Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats

Ellis N Ter Horst, Paul A J Krijnen, Nazanin Hakimzadeh, Lourens F H J Robbers, Alexander Hirsch, Robin Nijveldt, Ingrid Lommerse, Ruud D Fontijn, Elisa Meinster, Ronak Delewi, Niels van Royen, Felix Zijlstra, Albert C van Rossum, C Ellen van der Schoot, Tineke C T M van der Pouw Kraan, Anton J Horrevoets, Anja M van der Laan, Hans W M Niessen, Jan J Piek

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.

Original languageEnglish
Pages (from-to)1
JournalBasic Research in Cardiology
Volume114
Issue number1
DOIs
Publication statusPublished - 12 Nov 2018

Cite this

@article{9ba5113342ec4be9a29956f92776920a,
title = "Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats",
abstract = "Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.",
author = "{Ter Horst}, {Ellis N} and Krijnen, {Paul A J} and Nazanin Hakimzadeh and Robbers, {Lourens F H J} and Alexander Hirsch and Robin Nijveldt and Ingrid Lommerse and Fontijn, {Ruud D} and Elisa Meinster and Ronak Delewi and {van Royen}, Niels and Felix Zijlstra and {van Rossum}, {Albert C} and {van der Schoot}, {C Ellen} and {van der Pouw Kraan}, {Tineke C T M} and Horrevoets, {Anton J} and {van der Laan}, {Anja M} and Niessen, {Hans W M} and Piek, {Jan J}",
year = "2018",
month = "11",
day = "12",
doi = "10.1007/s00395-018-0709-7",
language = "English",
volume = "114",
pages = "1",
journal = "Basic Research in Cardiology",
issn = "0300-8428",
publisher = "D. Steinkopff-Verlag",
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}

Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats. / Ter Horst, Ellis N; Krijnen, Paul A J; Hakimzadeh, Nazanin; Robbers, Lourens F H J; Hirsch, Alexander; Nijveldt, Robin; Lommerse, Ingrid; Fontijn, Ruud D; Meinster, Elisa; Delewi, Ronak; van Royen, Niels; Zijlstra, Felix; van Rossum, Albert C; van der Schoot, C Ellen; van der Pouw Kraan, Tineke C T M; Horrevoets, Anton J; van der Laan, Anja M; Niessen, Hans W M; Piek, Jan J.

In: Basic Research in Cardiology, Vol. 114, No. 1, 12.11.2018, p. 1.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats

AU - Ter Horst, Ellis N

AU - Krijnen, Paul A J

AU - Hakimzadeh, Nazanin

AU - Robbers, Lourens F H J

AU - Hirsch, Alexander

AU - Nijveldt, Robin

AU - Lommerse, Ingrid

AU - Fontijn, Ruud D

AU - Meinster, Elisa

AU - Delewi, Ronak

AU - van Royen, Niels

AU - Zijlstra, Felix

AU - van Rossum, Albert C

AU - van der Schoot, C Ellen

AU - van der Pouw Kraan, Tineke C T M

AU - Horrevoets, Anton J

AU - van der Laan, Anja M

AU - Niessen, Hans W M

AU - Piek, Jan J

PY - 2018/11/12

Y1 - 2018/11/12

N2 - Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.

AB - Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.

U2 - 10.1007/s00395-018-0709-7

DO - 10.1007/s00395-018-0709-7

M3 - Article

VL - 114

SP - 1

JO - Basic Research in Cardiology

JF - Basic Research in Cardiology

SN - 0300-8428

IS - 1

ER -