
BCS Conference 2017 (Basic Science)
AbstractTitle: INFARCT SIZE IN A RAT MODEL OF ACUTE MYOCARDIAL INFARCTION IS REDUCED BY INTERLEUKIN-6 TRANS-SIGNALLING BLOCKADE USING SGP130FC BUT NOT AN ANTI-IL-6R MONOCLONAL ANTIBODY
Submission Date : 22/02/2017 13:08:03
Category: Basic Science
KeyWords
Myocardial Infarction, Interleukin-6, Inflammation
Abstract Body
Introduction: Interleukin-6
(IL-6) is elevated during acute myocardial infarction (AMI) particularly after
reperfusion with primary percutaneous coronary intervention (PPCI). Higher
circulating levels of IL-6 and its soluble receptor (sIL-6R) are associated
with adverse outcomes post AMI. Therefore while IL-6 is a potential therapeutic
target in AMI, animal models employing monoclonal antibodies (MAb) against the
IL-6R have failed to demonstrate benefit. We
hypothesised that blockade of the pro-inflammatory aspects of IL-6 signalling (trans-signalling)
with the sgp130Fc protein in an animal model of AMI would
result in reduced infarct size (IS) whereas blockade with a MAb against IL-6R (which
blocks both the pro and anti-inflammatory actions of IL-6) would not.
Methods: AMI was
induced in male Sprague-Dawley rats by occluding the left-anterior descending
artery for 50 minutes prior to reperfusion (analogous to PPCI). The model was
characterised by measuring the temporal profile of IL-6, sIL-6R and other
inflammatory mediators (MCP-1, KC/GRO, IL-1β, TNFα) within the heart
tissue and plasma by ELISA at 2,4,24,72,120 and 168 hours post AMI
(n=3-4/group). In addition, infarct progression over time (measured histologically
with TTC and Evans Blue dyes and with plasma myoglobin), and leukocyte
infiltration (flow-cytometry of cells obtained from heart digests) were measured.
In therapeutic experiments rats received either 4µg/g of a MAb against IL-6R
(clone 15A7), 0.5µg/g of sgp130Fc or vehicle alone given intravenously 1 minute
prior to reperfusion (n=7-8/group).
Results: IS/Area
at risk (AAR) increased from 31.81% at 4 hours to 46.1% at 24 hours (p=0.03),
with no further change at 48 hours. Myoglobin peaked at 24 hours. IL-6 levels
in the heart were biphasic; a robust early peak at 2-4 hours was followed by a
trough at 24 hours, and a more sustained peak between days 3-5. Only the early
peak was associated with significantly elevated circulating IL-6. The early peak
was temporally associated with infarct progression and neutrophil influx,
whereas the second was associated with classical mononcyte infiltration. Other inflammatory
mediators followed a similar but less pronounced biphasic pattern. Cardiac and
plasma sIL-6R peaked at 24 hours, coinciding with maximal cardiac neutrophil numbers.
Based on these data the effect of IL-6 antagonism was assessed at 24 hours.
IS/AAR after blockade with anti-IL-6R MAb was unchanged compared with control (46.8%
vs 46.1%). However, blockade with sgp130Fc resulted in a substantial reduction
in IS/ARR (26.32%, p 0.0004).
Conclusions: IL-6
trans-signalling blockade with sgp130Fc but not blockade with an anti-IL-6R MAb
reduces IS/AAR in an animal model of AMI with reperfusion. Ongoing experiments
seek to understand the mechanisms underpinning this observation and to explore
the effects on infarct healing and remodelling.
Submitter Details
Dr Marc Jonathan George
Authors
Names |
Presenting Author |
Institution |
Dr Marc Jonathan George |
Yes |
University College London |
Dr Daniel Stuckey |
No |
University College London |
Mrs Valerie Taylor |
No |
University College London |
Prof Aroon Hingorani |
No |
University College London |
Prof Derek Gilroy |
No |
University College London |
|