Novel mechanisms of adaptation to endothelial stress

Endothelial stress and dysfunction represent a key pathogenic event in a number of diseases, thus justifying the need of the analysis of endogenous mechanisms of cellular stress tolerance. This project will address novel mechanisms of endothelial protection using two independent approaches that are based on unpublished experimental findings done by applicants. First, we made an unexpected observation that oxidized phospholipids (OxPLs), that are increasingly recognized as atherogenic lipids inducing damage and dysfunction of endothelial cells, at lower concentrations demonstrated endothelium-protective action. These data allow hypothesizing that this effect represents a compensatory reaction against toxic action of OxPLs and that the induction of stress tolerance at least partially was mediated by induction of secreted protein mediators known to protect endothelium against stress and stimulate endothelial regeneration. Some of these proteins were identified in our preliminary experiments. The second approach was inspired by the results of biological screening of 40 medicinal plants that are used in traditional medicine for treatment and prophylactics of cardiovascular disease. Two of tested plant extracts (Paeonia lactiflora and Andrographis paniculata) reproducibly protected cultured endothelial cells from death induced by different types of cellular stress. The active compounds and the mechanisms of this protective action are not known but may include both production of soluble paracrine mediators, as well as intracellular regulators of cellular death. The project will capitalize on two lines of evidence described above and analyze mechanisms underlying protective action of OxPLs and two medicinal plants. The emphasis will be set on secreted endothelium-protective proteins and peptides that are induced by endothelial stress or constituents from medicinal plants (Paeonia lactiflora and Andrographis paniculata). Importantly, the project is focused on the analysis of molecular mechanisms protecting endothelium, rather than molecules (plant compounds or OxPLs) stimulating these mechanisms. In other words, the project doesnt aim at developing lead molecules but focuses on basic mechanisms of endothelial stress tolerance. Better understanding of these mechanisms will provide further insights into pathogenesis of multiple diseases associated with endothelial dysfunction and damage.