ROS are generated during the reduction of oxygen and comprise two groups of molecules: 1) free radicals with short biological half-lives, such as superoxide (O
2
•−
), hydroxyl (OH
•), and nitric oxide (
•NO), and 2) nonradicals, such as singlet oxygen (
1O
2), hydrogen peroxide (H
2O
2), hypochlorous acid (HOCl), peroxynitrite (ONOO
−), and lipid hydroperoxides (LOOH), which are more stable and have longer half-lives than free radicals. Cellular ROS formation is a physiologic process in the vasculature and occurs in endothelial and smooth muscle cells as well as fibroblasts. Although ROS are small, structurally simple molecules with high and random reactivity, they appear to be subtle physiologic modulators of biochemical processes involved in intracellular signaling [
1]. Signal transmission via ROS takes place at free sulfhydryl groups of cysteine residues, which are present in many enzymes, including kinases (eg, Src, Akt, protein kinase C [PKC], mitogen-activated protein kinases [MAPKs], and Rho kinases), phosphatases (eg, protein tyrosine phosphatases, SH2 domain-containing phosphatases, MAPK phosphatase), phospholipases (eg, phospholipase A
2), and small GTPases (eg, Rac1, RhoA), as well as transcription factors (see later) and ion channels (eg, Ca
2+ and K
+ channels). The ROS-induced oxidation of sulfhydryl groups leads to intra- and intermolecular disulfide bonds. This posttranslationally alters the conformation of proteins, eventually resulting in altered enzyme activity or DNA binding. Among the complex protein networks transmitting information from the cell surface to the nucleus, several transcription factors (eg, nuclear factor-κB [NF-κB]/Rel family, activator protein 1, hypoxia-inducible factors 1 and 2, p53, c-myc, metal-responsive transcription factor) were first discovered to become activated or inhibited by exogenous and/or ligand-induced oxidants. In the meantime, it is known that the signal propagation upon receptor binding of growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor, nerve-derived growth factor, and endothelin (ET)-1, as well as cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, is mediated via the generation of O
2
•−
and H
2O
2. Notably, the activation of G protein-coupled receptors such as β-adrenergic receptors and angiotensin (Ang) II type 1 (AT
1) receptors by particular agonists results in the production of ROS and/or
•NO, which act as signaling molecules in the receptor-mediated regulation of gene expression and cell growth [
2•]. To prevent potentially damaging actions and maintain cellular redox balance, enzymatic antioxidant defense systems, including catalase, superoxide dismutase, glutathione peroxidase, and thioredoxin, detoxify and remove ROS. However, when the balance between ROS production and scavenging becomes disturbed, oxidative stress occurs. In this state of excessive ROS production, the ROS-stimulated signaling process switches to a ROS-mediated decrease in bioavailable
•NO and damage to lipids, proteins, and DNA. As a consequence, uncontrolled cellular proliferation, apoptosis, increased cellular permeability, and cell death may occur, which in turn leads to endothelial dysfunction, inflammation, and vascular remodeling. All these events are crucial contributors to cardiovascular disease pathologies.