Kurzfassung

Dysfunctions in the cardiovascular system (seen for example in diabetes mellitus, hypertension and inflammatory arthritis) are among the leading risk factors/diseases that account for global deaths and disability-adjusted life years [Global Burden of Disease Study; (Lim et al. Lancet 2012)]. The interactions of immune cells, vascular cells and platelets play important roles in the development and progression of these risk factors and diseases. A tight balance between generation and...Dysfunctions in the cardiovascular system (seen for example in diabetes mellitus, hypertension and inflammatory arthritis) are among the leading risk factors/diseases that account for global deaths and disability-adjusted life years [Global Burden of Disease Study; (Lim et al. Lancet 2012)]. The interactions of immune cells, vascular cells and platelets play important roles in the development and progression of these risk factors and diseases. A tight balance between generation and detoxification of reactive oxygen/nitrogen species (ROS/RNS) has been shown to modulate cell physiology and development through redox signaling and oxidative stress. Research indicates that NADPH oxidase 2 (NOX2) is a major ROS producer in the vascular system (Wenzel et al. Free Radic Biol Med 2017). Recent studies reveal an important role of the antioxidant protein paraoxonase-2 (PON2) as well (Forstermann et al. Circ Res 2017). Our group showed that dysregulated redox regulation in PON2-ko mice causes endothelial dysfunction, vascular inflammation and tissue factor-dependent hypercoagulability (Ebert et al. Blood 2018). Our ongoing experiments (Petermann et al. unpublished , Spiecker et al. in preparation) show that hematopoietic stem cells, endothelial cells and platelets of PON2-ko mice display marked differences in development/activation compared to wild type (WT) cells.
ROS/RNS play a major role in chronic vascular and inflammatory diseases but the understanding of their cellular effects and regulation by inhibitors/inhibitory pathways in immune cells, vascular cells and platelets is limited. In order to better understand the underlying mechanisms this project aims to systematically analyze the role of cell-specific PON2 signaling pathways in hypertension, diabetes mellitus, inflammatory arthritis and ischemic heart/cerebrovascular disease. ROS/RNS signaling in the circulatory/vascular system takes place in all cell types (e.g. platelets, immune cells and vascular cells) important for cardiovascular health and disease. However, the exact contribution of each cell population to the role of PON2-dependent signaling for the development and progression of cardiovascular diseases is not known. Therefore, the redox-regulatory role of PON2 on mitochondrial- and NOX2-dependent ROS formation will be investigated by using cell-specific PON2 knockout mice in combination with specific inhibitors of mitochondrial- and NOX2-dependent ROS formation.» weiterlesen» einklappen