Gender-dependent impact on epigenetic modifications caused by nicotine in abdominal aortic aneurysm

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Abdominal aortic aneurysm (AAA) is a complex and and highly lethal disease. Since there are no conservative approaches to therapy, understanding of pathogenesis and influence of intrinsic and extrinsic risk factors is essential. Yet, smoking is considered as the main risk factor in AAA development likely due to nicotine, the main component of tobacco smoke. Thereby nicotine does not only influence inflammatory processes which accelerate aneurysm growth but also affects epigenetic regulatory mechanism. Epigenetic signalling includes changes in small, non-coding RNAs (microRNA), which regulate gene expression and chemical modification of gene-regions by methylation. In this way genes can either be activated or supressed. While smoking/nicotine exposure are considered as major risk factors for AAA development, female sex seems to have protective influence. This partly results from gender-dependent differences in estrogen signalling, since the protective effect is lost during menopause with increasing rate of AAA among post-menopausal women. Estrogen has proven to attenuate pro-inflammatory vascular processes and thereby partly countering nicotine-dependent effects on vasculature. Further, estrogen signalling was shown to regulate epigenetic mechanism like gene-methylation and microRNA expression. The protective effect of estrogen/female sex on AAA development is further supported by several animal model-based studies. Preliminary data from the applicant’s host laboratory suggest this to be constant under nicotine exposure as well. This projects aims to answer, whether this might be due to gender-dependent differences in epigenetic regulatory mechanism in response to nicotine. To address this context, mice of both genders will be treated with constant levels of nicotine followed by AAA induction utilizing two complementary murine AAA models. Additionally, estrogen levels will be altered in subset-groups by ovariectomy/sham operation or estrogen supplementation. Subsequently, tissue and blood samples will be probed for changes in epigenetic regulation of genes known to be affected by nicotine or that were shown to be regulated in AAA. Furthermore, differences in aneurysm morphology, aortic stiffness and changes of inflammatory factors will examined. To identify additional gender-dependent differently methylated gene-sites in response to nicotine, an epigenome-wide approach utilizing the Illumina 450K Methylation BeadChip will be implemented.