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

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

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
Pages (from-to)	e0167195
Journal	PLoS ONE
Volume	11
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0167195
Publication status	Published - 2016
Externally published	Yes

Keywords

Animals
Antibodies, Monoclonal/pharmacology
Disease Models, Animal
Fibrosis/metabolism
Heart/drug effects
Hemodynamics/drug effects
Hypertrophy/metabolism
Interleukin-6/blood
Male
Mice, Inbred C57BL
Microscopy, Fluorescence
Myocardial Infarction/metabolism
Myocardial Reperfusion Injury/metabolism
Myocardium/metabolism
Receptors, Interleukin-6/antagonists & inhibitors
Time Factors
Ventricular Remodeling/drug effects

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10.1371/journal.pone.0167195

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@article{a3a6811e6cb94226ad045001d30235f7,

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.",

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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 {Mateo Leach}, Irene and Rozemarijn Vliegenthart and Sillje, {Herman H W} and {van der Harst}, Pim",

year = "2016",

doi = "10.1371/journal.pone.0167195",

language = "English",

volume = "11",

pages = "e0167195",

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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 - Mateo Leach, Irene

AU - Vliegenthart, Rozemarijn

AU - Sillje, Herman H W

AU - van der Harst, Pim

PY - 2016

Y1 - 2016

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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KW - Antibodies, Monoclonal/pharmacology

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KW - Fibrosis/metabolism

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KW - Hemodynamics/drug effects

KW - Hypertrophy/metabolism

KW - Interleukin-6/blood

KW - Male

KW - Mice, Inbred C57BL

KW - Microscopy, Fluorescence

KW - Myocardial Infarction/metabolism

KW - Myocardial Reperfusion Injury/metabolism

KW - Myocardium/metabolism

KW - Receptors, Interleukin-6/antagonists & inhibitors

KW - Time Factors

KW - Ventricular Remodeling/drug effects

U2 - 10.1371/journal.pone.0167195

DO - 10.1371/journal.pone.0167195

M3 - Article

C2 - 27936014

SN - 1932-6203

VL - 11

SP - e0167195

JO - PLoS ONE

JF - PLoS ONE

IS - 12

ER -

Inhibition of Interleukin-6 Receptor in a Murine Model of Myocardial Ischemia-Reperfusion

Abstract

Keywords

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