Redox Regulation in the Extracellular Environment

Abstract

Molecular oxygen is involved in the oxidation of substrates used to produce energy; however, normal metabolism can also generate harmful (bio)chemical byproducts. These deleterious products are partially reduced forms of oxygen, and include free radicals such as superoxide anion radical, hydroxyl radical, or highly oxidizing non-radical species such as hydrogen peroxide (H2O2) and lipid peroxides, which are collectively known as ROS. 1 ROS typically derive from normal metabolism, activated leukocytes, and ambient oxygen in the environment. The production and accumulation of ROS and their downstream effects can be controlled or attenuated by antioxidants. When the ability of antioxidants to eliminate harmful cellular and extracellular ROS is compromised, the balance between ROS generation and antioxidant function to eliminate ROS is shifted in favor of an accumulation of oxidants, which defines the state of oxidative stress in a cell or organism. Oxidative damage can affect DNA, lipids, and proteins, and eventually compromise cell integrity. Many studies have implicated ROS in the pathological processes leading to heart disease, cancer, aging, AIDS, and inflammatory and autoimmune diseases.Oxidants, especially free radicals, are highly reactive. Superoxide can react within milliseconds with nitric oxide (NO) to produce peroxynitrite (ONOO -), a reactive nitrogen species (RNS). The nitrosium cation and nitroxyl anion are other RNS derived from NO. 2 Peroxynitrite is a strong oxidant involved in the nitrosative modification of proteins and lipids. Owing to its rapid reaction with NO, superoxide may modulate NO bioavailability and, subsequently, regulate vascular function. 3 Circulation Journal Vol.72, January 2008The cytosol, mitochondria, peroxisomes, and plasma are all potential sites of ROS formation. 4 The major sources of ROS are enzymatic via nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), xanthine oxidase, myeloperoxidase, endothelial NO synthase (eNOS), or as a consequence of normal mitochondrial respiration. In vascular cells, other enzymatic sources of ROS include cytochrome P450 isoenzymes, lipoxygenase, cyclooxygenase, heme oxygenase, and glucose oxidase. 1,3,[5][6][7] Most reviews to date have focused on the role of intracellular antioxidants that eliminate ROS from the intracellular environment. There are, however, several extracellular antioxidants that also play an equally important role in limiting ROS accumulation in the extracellular environment. Along with limiting ROS accumulation, extracellular redox status is essential for maintaining protein stability and function.The major enzymes important for the elimination of extracellular H2O2 are glutathione peroxidase-3 (GPx-3) and peroxiredoxin IV (Prx IV). Other extracellular antioxidants involved in ROS elimination include paraoxonase (PON), thioredoxin (Trx), Trx reductase (TrxR), glutaredoxin (Grx), extracellular superoxide dismutase (EC-SOD), and extracellular glutathione (GSH).Some of these antioxidants, notably glutathione...

C323 of SR-BI is required for SR-BI-mediated HDL binding and cholesteryl ester uptake

“…These data indicated that an oxidative status promotes SR-BI-mediated HDL binding and cholesteryl ester uptake, whereas a reductive status suppresses SR-BImediated HDL binding and cholesteryl ester uptake. Note that the extracellular compartment is an oxidative environment and that H 2 O 2 is one of the major oxidants in the extracellular compartment, which presents as high as submillimole per liter levels ( 37 ). Our data suggest that physiological relevant levels of H 2 O 2 can promote SR-BI-mediated HDL binding and cholesteryl ester uptake.…”

“…Different from a reducing environment in the intracellular compartment, the extracellular compartment is highly oxidative ( 37 ). Cysteinyl residues in the extracellular compartment can undergo a variety of oxidative modifi cations.…”

“…We found that H 2 O 2 upregulated the SR-BI-mediated cholesteryl ester uptake by 65%, whereas GSH or DTT signifi cantly downregulated SR-BImediated cholesteryl ester uptake by 45%. Of note, the extracellular compartment is highly oxidative ( 37 ). The extracellular compartment contains high levels (up to submilimole per liter) of H 2 O 2 ( 38 ).…”

Extracellular-Superoxide Dismutase Expression in COS7 Cells Exposed to Cadmium Chloride

“…EC-SOD is found in most tissues, but higher amounts of EC-SOD are present in vascular tissue, while EC-SOD is only present in small amounts in the liver, brain and heart compared with Cu, Zn-SOD and Mn-SOD. [15][16][17] EC-SOD is the only isozyme of SOD that is expressed extracellularly, binding to tissues via its heparin-binding domain to give affinity to heparan sulfate proteoglycans on the cell surface, in basal membranes and in the extracellular matrix. 14,18) The presence of EC-SOD on the vascular wall might have an important protective effect against the ROS generated in the vascular system.…”

Protective Effect of Galactomannan Extracted from Iraqi <i>Lycium barbarum</i> L. Fruits against Alloxan-Induced Diabetes in Rats

“…It is now recognized that sustained hyperglycemia in diabetic patient, causes protein glycation and generates free radicals through autooxidation and polyol pathways (Ramakrishna and Jailkhani, 2008;Sharma et al, 2003). High levels of free radicals with concurrent decline of antioxidant defense mechanism may lead to damage of cellular organelles and enzymes (Ottaviano et al, 2008). This can culminate in increased lipid peroxidation and development of insulin resistance, which may consequently promote the development of complications of diabetes mellitus (Demozay et al, 2008).…”