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Circulating Mitochondrial (mt) DNA Fragments as Precursors of Inflammation in Early Stages of Atherogenesis
Author(s) -
Ruchko Mykhaylo V.,
Pastukh Viktor M.,
Sukhanov Sergiy,
Gorodnya Olena M.,
Danchuk Svitlana D.,
Gillespie Mark N.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.677.10
Subject(s) - mitochondrial dna , inflammation , biology , apolipoprotein e , oxidative stress , dna damage , medicine , pathology , immunology , endocrinology , gene , dna , genetics , disease
Atherosclerosis and its vascular complications are the leading cause of morbidity and mortality among Western populations. It is widely accepted that inflammation plays a major role in all stages of atherogenesis, including its initial phases. However, the mechanisms of initiation of inflammatory response predisposing to the development of atherosclerosis are not well understood. Mitochondrial dysfunction underlies many key processes in the development of atherosclerosis, including generation of reactive oxygen species, apoptosis, and inflammation. There is growing evidence that oxidative mtDNA damage can directly promote atherosclerosis. The mechanism linking mitochondrial damage to atherogenesis remains unclear, but may include initiation of inflammation by circulating mtDNA fragments known as DAMPs (Damage Associated Molecular Patterns). Previously, we have demonstrated that mice deficient in DNA repair glycosylase Ogg1 and fed a high fat diet developed larger fatty streaks in the aortic valve as a sign of early atherogenesis that was correlated with higher mtDNA oxidative damage in cardiac tissue and elevated content of plasma mtDNA fragments in comparison to wild type animals. In the present study we tested the hypothesis that development of atherosclerosis in animal model is associated with increased abundance of circulating pro‐inflammatory mtDNA fragments. ApoE‐null and wild type mice of increasing age were analyzed for atherosclerotic burden within the aortic valve and for abundance of mtDNA fragments in plasma. ApoE‐null mice develop atherosclerotic plaque in the aortic valve either spontaneously with age or after feeding a high fat diet. Early lesions were detected in ApoE‐null mice by 3 months of age whereas in 5‐month old animals they became prominent. Atherosclerotic burden reached 30% of valve area in 10‐month old animals and remained at that level in 12‐month old mice. Wild type animals did not develop lesions within the aortic valve at any age. The abundance of circulating mtDNA fragments was higher in ApoE‐null mice in all age groups when compared to wild type animals. Importantly, the largest relative increase in mtDNA fragments (5 to 6.5 fold vs. age‐matched controls) was observed in ApoE‐null mice at 3 and 5 months. These results indicate that circulating mtDNA fragments could be precursors of inflammation development in early stages of atherogenesis and suggest that efficient maintenance of mtDNA integrity could be an important target for atheroprotection. Support or Funding Information NIH R01 HL113614