Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques.
OBJECTIVE
Expression patterns and association with cell specific gene expression signatures of the epigenetic regulator histone deacetylase 9 (HDAC9) and matrix metalloproteinase 12 (MMP12) in human plaque are not known.


METHODS
This was a prospective cohort study. Genome wide expression analysis was performed in carotid, femoral, aortic plaques (n = 68) and left internal thoracic (LITA) controls (n = 28) and plaque histological severity assessed. Correlation and hierarchical cluster analysis was utilised.


RESULTS
HDAC9 was associated with MMP12 expression in carotid plaques (r = .46, p = .012) and controls (r = -.44, p = .034). HDAC9 and MMP12 clustered with inflammatory macrophage markers but not with smooth muscle cell (SMC) rich markers. In plaques from all arterial sites, MMP12 but not HDAC9 showed positive correlation (p < .05) with M2 and M4 polarized macrophage markers, and negative correlation with SMC rich signatures. In the carotid plaques, all M4 macrophage markers associated with MMP12 and HDAC9. The negative association of MMP12 with SMC rich signatures was pronounced in the carotid plaques. Neither HDAC9 nor MMP12 associated consistently with plaque stabilisation or thrombosis related genes. Immunohistochemistry further supported the association between HDAC9 and MMP12 in atherosclerotic plaques.


CONCLUSIONS
M4 macrophages are a possible source for HDAC9 and MMP12 expression in advanced human plaques.
Department of Surgery, Tampere University Hospital and Surgery, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. Electronic address: nikuoksala@gmail.com.
N K J
NKJ
Oksala
Department of Clinical Chemistry, Fimlab Laboratories and Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
I
I
Seppälä
BioMediTech, University of Tampere and Fimlab Laboratories, Tampere, Finland.
R
R
Rahikainen
Department of Clinical Chemistry, Fimlab Laboratories and Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
K-M
KM
Mäkelä
Department of Clinical Chemistry, Fimlab Laboratories and Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
E
E
Raitoharju
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany; Institute for Human Genetics, and Hannover Unified Biobank, Hannover Medical School, Hanover, Germany.
T
T
Illig
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany.
N
N
Klopp
Department of Pathology, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Finland.
I
I
Kholova
Department of Clinical Chemistry, Fimlab Laboratories and Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
R
R
Laaksonen
Forensic Medicine, Faculty of Medicine and Life Sciences, University of Tampere, Finland, Science Centre, Tampere University Hospital, Tampere, Finland.
P J
PJ
Karhunen
BioMediTech, University of Tampere and Fimlab Laboratories, Tampere, Finland.
V P
VP
Hytönen
Department of Clinical Chemistry, Fimlab Laboratories and Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
T
T
Lehtimäki
D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D016000:Cluster Analysis; D020869:Gene Expression Profiling / Q000379:methods; D055106:Genome-Wide Association Study; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*
D012333:RNA, Messenger; D012097:Repressor Proteins; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
Advanced carotid plaques; Gene expression and regulation; HDAC9; MMP12