Nrf2 Activation Induced by Sirt1 Ameliorates Acute Lung Injury After Intestinal Ischemia/Reperfusion Through NOX4-Mediated Gene Regulation

Abstract

Background/Aims: Nuclear erythroid 2-related factor-2 (Nrf2) is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis. We investigated the effects of Nrf2 in regulating revascularization and modulating acute lung injury. Methods: The expression of Nrf2 and sirtuin1 (Sirt1) was assessed in lung tissue by western blotting and immunofluorescence staining after intestinal ischemia/reperfusion (IIR) in Nrf2–/– and wild-type (WT) mice. The involvement of Nrf2 in angiogenesis, cell viability, and migration was investigated in human pulmonary microvascular endothelial cells (PMVECs). Additionally, the influence of Nrf2 expression on NOX pathway activation was measured in PMVECs after oxygen–glucose deprivation/reoxygenation. Results: We found activation and nuclear accumulation of Nrf2 in lung tissue after IIR. Compared to IIR in WT mice, IIR in Nrf2–/– mice significantly enhanced leukocyte infiltration and collagen deposit, and inhibited endothelial cell marker CD31 expression. Nrf2 upregulation and translocation into the nucleus stimulated by Sirt1 overexpression exhibited remission of histopathologic changes and enhanced CD31 expression. Nrf2 knockdown repressed non-phagocytic cell oxidase 4 (NOX4), hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression after IIR. Nrf2 upregulation by Sirt1 enhances NOX4, HIF-1α and VEGF expression after IIR in WT mice. Furthermore, Nrf2 knockdown suppressed cell viability, capillary tube formation and cell migration in PMVECs after oxygen–glucose deprivation/reoxygenation and also inhibited NOX4, HIF-1 and VEGF expression. Moreover, NOX4 knockdown in PMVECs decreased the levels of VEGF, HIF-1α and angiogenesis. Conclusion: Nrf2 stimulation by Sirt1 plays an important role in sustaining angiogenic potential through NOX4-mediated gene regulation.

Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1

“…The mitochondria observed via transmission electron microscopy had shrunk in size, the cristae had decreased or disappeared, and the outer membrane had ruptured in the Nrf2 -/- IIR group, suggesting that Nrf2 can alleviate ferroptosis ( Figure 2D ). Similarly, the extent of pathological damage in the Nrf2 -/- IIR group was more severe than that observed in WT mice ( Figure 2E ), suggesting that Nrf2 plays a protective role in ALI, which is also consistent with previous studies [ 17 ]. The damage observed in the IIR + Fe group was more severe than that of the corresponding group of WT mice, and the damage in the Nrf2 knockout mice was also reduced following the administration of Fer-1 ( Figure 2E ).…”

Role of Resveratrol in Regulating Cutaneous Functions

“…Upregulation of SIRT1 expressions, in turn, increases expression levels of Nrf2 and phase 2 antioxidant enzymes, while silencing SIRT1 with siRNA decreases Nrf2 protein as well as activity of ARE promotor [182]. Moreover, upregulation and activation of Nrf2 expression by SIRT1 were also observed [183]. e second mechanism comprises direct upregulation of Nrf2 expression because studies have shown that resveratrol increases Nrf2 expression in kidney, heart, and lung tissues [184,185].…”

Melatonin and inflammation—Story of a double‐edged blade

“…Importantly, many effects of SIRT1 that are relevant to the suppression or avoidance of inflammation have been also observed upon treatment with melatonin (Figure ). In addition to the inhibition of NF‐κB activation, to Nrf2 upregulation, and to the avoidance of NLRP3 inflammasome activation, several further anti‐inflammatory actions of SIRT1 have become known. This concerns, for example, an inhibition of TLR4, which was demonstrated in renal collecting duct cells by either SIRT1 overexpression or activation by SRT1720, effects that were blocked by Sirt1 siRNA or the sirtuin inhibitors sirtinol and EX527 .…”