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NOX2 inhibition stabilizes vulnerable plaques by enhancing macrophage efferocytosis via MertK/PI3K/AKT pathway
Yue Wang1, Xin-Yan Liu1, Yue Wang1
1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Abstract:
NADPH oxidases 2 (NOX2) is the main source of ROS in macrophages, which plays a critical role in the formation of atherosclerosis. However, effects of NOX2 inhibition on established vulnerable plaques and the potential role involved remain unclear. The purpose of this study is to investigate the latent mechanism of NOX2-triggered vulnerable plaque development. We generated a vulnerable carotid plaque model induced by carotid branch ligation and renal artery constriction, combined with a high-fat diet in ApoE-/- mice. NOX2 specific inhibitor, GSK2795039 (10 mg/kg/day by intragastric administration for 8 weeks) significantly prevented vulnerable plaque, evaluated by micro-ultrasound imaging parameters. A profile of less intraplaque hemorrhage detection, increased collagen-lipid ratio, fibrous cap thickness and less necrotic core formation were also found in GSK2795039 treated group. Mechanistically, reduced 4-HNE, in situ lesional apoptosis and enhanced efferocytosis were involved in mice treated with NOX2 inhibitor. Further analysis in mouse macrophages confirmed the role of NOX2 inhibition in enhancing macrophage efferocytosis by regulating the MertK/PI3K/AKT pathway. In summary, our data defined previously few recognized roles of NOX2 in vulnerable plaque pathogenesis and an undescribed NOX2-ROS-MerTK axis acts involved in regulating macrophage efferocytosis in the formation of rupture-prone vulnerable plaques.
Insights
NADPH oxidase 2 (NOX2) inhibition prevents vulnerable plaque development by reducing ROS and enhancing macrophage efferocytosis via the MertK/PI3K/AKT pathway. This study uncovers a novel NOX2-ROS-MerTK axis in plaque pathogenesis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- NADPH oxidases 2 (NOX2) generates reactive oxygen species (ROS) crucial for atherosclerosis development.
- The precise role of NOX2 inhibition in established vulnerable plaques remains largely unknown.
Purpose of the Study:
- To elucidate the underlying mechanisms by which NOX2 inhibition impacts vulnerable plaque progression.
- To investigate the NOX2-ROS-MerTK signaling axis in macrophage efferocytosis and plaque stability.
Main Methods:
- A vulnerable carotid plaque mouse model (ApoE-/-) was established using surgical ligation, renal artery constriction, and a high-fat diet.
- Mice were treated with the NOX2 inhibitor GSK2795039 for 8 weeks, with plaque progression assessed via micro-ultrasound.
- Macrophage efferocytosis and related signaling pathways (MertK/PI3K/AKT) were analyzed in vivo and in vitro.
Main Results:
- GSK2795039 treatment significantly inhibited vulnerable plaque formation and improved plaque stability markers (increased collagen-lipid ratio, fibrous cap thickness; reduced necrotic core and intraplaque hemorrhage).
- NOX2 inhibition led to decreased oxidative stress (4-HNE), reduced lesional apoptosis, and enhanced macrophage efferocytosis.
- In macrophages, NOX2 inhibition promoted efferocytosis by activating the MertK/PI3K/AKT pathway.
Conclusions:
- NOX2 plays a significant role in the pathogenesis of vulnerable atherosclerotic plaques.
- NOX2 inhibition offers a potential therapeutic strategy for stabilizing vulnerable plaques.
- A novel NOX2-ROS-MerTK signaling pathway regulating macrophage efferocytosis in plaque development was identified.
