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

Research output: Contribution to journalArticleAcademicpeer-review

41 Citations (Web of Science)

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 languageEnglish
Article number10647
Number of pages11
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 13 Jul 2018

Keywords

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

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