Published online before print June 1, 2006, doi: 10.1161/01.ATV.0000229695.68416.76
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Novel Candidate Genes in Unstable Areas of Human Atherosclerotic Plaques
From the Academic Department of Surgery (M.P., A.S., K.G.B., P.T.), Cardiovascular Division, King’s College, London, UK; Division of Radiological Sciences and Medical Engineering (S.P.), King’s College, London, UK; Department of Atherosclerosis (K.E.S., C.H.J., L.P.), GlaxoSmithKline PLC, Medicines Research Centre, Stevenage, UK; and Sir William Dunn School of Pathology (D.R.G.), University of Oxford, United Kingdom.
Correspondence to Alberto Smith, Academic Department of Surgery, Cardiovascular Division, King’s College, First Floor North Wing, St. Thomas’ Hospital, London SE1 7EH UK. E-mail alberto.smith{at}kcl.ac.uk
Objective— Comparison of gene expression in stable versus unstable atherosclerotic plaque may be confounded by interpatient variability. The aim of this study was to identify differences in gene expression between stable and unstable segments of plaque obtained from the same patient.
Methods and Results— Human carotid endarterectomy specimens were segmented and macroscopically classified using a morphological classification system. Two analytical methods, an intraplaque and an interplaque analysis, revealed 170 and 1916 differentially expressed genes, respectively using Affymetrix gene chip analysis. A total of 115 genes were identified from both analyses. The differential expression of 27 genes was also confirmed using quantitative-polymerase chain reaction on a larger panel of samples. Eighteen of these genes have not been associated previously with plaque instability, including the metalloproteinase, ADAMDEC1 (
37-fold), retinoic acid receptor responder-1 (5-fold), and cysteine protease legumain (3-fold). Matrix metalloproteinase-9 (MMP-9), cathepsin B, and a novel gene, legumain, a potential activator of MMPs and cathepsins, were also confirmed at the protein level.
Conclusions— The differential expression of 18 genes not previously associated with plaque rupture has been confirmed in stable and unstable regions of the same atherosclerotic plaque. These genes may represent novel targets for the treatment of unstable plaque or useful diagnostic markers of plaque instability.
Differential gene expression in stable and unstable plaque was assessed by whole transcriptome analysis. Intraplaque analysis by QT-PCR confirmed the differential expression of 18 genes not associated previously with plaque rupture. These genes may represent novel targets for the treatment of unstable plaque or useful diagnostic markers of plaque instability.
Key Words: atherosclerosis • gene expression • stroke • affymetrix • MMP-9 • legumain • plaque instability
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