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Global effects of 2-methoxyestradiol on smooth muscle cell hyperproliferation and vascular remodeling in atherosclerosis

ABSTRACT: We used microarrays to detail transcriptional changes in cultured human smooth muscle cells in response to acute and chronic 2-methoxyestradiol treatment 2-ME, an endogenous metabolite. of estradiol, not only exerts cytotoxic effects on cancer cells but it also protects against multiple proliferative disorders, including atherosclerosis and injury-induced intimal thickening Keywords: treatment vs. control

ORGANISM(S): Homo sapiens

PROVIDER: GSE12261 | GEO | 2008/12/31

SECONDARY ACCESSION(S): PRJNA113643

REPOSITORIES: GEO

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Project description:Purpose: The goals of this study are to use RNA-Seq based transcriptome profiling to compare a very early stage of vascular disease (diffuse intimal thickening) with two advanced states of atherosclerosis (calcified and non-calcified fibroatheromas).methods and to evaluate protocols for optimal high-throughput data analysis Methods: Total RNA was extracted from sets of thawed plaque cryosections using the Qiagen RNeasy Mini kit (Qiagen). RNA-Seq libraries were constructed using the TruSeq Stranded Total RNA with Ribo-Zero Gold kit (Illumina). The pooled libraries were sequenced on a HiSeq2000 (Illumina) using version 3 chemistry and paired-end 125 bp reads. Raw sequence data were processed using RTA version 1.17.21.3 and CASAVA 1.8.2 (Ilumina). Reads were aligned with the STAR aligner, using the hg19 genome assembly and Ensembl transcript database (release 74), which includes both protein-coding genes and long non-coding RNAs. Quality control metrics were calculated and visualized using the QoRTs software package. Gene-level read counts were generated using the algorithm defined by the HTSeq package, and the differential expression analyses were performed via DESeq2. Results: We identified 1,052 and 1,959 candidate genes associated with non-calcified and calcified plaque formation, respectively. A smaller set of 42 genes were biomarkers specifically for plaque mineralization. Combining GWAS results for carotid atherosclerosis with our RNA-Seq data, we found that four previous genomic candidates (including PIK3CG, the top locus for carotid plaque) were also strongly perturbed at the transcript level. Functionally, we found overwhelming evidence for upregulation of the TREM1 signaling pathway in plaques, with 34 out of 75 genes differentially expressed. We characterized PIK3CG and TREM1 proteins by immunohistochemical stating of human plaques; both were strongly expressed in macrophage-rich areas of advanced lesions but absent in diffuse intimal thickening. Conclusions: Using a high-resolution technique, we show pervasive changes in the vascular wall transcriptome linked to formation of advanced atherosclerotic plaques, including genes specifically linked to plaque calcification. Using combined DNA, RNA, and protein characterization, we show that two prior disease candidates (PIK3CG and TREM1) are linked integratively to advanced atherosclerosis.

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Global effects of 2-methoxyestradiol on smooth muscle cell hyperproliferation and vascular remodeling in atherosclerosis

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