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要旨:
In the context of the cardiovascular system sex-specific differences have been observed in humans as well as in animal models. The incidence of cardiovascular disease differs significantly between men and women to a number of complex factors. The molecular basis of these differences however is still largely unknown. The aim of this project is to identify sex dimorphisms in the cardiovascular system of healthy mice and humans. Since microarray technology enables the analysis of the expression levels for thousands of genes in a single overnight hybridisation experiment, we determined the age-dependent gene expression profiles of murine whole hearts and human myocardial tissues of both genders. RNA was isolated from whole hearts of eight weeks and eight months old male as well as female mice (n = 6 per group). On the other hand, myocardial samples from <40 years old women (n = 3) and men (n = 4), as well as 50-60 years old women and men (n = 5, respectively) were analysed. RNAs were pooled according to age and gender, cDNAs synthesised and hybridised on microarrays containing either 8,600 mouse or 11,000 human cDNA clones, respectively. We detected genes deregulated between genders in individual experiments common to both ages in mice as well as in humans. Data analysis was also performed by sorting the corresponding deregulated genes into functional categories (i.e. according to their cellular component, gene family membership or molecular function) and several candidate genes were validated using quantitative RT-PCR approaches in individual samples.
Among several differentially expressed genes, we found higher expression levels of natriuretic peptide precursor B (BNP) transcripts in 50-60 years old women. Accordingly, higher plasma levels of BNP, a known marker for left ventricular dysfunction, were reported in earlier clinical studies in older women (Clark et. al. 1990; Wang et al., 2002). Another interesting candidate gene identified as significantly downregulated in <40 years old women was tumor necrosis factor receptor superfamily 11b (TNFRS), encoding osteoprotegerin. Along the same line of evidence, osteoprotegerin has been suggested as a risk factor for progressive atherosclerosis and cardiovascular disease in men and women of the 5th to 8th decades of age (Kiechl et al., 2004).
Altogether, the data obtained is currently being validated and candidate genes analysed in the context of disease pathomechanisms, such as in heart failure.
