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Master thesis

Profils génétiques de lignées cellulaires humaines modèles en physiopathologie et pharmacotoxicologie cardio-vasculaires

Abstract : Background : Nowadays, it is well known that genetic polymorphisms can modulate the expression of genes involved in the different biological pathways of a given organism. It is particularly true for the cardiovascular system where polymorphisms can directly influence the production of metabolic mediators, such as cholesterol,or the response to drugs used for the treatment of cardiovascular diseases. In addition, human cell lines are currently used as in vitro models to study biochemical mechanisms or to monitor drug effect. The existing polymorphisms in these cells still remain to be determined. Objectives : We attempted to analyze genetic profiles of 7 human cell lines for several genes implicated indifferent cardiovascular pathways. This work may constitute a useful data bank allowing researchers to choose the most appropriate cell line for a given experiment. In addition, it will highlight if each cell line does carrypolymorphisms which may influence in vitro studies or that could partly explain contradictions observed between in vitro and in vivo approaches.Methods : The commonly used human Thpl, U937, HepG2, HL60, K562, Kyn2 and Cac02 cell lines were genotyped for 120 polymorphisms in 68 genes involved in inflammation, cellular adhesion, lipid metabolism,blood pressure regulation, coagulation and other pathways related to the cardiovascular system. Three techniques were applied including a multiplex PCR-colorimetric detection assay, PCR-RFLP and assays based on theTaqMan technology. Results and discussion : We showed that the cell lines carry numerous polymorphisms of genes involved eitherin the initiation and the development of cardiovascular pathologies or in the drug treatment response. For example, concerning the inflammation process, data indicate that Thp 1 cells are homozygotes for mutatedalleles, which are associated with higher cardiovascular risk, at positions C-571A in IL10 and G-5nC in IL6 genes. By contrast, U937 cells are homozygotes for wild type allele at both positions. For blood pressureregulation, deletion in intron 16 of the ACE gene, known to be associated with lower ACE concentration and susceptibility to several cardiovascular pathologies, is found in ail cell lines except Kyn2 cells . In addition, a potential application of our work is illustrated by the results obtained for the lipid pathway. Lipid homeostasisand hypolipemic treatment outcome are influenced by numerous polymorphisms such as those in APOE. U937 cell line is the only one that expresses apoliporotein E4 isoform and is thus an interesting model . As a conclusion, our data suggest that these cell lines represent attractive and convenient in vitro models in thefields of cardiovascular physiopathology and pharmacotoxicology. They will contribute to a better understanding of the drug action mechanism or may lead to the discovery of new therapeutic targets.
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Elise Jeannesson. Profils génétiques de lignées cellulaires humaines modèles en physiopathologie et pharmacotoxicologie cardio-vasculaires. Sciences pharmaceutiques. 2007. ⟨hal-01738848⟩

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