Oksala N K J, Seppälä I, Rahikainen R, Mäkelä K-M, Raitoharju E, Illig T, Klopp N, Kholova I, Laaksonen R, Karhunen P J, Hytönen V P, Lehtimäki T
Department of Surgery, Tampere University Hospital and Surgery, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
Department of Clinical Chemistry, Fimlab Laboratories and Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
Eur J Vasc Endovasc Surg. 2017 May;53(5):632-640. doi: 10.1016/j.ejvs.2017.02.014. Epub 2017 Mar 23.
OBJECTIVE/BACKGROUND: 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.
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.
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.
M4 macrophages are a possible source for HDAC9 and MMP12 expression in advanced human plaques.
目的/背景：表观遗传调节因子组蛋白去乙酰化酶9（HDAC9）和基质金属蛋白酶12（MMP12）在人类斑块中的表达模式及其与细胞特异性基因表达特征的关联尚不清楚。
这是一项前瞻性队列研究。对颈动脉、股动脉、主动脉斑块（n = 68）和左胸廓内动脉（LITA）对照（n = 28）进行全基因组表达分析，并评估斑块组织学严重程度。采用相关性和层次聚类分析。
HDAC9与颈动脉斑块（r = 0.46，p = 0.012）和对照（r = -0.44，p = 0.034）中的MMP12表达相关。HDAC9和MMP12与炎症巨噬细胞标志物聚类，但不与富含平滑肌细胞（SMC）的标志物聚类。在所有动脉部位的斑块中，MMP12而非HDAC9与M2和M4极化巨噬细胞标志物呈正相关（p < 0.05），与富含SMC的特征呈负相关。在颈动脉斑块中，所有M4巨噬细胞标志物均与MMP12和HDAC9相关。MMP12与富含SMC的特征之间的负相关在颈动脉斑块中尤为明显。HDAC9和MMP12均未与斑块稳定或血栓形成相关基因持续相关。免疫组织化学进一步支持了HDAC9与动脉粥样硬化斑块中MMP12之间的关联。
M4巨噬细胞可能是晚期人类斑块中HDAC9和MMP12表达的来源。
