Abstract
Epidemiological and clinical data demonstrate differences in atherosclerotic coronary
heart disease prevalence between age-matched men and premenopausal women. Mechanisms
underlying relative athero-susceptibility in men and athero-resistance in premenopausal
women remain to be elucidated. Lack of informative animal models hinders research.
We report here a moderate-expresser line transgenic for human cholesteryl ester transfer
protein (CETP) in the Dahl salt-sensitive hypertensive rat strain, Tg25, that recapitulates
premenopausal female athero-resistance. Having ascertained identical genetic background,
environmental factors, and equivalent CETP hepatic RNA levels, we detect worse hypercholesterolemia,
hypertriglyceridemia, coronary plaques and survival outcome in Tg25 male rats compared
with Tg25 females. Hepatic transcription profiles of Tg25 males and females normalized
to respective gender- and age-matched non-transgenic controls exhibit significant
differences. Genes implicated on hierarchical cluster analysis and quantitative real-time
RT-PCR pinpoint pathways associated with coronary plaque progression such as inflammation
and arachidonic acid epoxygenation, and not just cholesterol metabolism pathways.
The data demonstrate gender-specific factors as key modulators of atherosclerosis
phenotype and suggest a possible role for the liver in atheroma progression as a large
organ source of proatherogenic systemic factors.
Keywords
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Article info
Publication history
Accepted:
June 14,
2004
Received:
January 29,
2004
Identification
Copyright
© 2004 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
