Circulating DNA

Vaart, Maniesh van der; Pretorius, P. J.

doi:10.1196/annals.1448.022

Cited by 168 publications

(58 citation statements)

References 45 publications

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“…Extracellular DNA (cell free DNA, cfDNA) is a degradation prod uct that appears as the result of necrosis or apoptosis of cells [6,7]; it is also suggested that cfDNA (metabolic DNA) may be released by living cells [8]. cfDNA com position differs from that of genomic DNA: similarly to bacterial DNA, cfDNA is significantly enriched with GC pairs [5,9,10].…”

Section: Introductionmentioning

confidence: 99%

Fragments of cell-free DNA increase transcription in human mesenchymal stem cells, activate TLR-dependent signal pathway, and suppress apoptosis

Kostyuk

Malinovskaya

Ermakov

et al. 2012

Biochem. Moscow Suppl. Ser. B

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Human mesenchymal stem cells (MSCs) are widely used in regenerative medicine. However, many questions on the role of different signaling pathways in the regulation of stem cell (SC) functional activ ity within the organism still remain unanswered. In lesion regions the level of cell death increases and DNA fragments from dead cells (cell free DNA, cfDNA) are accumulated in blood. We have shown that in vitro contact of adipose derived MSCs with cfDNA fragments the increase of transcription activity (evaluated by the increase of total cellular RNA and rRNA) is observed. GC rich cfDNA fragments (GC DNA) activated the TLR9 dependent signal pathway causing up regulation of expression of TLR9 and MyD88, the TLR9 signaling pathway adapter. AT rich DNA fragments did not increase the TLR9 expression, but did increase the level of MyD88 mRNA. So we suggest that AT DNA acts via some other receptors, which, nevertheless, activate MyD88 dependent signalling in MSCs. We have also shown that cfDNA fragments decreased the activity of caspase, an apoptotic enzyme. Thus, cfDNA can significantly influence the functional activity of MSC by activating the TLR9 and MyD88 dependent signal pathways and by lowering the apoptosis level.

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Section: Introductionmentioning

confidence: 99%

Fragments of cell-free DNA increase transcription in human mesenchymal stem cells, activate TLR-dependent signal pathway, and suppress apoptosis

Kostyuk

Malinovskaya

Ermakov

et al. 2012

Biochem. Moscow Suppl. Ser. B

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“…ecDNA can also enter the blood fl ow as a result of de novo synthesis in cells (metabolic DNA) [6,14]. ecDNA differ from DNA in cell nucleus: it contains single-and double-strand breaks, accumulates CGenriched genome fragments (CG-DNA), and loses ATenriched fragments [1,3].…”

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confidence: 99%

Extracellular DNA Affects NO Content in Human Endothelial Cells

et al. 2010

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Fragments of extracellular DNA are permanently released into the blood flow due to cell apoptosis and possible de novo DNA synthesis. To find out whether extracellular DNA can affect the synthesis of nitric oxide (NO), one of key vascular tone regulators, we studied in vitro effects of three artificial DNA probes with different sequences and 10 samples of extracellular DNA (obtained from healthy people and patients with hypertension and atherosclerosis) on NO synthesis in endothelial cell culture (HUVEC). For detection of NO in live cells and culture medium, we used a NO-specific agent CuFL penetrating into the cells and forming a fluorescent product FL-NO upon interaction with NO. Human genome DNA fragments affected the content of NO in endothelial cells; this effect depended on both the base sequence and concentration of DNA fragments. Addition of artificial DNA and extracellular DNA from healthy people into the cell culture in a low concentration (5 ng/ml) increased the detected NO concentration by 4-fold at most. Cytosine-guanine (CG)-rich fragment of the transcribed sequence of ribosomal repeat was the most powerful NO-inductor. The effect of DNA fragments on NO synthesis was comparable with that of low doses of oxidizing agents, H(2)O(2) and 17β-estradiol. Extracellular DNA samples obtained from patients with hypertension and atherosclerosis decreased NO content in cells and medium by 1.3-28 times compared to the control; the effect correlated with the content of CG-rich sequences.

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“…ecDNA circulates in the blood and other biological fl uids of the organism. The properties of ecDNA are modifi ed under pathological conditions [11]. Our previous studies showed that the concentration of ecDNA in the blood increases during cardiovascular diseases.…”

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confidence: 99%

Enhanced Expression of iNOS in Human Endothelial Cells during Long-Term Culturing with Extracellular DNA Fragments

et al. 2010

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NO synthesis by endothelial cells plays an important role in normal function of the cardiovascular system. This work was designed to evaluate the role of variations in properties of extracellular DNA in the regulation of NO synthesis. We studied the effect of four DNA samples with various base sequences (50 ng/ml) on functional activity of endothelial cells HUVEC during 24-h culturing. Human DNA fragments with high content of CG repeats increased intracellular content of NO and its metabolites (nitrites and nitrates) and accelerated oxidation of nitrites to nitrates. Changes in the content of NO metabolites after 24-h culturing was shown to depend on the expression of gene for inducible, but not for endothelial NO synthase. Increased expression of inducible NO synthase positively correlated with an increase in the content of mRNA for the adapter protein MyD88, but did not depend on TLR9 gene expression that encodes protein receptor for CG-DNA recognition. The intracellular concentration of MyD88 mRNA did not depend on the content of TLR9 mRNA. The existence of a variety of DNA-binding receptors apart from TLR9 receptor on the surface of endothelial cells was hypothesized. Activation of these receptors by extracellular DNA fragments stimulates expression of the adapter protein MyD88.Extracellular DNA (ecDNA) has attracted much interest over the past decade. ecDNA circulates in the blood and other biological fl uids of the organism. The properties of ecDNA are modifi ed under pathological conditions [11]. Our previous studies showed that the concentration of ecDNA in the blood increases during cardiovascular diseases. These changes are accompanied by an increase in the amount of CG-rich repeats in ecDNA (CG-DNA) [1]. Since vascular endothelial cells produce protein receptors (TLR9) for CG-DNA, it can be hypothesized that endogenous DNA fragments activate the intracellular signal pathway associated with activation of the expression of TLR9 gene and adapter protein MyD88 [9]. Binding of CG-DNA to TLR9 results in the synthesis of cellular cytokines, reactive oxygen species, and nitrogen [10]. TLR9 activation in some cells is accompanied by stimulation of NO synthesis due to an increase in the expression of inducible NO synthase (iNOS) [7]. It was hypothesized that functional activity of TLR receptors plays a role in the development of atherosclerosis [5].This work was designed to evaluate whether the properties of ecDNA (e.g., variations in CG-DNA content) may affect the endothelial function via activation of TLR9 expression. We studied the long-term effect

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Circulating DNA

Cited by 168 publications

References 45 publications

Fragments of cell-free DNA increase transcription in human mesenchymal stem cells, activate TLR-dependent signal pathway, and suppress apoptosis

Fragments of cell-free DNA increase transcription in human mesenchymal stem cells, activate TLR-dependent signal pathway, and suppress apoptosis

Extracellular DNA Affects NO Content in Human Endothelial Cells

Enhanced Expression of iNOS in Human Endothelial Cells during Long-Term Culturing with Extracellular DNA Fragments

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