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

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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 remains 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 low-density lipoprotein 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 for 16 weeks. We found that mitoOS in lesional myeloid cells was suppressed in aged mCAT→Ldlr−/− chimeric mice compared with 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 proinflammatory 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 wild-type→Ldlr−/− mice, whereas young mCAT→ and wild-type→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.

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