Nuclear receptor signaling pathways in cardiovascular disease: expression profile and pharmacogenetics of genes candidate to play a role in cardiovascular disease

• Author(s): Dias, Vera Lúcia Martins
• Date: 2014
• Persistent ID: http://hdl.handle.net/10400.1/4529
• Origin: Sapientia - Universidade do Algarve
• Subject(s): Biologia celular; Biologia molecular; Citocromos; Colesterol; Farmacologia; Genética
• Document Type: Doctoral thesis
• Language: English
• Advisor(s): Marques, Vera Linda Ribeiro
• Contributor(s): Sapientia

Description

Tese de dout., Ciências Biológicas (Biologia Celular e Molecular), Faculdade de Ciências e Tecnologia, Univ. do Algarve, 2010

Cardiovascular diseases are the major causes of death and morbidity in developed countries. Several risk factors have been associated to cardiovascular diseases, but the molecular mechanisms underlying the alteration of homeostasis are still largely unknown. There is increasing recent evidence that the drug metabolizing enzyme system associated to a number of membrane transport proteins is of particular relevance in relation to cardiovascular diseases, either in biosynthetic or degradative pathways. The overall aim of the present study was to characterize selected genes coding for drug metabolizing enzymes and influx and efflux transporters both from the point of view of pharmacogenetic diversity and from their response to increased cholesterol concentrations. Specifically we a) characterized, in a sample of the Portuguese population, selected genetic polymorphisms in cytochromes P450, influx and efflux transporters that are known to – or may be expected to - affect in vitro or in vivo the metabolism or transport of cholesterol and/or therapeutic drugs; b) evaluated the existence of ethnic variability in the frequency of these polymorphic variants, through the determination of their prevalence in other populations; and c) investigated to which extent the expression of these genes, in liver and intestine derived cells, may be influenced by the accumulation of cholesterol. Most of the polymorphisms analysed present a similar distribution between Portuguese and Colombian populations, but significant differences when compared with the Mozambican population, demonstrating that these polymorphisms are ethnicity-dependent. The expression profiling studies revealed a differential expression pattern for the analysed genes in cell culture models from liver and intestine and a differential response to cholesterol, pointing to significant differences in gene regulation in these tissues. Taken together, the results obtained in this study contribute to a better knowledge of drug metabolism and transport in hypercholesterolemia as well as to understanding the pharmacogenetic variability of the genes involved in these pathways.