title: Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans.
abstract: OBJECTIVE
  Monocytes play critical roles in tissue injury and repair following acute myocardial infarction (AMI). Specifically targeting inflammatory monocytes in experimental models leads to reduced infarct size and improved healing. However, data from humans are sparse, and it remains unclear whether monocytes play an equally important role in humans. The aim of this study was to investigate whether the monocyte response following AMI is conserved between humans and mice and interrogate patterns of gene expression to identify regulated functions.
  
  
  RESULTS
  Thirty patients (AMI) and 24 control patients (stable coronary atherosclerosis) were enrolled. Female C57BL/6J mice (n = 6/group) underwent AMI by surgical coronary ligation. Myocardial injury was quantified by magnetic resonance imaging (human) and echocardiography (mice). Peripheral monocytes were isolated at presentation and at 48 h. RNA from separated monocytes was hybridized to Illumina beadchips. Acute myocardial infarction resulted in a significant peripheral monocytosis in both species that positively correlated with the extent of myocardial injury. Analysis of the monocyte transcriptome following AMI demonstrated significant conservation and identified inflammation and mitosis as central processes to this response. These findings were validated in both species.
  
  
  CONCLUSIONS
  Our findings show that the monocyte transcriptome is conserved between mice and humans following AMI. Patterns of gene expression associated with inflammation and proliferation appear to be switched on prior to their infiltration of injured myocardium suggesting that the specific targeting of inflammatory and proliferative processes in these immune cells in humans are possible therapeutic strategies. Importantly, they could be effective in the hours after AMI.
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Ruparelia
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Jernej
authors.initials: J
authors.lastname: Godec
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Regent
authors.initials: R
authors.lastname: Lee
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Chai
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK Acute Vascular Imaging Centre, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Erica
authors.initials: E
authors.lastname: Dall'Armellina
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Debra
authors.initials: D
authors.lastname: McAndrew
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Digby
authors.affiliation: Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
authors.forename: J Colin
authors.initials: JC
authors.lastname: Forfar
authors.affiliation: Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Prendergast
authors.affiliation: Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kharbanda
authors.affiliation: Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Banning
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Haining
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK Acute Vascular Imaging Centre, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK robin.choudhury@cardiov.ox.ac.uk.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology*; D008026:Ligation; D018810:Magnetic Resonance Angiography; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000502:physiology
keywords: Acute myocardial infarction; Genomics; Inflammation; Mitosis; Monocytes