Ying Wang1, Wei Wang2, Nan Wang2, Alan R Tall2, Ira Tabas1. 1. 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. yingw2323@gmail.com iat1@cumc.columbia.edu. 2. 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.
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.
RATIONALE: Mitochondrial oxidative stress (mitoOS) has been shown to be increased in various cell types in humanatherosclerosis 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. mCATtransgenic mice contain ectopically expressed humancatalase 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.
Authors: Remco T A Megens; Santosh Vijayan; Dirk Lievens; Yvonne Döring; Marc A M J van Zandvoort; Jochen Grommes; Christian Weber; Oliver Soehnlein Journal: Thromb Haemost Date: 2012-02-08 Impact factor: 5.249
Authors: Pierre Rotzius; Sebastian Thams; Oliver Soehnlein; Ellinor Kenne; Chi-Nan Tseng; Niklas K Björkström; Karl-Johan Malmberg; Lennart Lindbom; Einar E Eriksson Journal: Am J Pathol Date: 2010-05-14 Impact factor: 4.307
Authors: Gabriel G Dorighello; Bruno A Paim; Ana Catarina R Leite; Anibal E Vercesi; Helena C F Oliveira Journal: Exp Gerontol Date: 2017-02-14 Impact factor: 4.032
Authors: Steven J Forrester; Daniel S Kikuchi; Marina S Hernandes; Qian Xu; Kathy K Griendling Journal: Circ Res Date: 2018-03-16 Impact factor: 17.367
Authors: Gautam Sule; Basel H Abuaita; Paul A Steffes; Andrew T Fernandes; Shanea K Estes; Craig Dobry; Deepika Pandian; Johann E Gudjonsson; J Michelle Kahlenberg; Mary X O'Riordan; Jason S Knight Journal: J Clin Invest Date: 2021-04-01 Impact factor: 14.808
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311