Redox regulation of endothelial cell fate

Abstract

Endothelial cells (ECs) are present throughout blood vessels and have variable roles in both physiological and pathological settings. EC fate is altered and regulated by several key factors in physiological or pathological conditions. Reactive nitrogen species and reactive oxygen species derived from NAD(P)H oxidases, mitochondria, or nitric oxide-producing enzymes are not only cytotoxic but also compose a signaling network in the redox system. The formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. We review the identities, sources, and biological actions of oxidants and reductants produced during EC function or dysfunction. Further, we discuss how ECs shape key redox sensors and examine the biological functions, transcriptional responses, and post-translational modifications evoked by the redox system in ECs. We summarize recent findings regarding the mechanisms by which redox signals regulate the fate of ECs and address the outcome of altered EC fate in health and disease. Future studies will examine if the redox biology of ECs can be targeted in pathophysiological conditions.

Fig. 1

Redox homeostasis in the endothelial cell. Mitochondrial electron-transport chain (ETC), membrane-bound NADPH-oxidase (NOX) complex, uncoupled endothelial nitric-oxide synthase (eNOS), endoplasmic-reticulum (ER) stress, and xanthine oxidase (XO) are the five major intracellular sources (shown in yellow background) of reactive oxygen species (ROS). Superoxide anion (O₂^·−) is the predominant ROS and is rapidly converted into hydrogen peroxide (H ₂ O ₂) by superoxide dismutases (SODs). Alternatively, O₂^·− can generate peroxynitrite (ONOO ⁻) by reacting with nitric oxide (NO). H₂O₂ can be catalyzed to ·OH in the presence of Fe²⁺ or Cu²⁺ ions or may be converted to H₂O and O₂ through a reaction catalyzed by catalase, glutathione peroxidase (Gpx), or peroxiredoxins (Prx). To maintain redox homeostasis, living cells engage powerful scavenger antioxidant enzyme systems (shown in green background) to eliminate intracellular oxidants (shown in red ). Major reductants are shown in green. Endogenous H₂S is produced from l-cysteine (Cys) by three enzymes, which are cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). GR glutathione reductase, GSH reduced glutathione, GSSG oxidized glutathione

Fig. 2

Reversible and irreversible redox modifications of protein cysteines in ECs. Oxidation of cysteine thiol (RSH) by ROS or RNS leads to the generation of highly reactive sulfenic acid (RSOH), which can react with another thiol to produce a disulfide bond (RSSR) or with GSH to become S-glutathionylated (RSSG). This oxidative modification is reversible, and reduction is catalyzed by the Trx or Grx system. Further oxidation of RSOH to sulfinic acid (RSO ₂ H) and sulfonic acid (RSO ₃ H) is thought to be generally irreversible in vivo. Free thiols can also be modified by sulfhydration or S-nitrosylation

Fig. 3

FoxO-mediated redox system and EC fate. FoxOs regulate EC fate by affecting apoptosis, survival, proliferation, and migration due to the expression of FoxO target genes that are associated with redox balance

Fig. 4

Redox-regulated EC fate in atherogenesis. AMPK activation in ECs inhibits NF-κB activation by suppressing 26S-proteasome activity or by directly phosphorylating IκK. This ameliorates the ER stress that is induced by ROS due to high glucose or a high-fat diet. Disturbed blood flow activates the NLRP3 inflammasome in ECs through SREBP2-mediated upregulation of NOX2. The activated NLRP3 inflammasome instigates EC inflammation, which accelerates atherogenesis. Cas-1 caspase-1; other abbreviations as indicated in the text