Inhibition of interleukin-6 receptor in a murine model of myocardial ischemia-reperfusion

Minke H.T. Hartman; Inge Vreeswijk-Baudoin; Hilde E. Groot; Kees W.A. Van De Kolk; Rudolf A. De Boer; Irene Mateo Leach; Rozemarijn Vliegenthart; Herman H.W. Sillje; Pim Van Der Harst

doi:10.1371/journal.pone.0167195

Inhibition of interleukin-6 receptor in a murine model of myocardial ischemia-reperfusion

Minke H.T. Hartman, Inge Vreeswijk-Baudoin, Hilde E. Groot, Kees W.A. Van De Kolk, Rudolf A. De Boer, Irene Mateo Leach^*, Rozemarijn Vliegenthart, Herman H.W. Sillje, Pim Van Der Harst

^*Corresponding author for this work

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

32 Citations (Scopus)

Abstract

Background:

Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R).

Methods:

CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks.

Results:

I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups.

Conclusion:

Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling.

Original language	English
Article number	e0167195
Journal	PLoS ONE
Volume	11
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0167195
Publication status	Published - 9 Dec 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Hartman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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10.1371/journal.pone.0167195Licence: CC BY

Inhibition of Interleukin-6 Receptor in a Murine Model of Myocardial Ischemia-ReperfusionFinal published version, 0.99 MBLicence: CC BY

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@article{14e371ecb0f44fd6904e5073a59d64a1,

title = "Inhibition of interleukin-6 receptor in a murine model of myocardial ischemia-reperfusion",

abstract = "Background: Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). Methods: CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. Results: I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. Conclusion: Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling.",

author = "Hartman, {Minke H.T.} and Inge Vreeswijk-Baudoin and Groot, {Hilde E.} and {Van De Kolk}, {Kees W.A.} and {De Boer}, {Rudolf A.} and Leach, {Irene Mateo} and Rozemarijn Vliegenthart and Sillje, {Herman H.W.} and {Van Der Harst}, Pim",

note = "Publisher Copyright: {\textcopyright} 2016 Hartman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2016",

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T1 - Inhibition of interleukin-6 receptor in a murine model of myocardial ischemia-reperfusion

AU - Hartman, Minke H.T.

AU - Vreeswijk-Baudoin, Inge

AU - Groot, Hilde E.

AU - Van De Kolk, Kees W.A.

AU - De Boer, Rudolf A.

AU - Leach, Irene Mateo

AU - Vliegenthart, Rozemarijn

AU - Sillje, Herman H.W.

AU - Van Der Harst, Pim

N1 - Publisher Copyright: © 2016 Hartman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2016/12/9

Y1 - 2016/12/9

N2 - Background: Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). Methods: CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. Results: I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. Conclusion: Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling.

AB - Background: Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). Methods: CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. Results: I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. Conclusion: Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling.

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SN - 1932-6203

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JO - PLoS ONE

JF - PLoS ONE

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Inhibition of interleukin-6 receptor in a murine model of myocardial ischemia-reperfusion

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