Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

Tanja Vajen; Rory R. Koenen; Isabella Werner; Mareike Staudt; Delia Projahn; Adelina Curaj; Tolga Taha Sonmez; Sakine Simsekyilmaz; David Schumacher; Julia Mollmann; Tilman M. Hackeng; Philipp von Hundelshausen; Christian Weber; Elisa A. Liehn

doi:10.1038/s41598-018-29026-0

Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

Tanja Vajen, Rory R. Koenen^*, Isabella Werner, Mareike Staudt, Delia Projahn, Adelina Curaj, Tolga Taha Sonmez, Sakine Simsekyilmaz, David Schumacher, Julia Mollmann, Tilman M. Hackeng, Philipp von Hundelshausen, Christian Weber, Elisa A. Liehn

^*Corresponding author for this work

Biochemie

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.

Original language	English
Article number	10647
Number of pages	11
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-29026-0
Publication status	Published - 13 Jul 2018

Keywords

ISCHEMIA/REPERFUSION INJURY
PLATELET CHEMOKINES
NEOINTIMA FORMATION
MONOCYTE SUBSETS
DEFICIENT MICE
ATHEROSCLEROSIS
CCR5
RANTES
PLATELET-FACTOR-4
INFECTION

Access to Document

10.1038/s41598-018-29026-0Licence: CC BY

https://doi.org/10.1038/s41598-018-29026-0

Cite this

Vajen, T., Koenen, R. R., Werner, I., Staudt, M., Projahn, D., Curaj, A., Sonmez, T. T., Simsekyilmaz, S., Schumacher, D., Mollmann, J., Hackeng, T. M., von Hundelshausen, P., Weber, C., & Liehn, E. A. (2018). Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis. Scientific Reports, 8(1), Article 10647. https://doi.org/10.1038/s41598-018-29026-0

@article{47109774f1b64028b835b4a9c7661280,

title = "Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis",

abstract = "Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.",

keywords = "ISCHEMIA/REPERFUSION INJURY, PLATELET CHEMOKINES, NEOINTIMA FORMATION, MONOCYTE SUBSETS, DEFICIENT MICE, ATHEROSCLEROSIS, CCR5, RANTES, PLATELET-FACTOR-4, INFECTION",

author = "Tanja Vajen and Koenen, {Rory R.} and Isabella Werner and Mareike Staudt and Delia Projahn and Adelina Curaj and Sonmez, {Tolga Taha} and Sakine Simsekyilmaz and David Schumacher and Julia Mollmann and Hackeng, {Tilman M.} and {von Hundelshausen}, Philipp and Christian Weber and Liehn, {Elisa A.}",

year = "2018",

month = jul,

day = "13",

doi = "10.1038/s41598-018-29026-0",

language = "English",

volume = "8",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Vajen, T, Koenen, RR, Werner, I, Staudt, M, Projahn, D, Curaj, A, Sonmez, TT, Simsekyilmaz, S, Schumacher, D, Mollmann, J, Hackeng, TM, von Hundelshausen, P, Weber, C & Liehn, EA 2018, 'Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis', Scientific Reports, vol. 8, no. 1, 10647. https://doi.org/10.1038/s41598-018-29026-0

TY - JOUR

T1 - Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

AU - Vajen, Tanja

AU - Koenen, Rory R.

AU - Werner, Isabella

AU - Staudt, Mareike

AU - Projahn, Delia

AU - Curaj, Adelina

AU - Sonmez, Tolga Taha

AU - Simsekyilmaz, Sakine

AU - Schumacher, David

AU - Mollmann, Julia

AU - Hackeng, Tilman M.

AU - von Hundelshausen, Philipp

AU - Weber, Christian

AU - Liehn, Elisa A.

PY - 2018/7/13

Y1 - 2018/7/13

N2 - Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.

AB - Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.

KW - ISCHEMIA/REPERFUSION INJURY

KW - PLATELET CHEMOKINES

KW - NEOINTIMA FORMATION

KW - MONOCYTE SUBSETS

KW - DEFICIENT MICE

KW - ATHEROSCLEROSIS

KW - CCR5

KW - RANTES

KW - PLATELET-FACTOR-4

KW - INFECTION

U2 - 10.1038/s41598-018-29026-0

DO - 10.1038/s41598-018-29026-0

M3 - Article

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10647

ER -

Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

Abstract

Keywords

Access to Document

Fingerprint

Cite this