The role of endothelium-derived nitric oxide (NO) in vascular function, enzyme systems generating and scavenging reactive oxygen species, and pharmacological strategies for the reversal and prevention of vascular oxidative stress and its pathophysiological consequences are the main target of our current research.
Endothelial cells control vascular homeostasis by generating paracrine factors that regulate vascular tone, inhibit platelet function, prevent adhesion of leukocytes, and limit proliferation of vascular smooth muscle. The dominant factor responsible for many of those effects is endothelium-derived nitric oxide (NO). Endothelial dysfunction characterized by enhanced inactivation or reduced synthesis of NO, alone or in combination, is seen in conjunction with risk factors for cardiovascular disease.
Vascular oxidative stress and increased production of reactive oxygen species contributes to vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase or the mitochondrial respiratory chain) and antioxidative enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase and paraoxonase). Expression and function of these enzymes are being investigated. Furthermore, small-molecular-weight antioxidants might have a role in the defense against oxidative stress.
Increased concentrations of reactive oxygen species reduce bioactive NO throught chemical inactivation, forming toxic peroxynitrite, which in turn can uncouple endothelial NO synthase to form a dysfunctional superoxide-generating enzyme that contributes further to vascular oxidative stress.
There is a close interaction with the the Biochemical and Cellular Pharmacology Group (Ellen I. Closs and collaborators) whose focus are biochemical pathways controlling amino acid levels in cells. Disturbances in these pathways may also contribute to endothelial dysfunction.