Kurzfassung

Various kinds of cardiovascular pathophysiology are associated with vascular oxidative stress. NADPH oxidases represent a major source of reactive oxygen species (ROS) in the vasculature. Enhanced expression of these NADPH oxidases contributes significantly to cardiovascular pathophysiology. Interestingly, certain drugs (e.g. non-steroidal anti-inflammatory drugs, NSAIDs) seem to mimic this pathophysiology by also upregulating NADPH oxidases. Molecular mechanisms controlling vascular NADPH...Various kinds of cardiovascular pathophysiology are associated with vascular oxidative stress. NADPH oxidases represent a major source of reactive oxygen species (ROS) in the vasculature. Enhanced expression of these NADPH oxidases contributes significantly to cardiovascular pathophysiology. Interestingly, certain drugs (e.g. non-steroidal anti-inflammatory drugs, NSAIDs) seem to mimic this pathophysiology by also upregulating NADPH oxidases. Molecular mechanisms controlling vascular NADPH oxidase expression are largely unknown and no therapeutic approach targeting NADPH oxidase expression is available. We have previously demonstrated that (i) the expression of vascular NADPH oxidases is increased in animal models of diabetes and hypertension; (ii) some of the cardiovascular side effects of NSAIDs may be caused by an induction of NADPH oxidase expression; (iii) part of these effects seem to be mediated through PKC (probably by induction of other signaling proteins). (iv) On the other hand, we were able to show that two naturally occurring pentacyclic triterpenes, ursolic acid and betulinic acid, reduce vascular NADPH oxidase expression in endothelial cells. In the present research proposal, we plan to investigate molecular mechanisms underlying enhanced vascular NADPH oxidase expression in response to stimuli mimicking cardiovascular risk factors (high concentrations of glucose, angiotensin II, tumor necrosis factor-alpha, interleukin-6). Also NSAIDs and compounds activating PKC will be used as stimuli. In parallel, mechanisms mediating the NADPH oxidase suppressing effects of ursolic acid and betulinic acid will be investigated. This will be done in cultured human endothelial cells, smooth muscle cells and adventitial fibroblasts. Responsible cis-regulatory elements and transcription factors involved in promoter activation or inhibition will be identified. Also, mechanisms controlling mRNA stability of vascular NADPH oxidases (e.g. AU-rich elements and RNA-binding proteins) will be studied. Results from our studies may provide valuable information that can serve as a basis for novel therapeutics. » weiterlesen» einklappen