Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA96357 | ENA |
REPOSITORIES: ENA
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Project description:Background: Drug-eluting stents (DES) have rapidly become a standard therapy for treatment of obstructive coronary artery disease. Differences exist in therapeutic responses to different DES formulations, and mechanisms to predict drug responses in the preclinical setting have not been standardized. Results: We have used gene expression profiling to characterize the patterns of gene regulation within cultures of rat aortic smooth muscle cells (RASMC) treated with rapamycin or paclitaxel, the two drugs widely used in commercially available DES. These studies further validate the use of the in vitro RASMC culture system as a model of insulin resistance. Gene expression profiles easily distinguish RASMC grown under normal or high glucose conditions, and we therefore followed this approach in order to understand the activity of these drugs under conditions that approximate those seen in type 2 diabetics. Remarkably, although both drugs are used to arrest smooth muscle proliferation when delivered by DES, there were major differences in gene regulatory responses. Paclitaxel caused marked changes in expression of tubulin-related genes, and also caused striking changes in the transcription of VEGF, PDGF, JAG-1 and their respective receptors, suggesting an important effect on paracrine and autocrine response to mitogens. However, the gene expression signatures elicited by paclitaxel showed little variation under different cell culture conditions. In contrast, these gene expression responses to rapamycin varied considerably depending on the glycemic conditions of culture, and rapamycin had a dramatic dose- and metabolic status- dependent effect on the transcription of key members of the AKT signaling axis, providing a transcriptional explanation for the paradoxical proliferative effect of rapamycin at low dose in the setting of high glucose concentrations and insulin resistance. Conclusions: Gene expression signatures for drugs eluted from coronary stents vary dramatically in ways that correlate with known differences in biological activities of these drugs. Gene expression profiling may provide a useful preclinical method to characterize the activities of candidate drugs for stent impregnation and to understand their biological activities. Keywords: Cardiovascular disease, drug eluting stent, vascular smooth muscle, rapamycin, paclitaxel
2006-12-31 | GSE5337 | GEO
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