The Antioxidant MitoQ Protects Against CSE-Induced Endothelial Barrier Injury and Inflammation by Inhibiting ROS and Autophagy in Human Umbilical Vein Endothelial Cells

Abstract

Chronic obstructive pulmonary disease (COPD) is a common disease characterized by persistent airflow limitation. Pulmonary vascular endothelial barrier injury and inflammation are increasingly considered to be important pathophysiological processes in cigarette smoke extract (CSE)-induced COPD, but the mechanism remains unclear. To identify the cellular mechanism of endothelial barrier injury and inflammation in CSE-treated human umbilical vein endothelial cells (HUVECs), we investigated the effect of the mitochondrion-targeting antioxidant mitoquinone (MitoQ) on endothelial barrier injury and inflammation. We demonstrated that MitoQ restored endothelial barrier integrity by preventing VE-cadherin disassembly and actin cytoskeleton remodeling, as well as decreased inflammation by the NF-κB and NLRP3 inflammasome pathways in endothelial cells. In addition, MitoQ also maintained mitochondrial function by reducing the production of ROS and excess autophagy. Inhibition of autophagy by 3-MA protected against cytotoxicity that was induced by CSE in HUVECs. Overall, our study indicated that mitochondrial damage is a key promoter in the induction of endothelial barrier dysfunction and inflammation by CSE. The protective effect of MitoQ is related to the inhibition of ROS and excess autophagy in CSE-induced HUVEC injury.

Thymoquinone (Tq) protects necroptosis induced by autophagy/mitophagy‐dependent oxidative stress in human bronchial epithelial cells exposed to cigarette smoke extract (CSE)

“…Our data showed reduction of G R levels in CSE exposed cells which was reversed by Tq. These observations were consistent with earlier findings identifying CSE as an inducer of oxidative stress through generation of ROS and depletion of intracellular GSH levels (Rahman et al, 2002) which could possibly be due to their utilization in scavenging free radical and Tq nevertheless, Accumulating evidence report autophagy as the mode of cell death in CSE-exposed cells (Chen et al, 2019;Vij et al, 2018).…”

Activation of autophagy inhibits nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome activation and attenuates myocardial ischemia‐reperfusion injury in diabetic rats

“…However, autophagy can help eliminate damaged organelles, misfolded proteins, stress products, such as ROS, and so on. Autophagy itself, under normal circumstances, is a kind of protective mechanism for the body 17,28 . In pathological conditions, such as diabetes, I/RI or cardiac hypertrophy, autophagy is impaired (inhibited or excessive autophagy ) 29,30 .…”

“…Autophagy can directly remove inflammasomes. In addition, autophagy can also reduce inflammation by eliminating inflammatory stimuli, such as ROS, mitochondrial deoxyribonucleic acid or damaged organelles, to maintain homeostasis 17,18 . Previous observations found that autophagic activity can attenuate cerebral and intestinal I/RI by eliminating mitochondrial deoxyribonucleic acid and mitochondrial ROS, and inhibiting the activation of NLRP3 inflammasome 19,20 .…”

NLRP3 inflammasome in endothelial dysfunction

“…This study unraveled a novel mechanism of aspirin in ameliorating endothelial dysfunction by blocking redox signaling and NLRP3 inflammasome activation, providing a new viewpoint on the clinical potential of aspirin in the early prevention of cardiovascular diseases 105 . The mitochondrion-targeting antioxidant mitoquinone (MitoQ) was found to inhibit endothelial inflammation and barrier injury in cigarette smoke extract (CSE)-treated HUVECs via restoring mitochondrial damage 106 . Mechanistically, the protective effects of MitoQ depend on suppressing the internalization of VE cadherin and cytoskeleton remodeling, and inhibiting the activation of NF-κB/NLRP3 inflammasome pathway, as well as restraining the production of mtROS and autophagy 106 .…”