GE Liverpool, UK.
5. ⁵INSERM, Université de Caen-Normandie, CHU de Caen, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, GIP Cyceron, 14074 Caen, France.
6. ⁶Institute of Laboratory Medicine, Klinikum der Universität München, 81377 Munich, Germany.
7. ⁷Department of Medicine, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
8. ⁸Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
9. ⁹Faculty of Medicine, San Raffaele University, 20132, Milan, Italy.

1. ↵*Corresponding author. Email: arthur.liesz@med.uni-muenchen.de

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Science Translational Medicine  14 Mar 2018:
Vol. 10, Issue 432, eaao1313
DOI: 10.1126/scitranslmed.aao1313

Stefan Roth

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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Vikramjeet Singh

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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Steffen Tiedt

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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Lisa Schindler

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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Georg Huber

Institute of Structural Biology, Helmholtz Centre Munich, 85764 Munich, Germany.

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Arie Geerlof

Institute of Structural Biology, Helmholtz Centre Munich, 85764 Munich, Germany.

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Daniel J. Antoine

Medical Research Council Center for Drug Safety Science, Department for Molecular and Clinical Pharmacology, University of Liverpool, L69 3GE Liverpool, UK.

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Antoine Anfray

INSERM, Université de Caen-Normandie, CHU de Caen, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, GIP Cyceron, 14074 Caen, France.

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Cyrille Orset

INSERM, Université de Caen-Normandie, CHU de Caen, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, GIP Cyceron, 14074 Caen, France.

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Maxime Gauberti

INSERM, Université de Caen-Normandie, CHU de Caen, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, GIP Cyceron, 14074 Caen, France.

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Antoine Fournier

INSERM, Université de Caen-Normandie, CHU de Caen, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, GIP Cyceron, 14074 Caen, France.

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Lesca M. Holdt

Institute of Laboratory Medicine, Klinikum der Universität München, 81377 Munich, Germany.

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Helena Erlandsson Harris

Department of Medicine, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

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Britta Engelhardt

Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.

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Marco E. Bianchi

Faculty of Medicine, San Raffaele University, 20132, Milan, Italy.

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Denis Vivien

INSERM, Université de Caen-Normandie, CHU de Caen, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, GIP Cyceron, 14074 Caen, France.

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Christof Haffner

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.

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Jürgen Bernhagen

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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Martin Dichgans

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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Arthur Liesz

Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany.Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany.

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• For correspondence: arthur.liesz@med.uni-muenchen.de

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An alarmin(g) consequence of stroke

Patients surviving a stroke are at an increased risk for subsequent cardiovascular events. Preclinical models have shown accelerated atherosclerosis after stroke; however, the mechanisms underlying this enhanced plaque formation and inflammation in arteries have not been investigated. Now, Roth et al. have discovered that stroke-induced alarmin high-mobility group box 1 (HMGB1) release and sympathetic stress response activation exert a synergistic effect, resulting in exacerbation of atherosclerotic plaques in mice. The authors suggest that interfering with these processes after stroke might reduce the risk of secondary cardiovascular events.

Abstract

Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis—a major source of recurrent vascular events—have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)–signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2–CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of β3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke.

• Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

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