Mitochondrial Oxidative Stress Promotes Atherosclerosis and Neutrophil Extracellular Traps in Aged Mice

Abstract

Rationale Mitochondrial oxidative stress (mitoOS) has been shown to be increased in various cell types in human atherosclerosis and with aging. However, the role of cell type-specific mitoOS in atherosclerosis in the setting of advanced age and the molecular mechanisms remain to be determined in vivo. Objective The aim of this study was to examine the role of myeloid-cell mitoOS in atherosclerosis in aged mice. Approach and Results Lethally irradiated Ldl receptor-deficient mice (Ldlr−/−) were reconstituted with bone marrow from either wild type or mitochondrial catalase (mCAT) mice. mCAT transgenic mice contain ectopically expressed human catalase gene in mitochondria, which reduces mitoOS. Starting at the age of 36 weeks, mice were fed the Western-type diet (WD) for 16 weeks. We found that mitoOS in lesional myeloid cells was suppressed in aged mCAT→Ldlr−/− chimeric mice compared to aged controls, and this led to a significant reduction in aortic root atherosclerotic lesion area despite higher plasma cholesterol levels. Neutrophil extracellular traps (NETs), a pro-inflammatory extracellular structure that contributes to atherosclerosis progression, were significantly increased in the lesions of aged mice compared with lesions of younger mice. Aged mCAT→Ldlr−/− mice had less lesional neutrophils and decreased NETs compared with age-matched WT→Ldlr−/− mice, while young mCAT→ and WT→ Ldlr−/− mice had comparable numbers of neutrophils and similar low levels of lesional NETs. Using cultured neutrophils, we showed that suppression of mitoOS reduced 7-ketocholesterol-induced NET release from neutrophils of aged but not younger mice. Conclusions MitoOS in lesional myeloid cells enhanced atherosclerosis development in aged mice, and this enhancement was associated with increased lesional NETs. Thus, mitoOS-induced NET formation is a potentially new therapeutic target to prevent atherosclerosis progression during aging.

Monocyte-Macrophages and T Cells in Atherosclerosis

“…In vitro experiments show that this metabolic phenotype leads to activation of a pathway involving mitochondrial oxidative stress (mitoOS) and pyruvate kinase M2-mediated STAT3 activation, resulting in increased production of pro-atherogenic IL-6 and IL-1β. Other studies have suggested additional links between mitoOS and human CAD (Paneni et al, 2017), and mitoOS in macrophages increases plaque progression, activates macrophage NF-κB, and promotes the formation of potentially atherogenic neutrophil extracellular traps (NETs) in mouse models of atherosclerosis (Wang et al., 2014; Wang et al, 2017). …”

The Phenomenon of Neutrophil Extracellular Traps in Vascular Diseases

“…Recent results of the study conducted by Wang et al (2017) indicated a significant relationship between mitochondrial oxidative stress (mitoOS) and generation of NETs in aged mice with atherosclerosis. Authors of this publication observed that inhibition of mitoOS in aged mice leads to reduction of NET formation, which could not be observed in younger specimens.…”

Redox Control of Vascular Function

“…57 The perivascular neutrophil microenvironment has been identified as a malleable niche, influenced by the presence of excess O 2 − generated from mitochondria. 58 Likewise, lysophosphatidylcholine has been implicated in mitochondrial ROS production and endothelial cell activation likely due to electron leakage across mitochondrial membranes. 59 Both of these conditions have been implicated in the progression of atherosclerosis through surplus mitochondrial ROS.…”