Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice

Vincent Braunersreuther; Fabrizio Montecucco; Graziano Pelli; Katia Galan; Amanda E. Proudfoot; Alexandre Belin; Nicolas Vuilleumier; Fabienne Burger; Sébastien Lenglet; Irene Caffa; Debora Soncini; Alessio Nencioni; Jean-Paul Vallée; François Mach

doi:10.1160/TH13-04-0297

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(04): 807-825
DOI: 10.1160/TH13-04-0297

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice

Vincent Braunersreuther^*

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

,

Fabrizio Montecucco^*

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

²First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Graziano Pelli

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

,

Katia Galan

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

,

Amanda E. Proudfoot

³Merck Serono Geneva Research Centre, Geneva, Switzerland

,

Alexandre Belin

⁴Department of Radiology – CIBM, Geneva, University Hospital, Geneva, Switzerland

,

Nicolas Vuilleumier

⁵Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Switzerland

⁶Department of Human Protein Science, Geneva Faculty of Medicine, Geneva, Switzerland

,

Fabienne Burger

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

,

Sébastien Lenglet

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

,

Irene Caffa

²First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Debora Soncini

²First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Alessio Nencioni

²First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Jean-Paul Vallée^#

⁴Department of Radiology – CIBM, Geneva, University Hospital, Geneva, Switzerland

,

François Mach^#

¹Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland

› Author Affiliations

Abstract

summary

Chemokines trigger leukocyte trafficking and are implicated in cardiovascular disease pathophysiology. Chemokine-binding proteins, called “Evasins” have been shown to inhibit both CC and CXC chemokinemediated bioactivities. Here, we investigated whether treatment with Evasin-3 (CXC chemokine inhibitor) and Evasin-4 (CC chemokine inhibitor) could influence post-infarction myocardial injury and remodelling. C57Bl/6 mice were submitted in vivo to left coronary artery permanent ligature and followed up for different times (up to 21 days). After coronary occlusion, three intraperitoneal injections of 10 μg Evasin-3, 1 μg Evasin-4 or equal volume of vehicle (PBS) were performed at 5 minutes, 24 hours (h) and 48 h after ischaemia onset. Both anti-chemokine treatments were associated with the beneficial reduction in infarct size as compared to controls. This effect was accompanied by a decrease in post-infarction myocardial leukocyte infiltration, reactive oxygen species release, and circulating levels of CXCL1 and CCL2. Treatment with Evasin-4 induced a more potent effect, abrogating the inflammation already at one day after ischaemia onset. At days 1 and 21 after ischaemia onset, both anti-chemokine treatments failed to significantly improve cardiac function, remodelling and scar formation. At 21-day follow-up, mouse survival was exclusively improved by Evasin-4 treatment when compared to control vehicle. In conclusion, we showed that the selective inhibition of CC chemokines (i.e. CCL5) with Evasin-4 reduced cardiac injury/inflammation and improved survival. Despite the inhibition of CXC chemokine bioactivities, Evasin-3 did not affect mouse survival. Therefore, early inhibition of CC chemokines might represent a promising therapeutic approach to reduce the development of post-infarction heart failure in mice.

Keywords

Chemokines - neutrophils - inflammation - acute myocardial infarction

Full Text

References

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