- Project 5
Reactive Oxygen Species, Glutathione and Vascular Response to Diesel Exhaust
- Exposure to traffic-related air pollution such as diesel exhaust (DE) is associated with an increase in the level of reactive oxygen species (ROS) in multiple cell types. These ROS include the superoxide anion radical, hydrogen peroxide, lipid peroxides and hydroxyl radical. ROS can have deleterious effects on cells, but they are also known to be involved in normal transmembrane signaling and metabolic control in the cardiovascular system.
For instance, two potent vasoconstrictors, angiotensin II and endothelin-1, can increase production of ROS by smooth muscle cell NADPH oxidase, thus causing an increase in the intracellular concentrations of superoxide and hydrogen peroxide. Superoxide can bind to nitric oxide (NO) to form peroxynitrite, which can cause cellular injury, but also limit the amount of NO available for vasorelaxation. ROS generated in this way can also oxidize tetrahydrobiopterin, a necessary cofactor for NO synthase (NOS), resulting in uncoupling of NOS and production of more superoxide and peroxynitrite. Consumption of NO by superoxide in this way can result in vasoconstriction. ROS are thus able to influence cardiovascular performance and vascular reactivity.
Glutathione (GSH) is an abundant non-protein thiol which is a potent scavenger of ROS, including hydrogen peroxide, lipid peroxides, and importantly, peroxitrite (ONOO-). GSH is a tripeptide thiol present in millimolar concentrations in most cells. The first and rate-limiting step in GSH synthesis is carried out by the enzyme glutamate cysteine ligase (GCL), which is composed of two subunits, a catalytic subunit (GCLC) and a modifier or regulatory subunit (GCLM).
Importantly, single nucleotide polymorphisms (SNPs) in both GCLC and GCLM have been shown to be important in myocardial infarction, as well as controlling vascular reactivity in humans. In this project, we will investigate the reasons for this effect of GCL by using a comparative approach.
Director: Terry Kavanagh PhD, MS
Michael Rosenfeld, PhD
Daniel Luchtel, PhD
Stephen Schwartz, MD, PhD
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