Inflammatory role and prognostic value of platelet chemokines in acute coronary syndrome

Xavier Blanchet; Katja Cesarek; Johanna Brandt; Heiko Herwald; Daniel Teupser; Helmut Küchenhoff; Ela Karshovska; Sebastian F. Mause; Wolfgang Siess; Hermann Wasmuth; Oliver Soehnlein; Rory R. Koenen; Christian Weber; Philipp von Hundelshausen

doi:10.1160/th14-02-0139

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(06): 1277-1287
DOI: 10.1160/th14-02-0139

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Inflammatory role and prognostic value of platelet chemokines in acute coronary syndrome

Xavier Blanchet^*

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

,

Katja Cesarek^*

²Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany

,

Johanna Brandt

³Statistical Consulting Unit, Department of Statistics, Ludwig-Maximilians-University, Germany

,

Heiko Herwald

⁴Department of Infection Medicine, Lund University, and Lund University Hospital, Lund, Sweden

,

Daniel Teupser

⁵Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Germany

,

Helmut Küchenhoff

³Statistical Consulting Unit, Department of Statistics, Ludwig-Maximilians-University, Germany

,

Ela Karshovska

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

,

Sebastian F. Mause

²Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany

,

Wolfgang Siess

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

,

Hermann Wasmuth

⁶Medizinische Klinik, Luisenhospital, Aachen, Germany

,

Oliver Soehnlein

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

⁹Department of Pathology, Academic Medical Center Amsterdam, Amsterdam University, the Netherlands

,

Rory R. Koenen

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

⁷Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

,

Christian Weber

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

⁷Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

,

Philipp von Hundelshausen

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

⁸DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

› Author Affiliations

Abstract

Summary

Activated platelets and neutrophils exacerbate atherosclerosis. Platelets release the chemokines CXCL4, CXCL4L1 and CCL5, whereas myeloperoxidase (MPO) and azurocidin are neutrophil-derived. We investigated whether plasma levels of these platelet and neutrophil mediators are affected by the acute coronary syndrome (ACS), its medical treatment, concomitant clinical or laboratory parameters, and predictive for the progression of coronary artery disease (CAD). In an observational study, the association of various factors with plasma concentrations of platelet chemokines and neutrophil mediators in 204 patients, either upon admission with ACS and 6 hours later or without ACS or CAD, was determined by multiple linear regression. Mediator release was further analysed after activation of blood with ACS-associated triggers such as plaque material. CXCL4, CXCL4L1, CCL5, MPO and azurocidin levels were elevated in ACS. CXCL4 and CCL5 but not CXCL4L1 or MPO were associated with platelet counts and CRP. CXCL4 (in association with heparin treatment) and MPO declined over 6 hours during ACS. Elevated CCL5 was associated with a progression of CAD. Incubating blood with plaque material, PAR1 and PAR4 activation induced a marked release of CXCL4 and CCL5, whereas CXCL4L1 and MPO were hardly or not altered. Platelet chemokines and neutrophil products are concomitantly elevated in ACS and differentially modulated by heparin treatment. CCL5 levels during ACS predict a progression of preexisting CAD. Platelet-derived products appear to dominate the inflammatory response during ACS, adding to the emerging evidence that ACS per se may promote vascular inflammation.

Note: The review process for this paper was fully handled by Gregory Y. H. Lip, Editor in Chief.

Keywords

Acute coronary syndrome - atherosclerosis - chemokines - platelets - neutrophils

Full Text

References

References
1 Massberg S. et al. A critical role of platelet adhesion in the initiation of athero-sclerotic lesion formation. J Exp Med 2002; 196: 887-896.
2 Huo Y. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-67.
3 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
4 Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res 2012; 110: 875-888.
5 Montecucco F. et al. Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischaemic stroke. Stroke 2010; 41: 1394-1404.
6 Montecucco F. et al. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J 2012; 33: 846-856.
7 Quercioli A. et al. Receptor activator of NF- kappaB ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability. Thromb Haemost 2012; 107: 124-139.
8 Dutta P. et al. Myocardial infarction accelerates atherosclerosis. Nature 2012; 487: 325-329.
9 Liehn EA. et al. Repair after myocardial infarction, between fantasy and reality: the role of chemokines. J Am Coll Cardiol 2011; 58: 2357-2362.
10 Karshovska E. et al. Platelet chemokines in health and disease. Thromb Hae-most 2013; 110: 894-902.
11 Koenen RR. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15: 97-103.
12 Gleissner CA. et al. CXCL4 downregulates the atheroprotective hemoglobin receptor CD163 in human macrophages. Circ Res 2010; 106: 203-211.
13 Struyf S. et al. Platelets release CXCL4L1, a nonallelic variant of the chemokine platelet factor-4/CXCL4 and potent inhibitor of angiogenesis. Circ Res 2004; 95: 855-857.
14 Struyf S. et al. Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3. Blood 2011; 117: 480-488.
15 Sarabi A. et al. CXCL4L1 inhibits angiogenesis and induces undirected endothelial cell migration without affecting endothelial cell proliferation and monocyte recruitment. J Thromb Haemost 2011; 09: 209-219.
16 De Sutter J. et al. PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function. PLoS One 2012; 07: e31343.
17 Sachais BS. et al. Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE-/- mice. Thromb Haemost 2007; 98: 1108-1113.
18 Scirica BM. et al. Assessment of multiple cardiac biomarkers in non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 trial. Eur Heart J 2011; 32: 697-705.
19 Gautam N. et al. Heparin-binding protein (HBP/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability. Nat Med 2001; 07: 1123-1127.
20 Soehnlein O. et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 2008; 112: 1461-1471.
21 Berres ML. et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest 2010; 120: 4129-4140.
22 Burkhart JM. et al. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 2012; 120: e73-82.
23 Hartwig H. et al. Platelet-derived PF4 reduces neutrophil apoptosis following arterial occlusion. Thromb Haemost 2014; 111: 562-564.
24 Sabatine MS. et al. Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy- Thrombolysis in Myocardial Infarction 18 trial)substudy. J Am Coll Cardiol 2002; 40: 1761-1768.
25 Holmer-Jensen J. et al. Differential effects of dietary protein sources on post-prandial low-grade inflammation after a single high fat meal in obese non-diabetic subjects. Nutrition J 2011; 10: 115.
26 Aye MM. et al. Acute Hypertriglyceridemia Induces Platelet Hyperactivity That is Not Attenuated by Insulin in Polycystic Ovary Syndrome. J Am Heart Assoc 2014; 03: e000706.
27 Soehnlein O. et al. Distinct functions of chemokine receptor axes in the atherogenic mobilisation and recruitment of classical monocytes. EMBO Mol Med 2013; 05: 471-481.
28 Morrow DA. Appraisal of myeloperoxidase for evaluation of patients with suspected acute coronary syndromes. J Am Coll Cardiol 2007; 49: 2001-2002.
29 Baldus S. et al. Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. J Clin Invest 2001; 108: 1759-1770.
30 Rudolph TK. et al. Contribution of myeloperoxidase to smoking-dependent vascular inflammation. Proc Am Thoracic Soc 2008; 05: 820-823.
31 Mazor R. et al. Primed polymorphonuclear leukocytes constitute a possible link between inflammation and oxidative stress in hyperlipidemic patients. Atherosclerosis 2008; 197: 937-943.
32 Wanten GJA. et al. Saturated triglycerides and fatty acids activate neutrophils depending on carbon chain-length. Eur J Clin Invest 2002; 32: 285-289.
33 Ritter L. et al. Exaggerated Neutrophil-Mediated Reperfusion Injury after Ischaemic Stroke in a Rodent Model of Type 2 Diabetes. Microcirculation 2011; 18: 552-561.
34 Zhang S. et al. Heparin-induced Leukocytosis Requires 6-O-Sulfation and Is Caused by Blockade of Selectin- and CXCL12 Protein-mediated Leukocyte Trafficking in Mice. J Biol Chem 2012; 287: 5542-5553.
35 Kraaijeveld AO. et al. CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischaemic symptoms. Circulation 2007; 116: 1931-1941.
36 Brummel-Ziedins K. et al. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition. J Thromb Haemost 2008; 06: 104-110.
37 Wang L. et al. P2 receptor mRNA expression profiles in human lymphocytes, monocytes and CD34+ stem and progenitor cells. BMC Immunol 2004; 05: 16.
38 Colognato R. et al. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood 2003; 102: 2645-2652.
39 Bolton SJ. et al. Expression of and functional responses to protease-activated receptors on human eosinophils. J Leukoc Biol 2003; 74: 60-68.
40 Jonnalagadda D. et al. Platelet secretion is kinetically heterogeneous in an agonist-responsive manner. Blood 2012; 120: 5209-5216.
41 Reichel CA. et al. Chemokine receptors Ccr1, Ccr2, and Ccr5 mediate neutro-phil migration to postischaemic tissue. J Leukoc Biol 2006; 79: 114-122.
42 Drechsler M. et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis in mice. Circulation 2010; 122: 1837-1845.
43 Grommes J. et al. CCR5 and FPR1 Mediate Neutrophil Recruitment in Endotoxin-Induced Lung Injury. J Innate Immun 2014; 06: 111-116.
44 Reininger AJ. et al. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J Am Coll Cardiol 2010; 55: 1147-1158.

Supplementary Material

Online Supplementary Material (PDF)