DNA repair and DNA damage response for the maintenance of endothelial cell function during genotoxic stress

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A number of autosomally recessive hereditary disorders is characterized by increased genomic instability, caused by insufficient DNA repair and a related increase of tumor incidence. One of these disorders is the Werner syndrome, which is characterized not only by a repair defect but also by an accelerated ageing process in affected patients (adult progerie). Contrary to other known genetic instability syndromes, post-pubescent Werner patients develop rapid and pronounced geriatric symptoms such as osteoporosis, diabetes mellitus (type II) and arteriosclerosis. Arteriosclerical changes (myocardial infarction, apoplexis) are, besides tumor development, the most significant reason for the relatively short lifespan (40 to 50 yrs) of Werner patients. The defective gene in these patiens encodes the RecQ helicase (WRN). This DNA helicase is essentially involved in DNA repair and DNA damage-dependent stress responses, caused by, among others, reactive oxygen species (ROS) or alkylating agents. ROS-induced DNA damage compromises the physiological function of endothelial cells (endothelial dysfunction), hence being relevant for the pathogenesis of arteriosclerosis. Whether DNA methylation, which can result from endogenous formation of nitrosamines, impacts endothelial cell functions is poorly investigated. We posit that impairment of WRN associated DNA repair and stress responses impacts the endothel cell-related functions, which eventually result in the known cardiovascular complications observed in Werner patients. In addition, we hypothesize that DNA repair in general, also independent of WRN, is a major determinant for the preservation of endothel cell function. Using primary human endothelial cells we will address the question to which extent an RNAi mediated downregulation of WRN, WRN associated and WRN independent DNA repair factors influences endothelial cell function following genotoxic stress provoked by oxidants and alkylating agents. Bearing in mind that statins are well known vessel protective therapeutics, we aim to investigate their potency for maintaining endothelial function and viability following genotoxic stress even under conditions of compromised DNA repair.