Circulating cell‐free mitochondrial deoxyribonucleic acid is increased in coronary heart disease patients with diabetes mellitus

Liu, Jing; Zou, Ying; Tang, Yi; Xi, Mingming; Xie, Liang; Zhang, Qigao; Gong, Jianbin

doi:10.1111/jdi.12366

Cited by 42 publications

(30 citation statements)

References 23 publications

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“…90,106 Diabetes patients with ischemic heart disease (IHD) also have higher levels of mtDNA in circulation than nondiabetic IHD patients. 107 In addition, highest levels of DNA-MPO complexes are found in plasma from APS patients with a history of thrombosis. 103 These data suggest that comorbidities may contribute to increase the concentration of ceDNA in thrombosis-associated diseases.…”

Section: Discussionmentioning

confidence: 99%

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Jiménez-Alcázar

Kim

Fuchs

2017

Semin Thromb Hemost

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Thrombosis leads to ischemic organ damage in cardiovascular and thromboembolic diseases. Neutrophils promote thrombosis in vitro and in vivo by releasing neutrophil extracellular traps (NETs). NETs are composed of DNA filaments coated with histones and neutrophil enzymes such as myeloperoxidase (MPO). Circulating extracellular DNA (ceDNA) is widely used as a surrogate marker to monitor NET formation in thrombosis. This narrative review summarizes the association of ceDNA with human thrombosis. Levels of ceDNA indicate the extent and outcome of several cardiovascular and thromboembolic diseases, including myocardial infarction, stroke, and venous thromboembolism. ceDNA correlates with markers of coagulation and platelet consumption, thus supporting the hypothesis that ceDNA may be a surrogate marker of thrombus formation. In addition, ceDNA levels correlate with markers of cell injury and size of ischemic lesions, suggesting that ceDNA does not derive from NETs but is probably released from damaged organs. Few studies identified NET-specific biomarkers such as DNA-MPO complexes in the blood of patients with thrombosis. In conclusion, it remains to be established whether ceDNA in patients derives from NETs and is a cause or consequence of thrombosis.

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Section: Discussionmentioning

confidence: 99%

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Jiménez-Alcázar

Kim

Fuchs

2017

Semin Thromb Hemost

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“…Post-myocardial infarction patients have increased circulating mDNA levels, accompanied by higher levels of inflammatory cytokines, such as TNF-α and IL-6, compared to healthy individuals (Qin et al, 2017). Patients with breast cancer (Mahmoud et al, 2015), gastric cancer (Fernandes et al, 2014), diabetes and retinopathy (Malik et al, 2015), coronary artery disease (Liu et al, 2016) also have higher levels of circulating mDNA. These results corroborate data from our study showing that patients with type 1 diabetes present an increase in circulating mDNA and the increased release of mDNA from pancreatic cells observed in our study may be related to the apoptotic and necrotic processes triggered in the endocrine pancreas by diabetes, which enables extracellular genetic content extravasation.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes

et al. 2020

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Introduction NLRP3 inflammasome is a molecular platform of innate immune system that regulates the inflammatory response through the activation of caspase‐1 and IL‐1β. It can be activated by several ligands, for example, mitochondrial DNA (mDNA). Some studies have shown that circulating mDNA is increased in patients with diabetes and play a role in the development of the disease; however, its role in vascular changes is still unknown. In this sense, we tested the hypothesis that mDNA contributes to vascular inflammatory/oxidative processes associated to type 1 diabetes (T1D) via NLRP3 inflammasome activation. Methods Wild‐type and NLRP3‐deficient (NLRP3−/−) mice were treated with vehicle (Veh) or streptozotocin (40 mg/kg) (T1D) for 5 days. Vascular reactivity was determined in mesenteric arteries. Caspase‐1 and IL‐1β expression were evaluated by western blot. Pancreatic mDNA was extracted from control (cmDNA) and diabetic animals (dmDNA) for endothelial cells stimulation. ROS generation was determined by chemiluminescence. Hydrogen peroxide (H2O2) production and calcium influx were determined by fluorescence. Data are presented as mean ± standard error of the mean. Results Diabetes increased vascular caspase‐1 and IL‐1β activation [arbitrary units (a.u.), 1.2±0.1 vs. 0.8±0.1; 4.8±1.1 vs. 0.8±0.5 vs. the Veh, respectively, p <0.05]. However, this activation was attenuated in T1D NLRP3−/−. Mesenteric arteries from T1D exhibited decreased ACh‐induced vasodilatation vs. Veh [(Emax), 46.6±4.0 vs. 91.5±2.8, n=4–5, p<0.05], which was not observed in T1D NLRP3−/−. The NLRP3 inhibitor MCC950 acutely improved endothelium‐dependent vasodilation in T1D [(Emax), 62.5±3.8 vs. 85.6±3.7, n=4–5, p<0.05]. ROS generation [(Relative luminescence unit, RLU), 1.5×107±2.3 vs. 48.9×103±1.1, n=4–5, p<0.05] as well as H2O2 production [(Relative fluorescence unit, RFU), 1082±242.6 vs. 232.0±42.8, n=4–5, p<0.05] were lower in mesenteric bed from T1D NLRP3−/− than T1D. Only incubation with dmDNA reduced ACh‐induced vasodilation [(Emax), 48.4 ± 4.1 vs. 90.7 ± 3.4, n=4–5, p<0.05], which was attenuated by the presence of an antioxidant [(Emax), 48.4 ± 4.1 vs. 71.5 ± 3.1, n=4–5, p<0.05]. Similarly, only LPS‐primed cells incubated with dmDNA had significant NLRP3 activation (caspase‐1 and IL‐1β activation, respectively) [(u.a.), 1.6 ± 0.2 vs. 0.9 ± 0.1; and 1.6 ± 0.2 vs. 1.0 ± 0.1, n=4–5, p<0.05]. The dmDNA induced in a time‐dependent way both calcium influx and ROS generation in endothelial cells, being the last reversed by the presence of an antioxidant. Likewise, T1D patients had increased circulating mDNA vs. healthy volunteers and also higher NLRP3 serum expression, and caspase‐1/IL‐1β activation. Conclusion The T1D increases mDNA release which in turn stimulates increased calcium influx, induces ROS generation, and triggers vascular NLRP3 inflammasome activation contributing to inflammatory response and endothelial dysfunction in diabetes. Support or Funding Information Financial Support: FAPESP and CAPES. Ethics Committee number (026/2015)...

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“…Increased blood levels of free-circulating mtDNA have been shown in a number of different somatic conditions such as diabetes, 30 cancers, 31 trauma, 32 myocardial infarction 33 and sepsis; 34 thus, it is unlikely that enhanced mtDNA levels are specific for suicide attempters. Rather, cellular aging, caused by metabolic stress, inflammatory triggers or (as in the case of suicidality) severe and long-lasting psychological stress, 35 may be a common denominator across these conditions potentially leading to increased apoptosis and a subsequent leakage of mtDNA from the damaged cells into the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

Stress: A deadly weapon

Peñagarikano

2016

Sci. Transl. Med.

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Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic-pituitaryadrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre-and post-DST; all P-values o2.98E − 12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho = 0.49, P o 0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.

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Circulating cell‐free mitochondrial deoxyribonucleic acid is increased in coronary heart disease patients with diabetes mellitus

Cited by 42 publications

References 23 publications

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes

Stress: A deadly weapon

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