MitoQ protects against hyperpermeability of endothelium barrier in acute lung injury via a Nrf2-dependent mechanism

Abstract

Recently, numerous evidence has revealed that excessive reactive oxygen species (ROS) production and mitochondrial disruption during acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) will aggravate the inflammatory process. To identify whether antioxidation can be one of the treatment strategies during this progress, we chose mitoQ, a mitochondria-targeted antioxidant that was proved to be effective in reducing ROS generated in mitochondria, as a ROS scavenger to investigate the role of antioxidation in ALI. We demonstrated that overoxidation occurred during the process of ALI, which could be reduced by mitoQ. In the meantime, apoptosis of endothelial cells of ALI mice, accompanied by hyperpermeability of pulmonary vascular and impaired pulmonary function, was partially reversed following an intraperitoneal injection of mitoQ. Moreover, in in vitro study, lipopolysaccharides (LPS) induced excessive ROS production, mitochondrial dysfunction and apoptosis in human pulmonary microvascular endothelial cells (HPMECs), which were rectified by mitoQ. To explore underlying mechanisms, we proceeded RNA-sequencing and found significantly upregulated expression of musculoaponeurotic fibrosarcoma F ( MafF) in mitoQ treated group. Additionally, mitoQ inhibited the degradation and increased nuclear translocation of NF-E2-related factor 2 (Nrf2) and upregulated its downstream antioxidant response elements (AREs), such as heme oxygenase (HO)-1 and NAD(P)H:quinone oxidoreductase (NQO)-1. This effect was abolished by transfecting HPMECs with Nrf2 or Maff siRNA. In Nrf2 deficient mice, the protective effects of mitoQ on LPS model of ALI were largely vanished. Taken together, these results provide insights into how antioxidation exerts beneficial effects on ALI via maintaining mitochondrial hemostasis, inhibiting endothelial cells apoptosis, attenuating the endothelial disruption and regulating lung inflammation via Nrf2-MafF/ARE pathway.

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…These are generally purposely synthesized for targeting mitochondria. One well-known compound is mitoQ that has been investigated in a variety of diseases including kidney disease [ 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 ]. Using type 1 diabetic Akita mouse model, Chacko et al [ 163 ] demonstrated that mitoQ administration over a 12-week period improved tubular and glomerular function in the Akita diabetic mice and decreased urinary albumin content to the level as observed in healthy controls.…”

Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

“…Nrf2 is a pleiotropic transcription factor through antioxidant response elements within the regulatory region of many target genes such as HO-1 and NQO1, coordinates antioxidative allowing all types of cells adapt to detrimental conditions caused by intracellular or extracellular stress [28,31]. In this study, we found that DMF obviously promoted the expression of Nrf2 and inhibited the production of ROS in LPSinduced BEAS-2B cells.…”

The critical roles of histone deacetylase 3 in the pathogenesis of solid organ injury

“…Acute injury includes myocardial, cerebral, renal, and hepatic ischemia-reperfusion injury (IRI) [ 1 , 2 ]. Acute organ injury is characterized by potent proinflammatory responses involving leukocyte migration, cytokine release, microvascular thromboses, and cell death [ 3 – 5 ]. The proinflammatory phase of acute injury-associated systemic immune responses is often followed by an immunosuppressive phase [ 6 ].…”