Vascular Oxidative Stress: Impact and Therapeutic Approaches

Abstract

Oxidative stress has been defined as an imbalance between oxidants and antioxidants and more recently as a disruption of redox signaling and control. It is generally accepted that oxidative stress can lead to cell and tissue injury having a fundamental role in vascular dysfunction. Physiologically, reactive oxygen species (ROS) control vascular function by modulating various redox-sensitive signaling pathways. In vascular disorders, oxidative stress instigates endothelial dysfunction and inflammation, affecting several cells in the vascular wall. Vascular ROS are derived from multiple sources herein discussed, which are prime targets for therapeutic development. This review focuses on oxidative stress in vascular physiopathology and highlights different strategies to inhibit ROS production.

Keywords: antioxidants; oxidative stress; reactive oxygen species; therapies; vasculature.

FIGURE 1

Schematic outline of the interrelationships between some of the more relevant reactive oxygen species (ROS) that affect the vascular wall. Superoxide (${\text{O}}_2^{\mathrm{•-}}$) is produced from molecular oxygen (O₂) by different sources such as nicotinamide adenine dinucleotide phosphate – NADPH oxidase (Nox), mitochondrial respiratory chain, xanthine oxidase, uncoupled endothelial nitric oxide synthase (eNOS) and lipoxygenases. Superoxide can directly affect vascular cells but can also be converted by superoxide dismutases (SOD) to hydrogen peroxide (H₂O₂). H₂O₂ can undergo spontaneous conversion to hydroxyl radical (OH∙, extremely reactive – attacks most cellular components) in the presence of iron (Fe²⁺) via the Fenton reaction. H₂O₂ produces direct effects on the vascular wall or can be detoxified via glutathione peroxidase (GPx), catalase (Cat), or thioredoxin (Trx) peroxidase to H₂O and O₂. Superoxide can also react with nitric oxide (NO) or arachidonic acid to form peroxynitrite (ONOO^⋅-) or isoprostanes, respectively. In addition to other signaling effects, H₂O₂ can activate Nox, resulting in further production of superoxide. The enzyme myeloperoxidase (MPO) can use H₂O₂ to oxidize chloride to the strong-oxidizing agent hypochlorous acid (HOCl). HOCl can chlorinate and thereby inactivate various biomolecules including lipoproteins and the eNOS substrate L-arginine. Besides HOCl generation, myeloperoxidase can oxidize (and thus inactivate) NO to nitrite (${\text{NO}}_2^{\mathrm{-}}$) in the vasculature. Paraoxonase (PON) isoforms 2 and 3 can prevent mitochondrial O₂∙– generation (Adapted with modifications from De Silva and Faraci, 2017).