Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation

Abstract

Objective Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. Approach and Results Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0 and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout (ApoE−/−) mice during early atherosclerosis. Using electron spin resonance and flow cytometry, we found that LPC 16:0, 18:0 and 18:1 induced mtROS in primary human aortic ECs (HAECs), independently of the activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Mechanistically, using confocal microscopy and Seahorse XF mitochondrial analyzer, we showed that LPC induced mtROS via unique calcium entry-mediated increase of proton leak and mitochondrial O2 reduction. In addition, we found that mtROS contributed to LPC-induced EC activation by regulating nuclear binding of AP-1 and inducing intercellular adhesion molecule 1 (ICAM-1) gene expression in vitro. Furthermore, we showed that mtROS inhibitor MitoTEMPO suppressed EC activation and aortic monocyte recruitment in ApoE−/− mice using intravital microscopy and flow cytometry methods. Conclusions ATP synthesis-uncoupled, but proton leak-coupled mtROS increase mediates LPC-induced EC activation during early atherosclerosis. These results indicate that mitochondrial antioxidants are promising therapies for vascular inflammation and cardiovascular diseases.

Thrombotic Regulation From the Endothelial Cell Perspectives

“…56 Furthermore, endothelial-specific deletion of Txnrd2, an enzyme negatively regulates the levels of mitochondrial ROS, robustly enhances fibrin deposition. 57 In line with this study, Li et al 58 showed that mitochondrial ROS was responsible for lysophosphatidylcholine-induced EC activation. Particularly, ROS modulated by Txnrd2 in the endothelial compartment promoted thrombus formation.…”

Particulate Matter Exposure and Stress Hormone Levels

“…48 In addition, lysophosphatidylcholine may induce production of mitochondria reactive oxygen species, upregulate the levels of adhesion molecules, and stimulate secretions of inflammatory chemokines and superoxide anion; these changes may, in turn, lead to endothelial cell activation and vascular endothelial inflammation responses. [49][50][51][52] We consistently found increments of inflammatory and oxidative stress biomarkers in association with higher PM exposure. These biological changes may be responsible in part for the adverse cardiovascular effects caused by PM exposure.…”

Reactive Oxygen Species Generation and Atherosclerosis

“…58 Interestingly, lysophosphatidylcholines (LPC)-proinflammatory lipids-can contribute to the ROS formation in atherosclerosis. 59 The concentration of LPC, as well as expression of Pla2g7 and Pla2g4c, were higher in Apoe −/− aortas than in control ones. LPC quickly induced both mitochondrial ROS and to lesser levels cytoplasmatic ROS.…”