Wang Ying, Wang Wei, Wang Nan, Tall Alan R, Tabas Ira
From the Division of Cardiology (Y.W.), Division of Molecular Medicine (W.W, A.R.T., I.T.), Division of Molecular Medicine, Department of Medicine (N.W.), Columbia University Medical Center, New York, NY.
Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):e99-e107. doi: 10.1161/ATVBAHA.117.309580. Epub 2017 Jun 8.
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.
The aim of this study was to examine the role of myeloid cell mitoOS in atherosclerosis in aged mice.
Lethally irradiated low-density lipoprotein receptor-deficient mice () 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→ 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→ mice had less lesional neutrophils and decreased NETs compared with age-matched wild-type→ mice, whereas young mCAT→ and wild-type→ 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.
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.
线粒体氧化应激（mitoOS）在人类动脉粥样硬化的各种细胞类型中以及随着衰老而增加。然而，在高龄情况下细胞类型特异性mitoOS在动脉粥样硬化中的作用及其分子机制仍有待在体内确定。
本研究旨在探讨髓样细胞mitoOS在老年小鼠动脉粥样硬化中的作用。
对经致死剂量照射的低密度脂蛋白受体缺陷小鼠（）用来自野生型或线粒体过氧化氢酶（mCAT）小鼠的骨髓进行重建。mCAT转基因小鼠的线粒体中异位表达人过氧化氢酶基因，可降低mitoOS。从36周龄开始，给小鼠喂食西式饮食16周。我们发现，与老年对照组相比，老年mCAT→嵌合小鼠病变髓样细胞中的mitoOS受到抑制，尽管血浆胆固醇水平较高，但这导致主动脉根部动脉粥样硬化病变面积显著减少。中性粒细胞胞外陷阱（NETs）是一种促炎细胞外结构，有助于动脉粥样硬化进展，与年轻小鼠的病变相比，老年小鼠病变中的NETs显著增加。与年龄匹配的野生型→小鼠相比，老年mCAT→小鼠的病变中性粒细胞较少，NETs减少，而年轻的mCAT→和野生型→小鼠的中性粒细胞数量相当，病变NETs水平相似且较低。使用培养的中性粒细胞，我们发现抑制mitoOS可减少7-酮胆固醇诱导的老年小鼠而非年轻小鼠中性粒细胞释放NETs。
病变髓样细胞中的mitoOS促进了老年小鼠动脉粥样硬化的发展，这种促进作用与病变中NETs增加有关。因此，mitoOS诱导的NET形成是预防衰老过程中动脉粥样硬化进展的一个潜在新治疗靶点。
