Targeted Interception of Signaling Reactive Oxygen Species in the Vascular Endothelium

Abstract

Reactive oxygen species (ROS) are implicated as injurious and as signaling agents in human maladies including inflammation, hyperoxia, ischemia-reperfusion and acute lung injury. ROS produced by the endothelium play an important role in vascular pathology. They quench, for example, nitric oxide, and mediate pro-inflammatory signaling. Antioxidant interventions targeted for the vascular endothelium may help to control these mechanisms. Animal studies have demonstrated superiority of targeting ROS-quenching enzymes catalase and superoxide dismutase to endothelial cells over nontargeted formulations. A diverse arsenal of targeted antioxidant formulations devised in the last decade shows promising results for specific quenching of endothelial ROS. In addition to alleviation of toxic effects of excessive ROS, these targeted interventions suppress pro-inflammatory mechanisms, including endothelial cytokine activation and barrier disruption. These interventions may prove useful in experimental biomedicine and, perhaps, in translational medicine. Reactive oxygen species & vascular pathologyReactive oxygen species (ROS) superoxide anion (O 2 •− ) and hydrogen peroxide (H 2 O 2 ) are small molecules implicated as injurious and signaling agents in human maladies including inflammation, hyperoxia, ischemia-reperfusion (I/R) and acute lung injury (ALI) [1]. Activated phagocytes release ROS, causing tissue damage. Endothelial cells (ECs) lining the luminal surface of blood vessels also produce ROS [2] using the mitochondrial respiratory chain [3], membrane-bound NADPH oxidases (NOX) [4], xanthine oxidase [5], uncoupled nitric oxide synthase (NOS) [6] and other enzymatic systems ( Figure 1). The mitochondrial respiratory chain is the major producer of injurious ROS that play an important role in apoptosis and cell pathology [7]. ECs play key regulatory functions in the vascular system and, therefore, effects of endothelial ROS, both endogenous and exogenous, are of great biomedical importance [8].* Author for correspondence: Tel.: +1 215 898 9823, Fax: +1 215 573 2236, muzykant@mail.med.upenn.edu. Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.No writing assistance was utilized in the production of this manuscript. HHS Public AccessAuthor manuscript In order to control these effects of ROS in ECs (and, presumably, other cell types), at least two key intertwined aims must be achieved. First, we need to understand signaling and injurious mechanisms of ROS at a subcellular level. Second, we need means to interfere in these mechanisms at this level in selected cell types and phenotypes; for example, in the signaling endosomes of pathologically activated ECs. This article reviews these two aspects of targeted antioxidant interventions. ROS. This mechanism has been demonstrated for pro-inflammatory signaling induced ...

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