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Figure 8 | Respiratory Research

Figure 8

From: Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology

Figure 8

Schematic diagram of HIF-1α activation circuits and oxygen-signaling mechanisms in hypoxia. The reduction of oxidized glutathione (GSSG) forms reduced glutathione (2GSH), capable of inducing HIF-1α activation. GSSG recycling to GSH is blocked by 1,3- bis-(2-chloroethyl)-1-nitrosourea (BCNU), a specific glutathione reductase inhibitor, thus increasing intracellular [GSSG], a potent inhibitor of DNA binding. In oxidative stress, γ-glutamylcysteine synthetase is transformed from the native, inactive form (nγ-GCS) to the active form (γ-GCS), which increases de novo synthesis of GSH. This pathway is blocked by L-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of γ-GCS, thus affecting HIF-1α activation. Reactive oxygen species (ROS), derived from oxygen metabolites (ROOH), tend to block the activation of HIF-1α. N-acetyl-L-cysteine (NAC), an antioxidant, releases this inhibitory effect by scavenging ROS. NAC, in addition, is a major precursor of GSH, a thiol antioxidant, thereby elevating [GSH] (↑GSH) and inducing HIF-1α activation. Pyrrolidine dithiocarbamate (PDTC) is an antioxidant; although it possesses ROS-scavenging properties, its ability to activate HIF-1α under reducing conditions is not established. PDTC (as a pro-oxidant), like other dithiocarbamates, lowers the GSH/GSSG ratio by oxidizing GSH. The elevated [GSSG] (↑GSSG) has the potential to block HIF-1α activation. Upon HIF-1α binding to the hypoxia response element (HRE), hypoxia-responsive genes are upregulated.

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