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Nuclear receptor signaling pathways in cardiovascular disease: expression profile and pharmacogenetics of genes candidate to play a role in cardiovascular disease
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Advisor(s)
Abstract(s)
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.
Description
Tese de dout., Ciências Biológicas (Biologia Celular e Molecular), Faculdade de Ciências e Tecnologia, Univ. do Algarve, 2010
Keywords
Biologia celular Biologia molecular Citocromos Colesterol Farmacologia Genética