Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin.
Circulating monocytes and plaque macrophages mediate inflammation in the pathogenesis of atherosclerosis. We purified these cells from patients undergoing carotid endarterectomy for advanced atherosclerosis and examined their in vivo transcriptomes using the serial analysis of gene expression (SAGE) technique. We observed striking differences in transcriptional regulators as monocytes transformed into plaque macrophages in contrast to monocytes and lung macrophages from normal subjects. Consistent with its role in moderating inflammation, tristetraprolin (TTP, ZFP36) was among the most highly expressed macrophage transcriptional regulators. Interestingly, the mRNAs of a subset of the macrophage transcriptional regulators specifically interacted with TTP, revealing a network of genes that may be important in controlling macrophage inflammatory activity. Giving functional significance to this interaction, the knockdown of TTP increased both cognate macrophage gene mRNAs and inflammatory tumor necrosis factor protein release. In contrast, transient overexpression of TTP resulted in decreased levels of the same genes supporting its role in regulating macrophage gene expression. Together, our results indicate that the in vivo gene expression analyses of cells involved in pathogenesis can provide biological insights for functional studies with potential clinical implications.
Patino
Willmar D
WD
Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Kang
Ju-Gyeong
JG
Matoba
Satoaki
S
Mian
Omar Y
OY
Gochuico
Bernadette R
BR
Hwang
Paul M
PM
D000368:Aged; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D005260:Female; D015723:Gene Library; D006801:Humans; D002537:Intracranial Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000097:blood*; D051816:Tristetraprolin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha