Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.

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The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPAR␣ (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPAR␥ (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPAR␣ are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPAR␥ agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPAR␦ (NR1C2) and the physiological roles of PPAR␦ are unclear. In this report we demonstrate that the expression of PPAR␦ is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPAR␦ (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPAR␦ activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPAR␦ and have confirmed that PPAR␦ is a powerful promoter of macrophage lipid accumulation. These data suggest that PPAR␦ may play a role in the pathology of diseases associated with lipidfilled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.

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 (Ϸ37-fold), retinoic acid receptor responder-1 (Ϸ5-fold), and cysteine protease legumain (Ϸ3-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. Key Words: atherosclerosis Ⅲ gene expression Ⅲ stroke Ⅲ affymetrix Ⅲ MMP-9 Ⅲ legumain Ⅲ plaque instability A therosclerosis is a chronic inflammatory disease that remains a major cause of morbidity in the Western world. The composition and vulnerability of the atherosclerotic plaque are considered to be important factors in the development of arterial thrombus and embolic complications. 1 However, the precise mechanisms by which plaque ruptures remain to be determined 2,3 Gene expression techniques such as microarrays and representational difference analysis are powerful tools that can be used to probe the complexities underlying atherosclerotic plaque initiation and progression. 4 -6 These techniques have already been used to show altered gene expression between normal and diseased arteries, 6,7 between different stages in disease progression 8,9 and differential expression in samples of atherosclerotic plaque classified according to patient symptomatology. 10 However, there are drawbacks to these types of comparisons. The differences in the cellular composition and morphology between plaque and normal arterial wall may lead to differences in gene expression that simply reflect this variation. In addition, the high degree of variability in plaque composition and gene expression in different patients may confound comparative analysis in studies that use pooled samples. [11][12][13] Features of unstable plaque such as surface ulceration and rupture occur in both symptomless and symptomatic patients, 14 and this can also confound studies that classify samples according to patient symptomatology. Conclusions-TheThe aim of this study was to use a whole transcriptome analysis to characterize the gene expression signature of unstable regions of carotid endarterectomy (CEA) specimens using a stable region of the same specimen as an internal control. ...