Pro‐inflammatory role of <scp>cell‐free</scp> mitochondrial <scp>DNA</scp> in cardiovascular diseases

Nie, Shu; Lu, Junying; Wang, Lina; Gao, Man

doi:10.1002/iub.2339

Cited by 22 publications

(3 citation statements)

References 114 publications

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“…11 Under hemodynamic overload, the levels of mtDNA regulators are decreased, leading to the cytoplasmic leakage of mtDNA in cardiomyocytes. 24,25 In support of these findings, our results showed that Ang II stimulation caused mtDNA leakage into the cytoplasm in NRPCs, whereas GSDMD silencing mitigated Ang II-induced mtDNA release (Figure 4F). Leakage of self-DNA promotes STING signaling pathway activation via cGAS in pressure overload-induced cardiac hypertrophy.…”

Section: Ang Ii-mediated Gsdmd Cleavage Induces Mitochondrial Dysfunc...supporting

confidence: 80%

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

et al. 2022

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Background: Cardiac hypertrophy is initially an adaptive response of cardiomyocytes to neurohumoral or hemodynamic stimuli. Evidence indicates that Ang II (angiotensin II) or pressure overload causes GSDMD (gasdermin D) activation in cardiomyocytes and myocardial tissues. However, the direct impact of GSDMD on cardiac hypertrophy and its underlying mechanisms are not fully understood. Methods and Results: In this study, we examined the aberrant activation of GSDMD in mouse and human hypertrophic myocardia, and the results showed that GSDMD deficiency reduced Ang II or pressure overload–induced cardiac hypertrophy, dysfunction, and associated cardiomyocyte pyroptosis in mice. Mechanistically, Ang II–mediated GSDMD cleavage caused mitochondrial dysfunction upstream of STING (stimulator of interferon genes) activation in vivo and in vitro. Activation of STING, in turn, potentiated GSDMD-mediated cardiac hypertrophy. Moreover, deficiency of both GSDMD and STING suppressed cardiac hypertrophy in cardiac-specific GSDMD-overexpressing mice. Conclusions: Based on these findings, we propose a mechanism by which GSDMD generates a self-amplifying, positive feed-forward loop with the mitochondria-STING axis. This finding points to the prospects of GSDMD as a key therapeutic target for hypertrophy-associated heart diseases.

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Section: Ang Ii-mediated Gsdmd Cleavage Induces Mitochondrial Dysfunc...supporting

confidence: 80%

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

et al. 2022

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“…But interestingly, in most metabolic disorders and CVDs, mitophagy is relatively impaired, the levels of regulators of mtDNA are decreased, and abnormal metabolic processes also impact mitochondria integrity and structure, leading to mitochondrial stress. Therefore, in most cases, for example, in obese, type two diabetic, and CVDs patients, plasma levels of mtDNA fragments and mtDNA damage are profoundly high and positively correlate with disease severity, chronic inflammation, oxidative stress, and insulin resistance 105 , 106 .…”

Section: Sting Serves As Intracellular Damage Sensor and Regulator Of Cellular Metabolism And Inflammationmentioning

confidence: 99%

The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Oduro

Zheng

Wei

et al. 2022

Acta Pharmaceutica Sinica B

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The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS–STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS–STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS–STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

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“…EcDNA can be degraded by deoxyribonucleases (DNases) active in the circulation, and it was already hypothesized that it can be protected from nuclease digestion [ 4 , 5 ]. EcDNA could have an immunomodulatory effect [ 4 , 5 , 6 ] and proinflammatory effect [ 5 ], and it could be involved in the development of various diseases, such as autoimmune diseases [ 7 ], inflammatory bowel diseases [ 8 ] or cardiovascular diseases [ 9 , 10 ]. EcDNA could be in the circulation in various forms—free or as a component of various structures, such as nucleosomes [ 11 ], virtosomes [ 12 ], neutrophil extracellular traps [ 13 ] or extracellular vesicles (EVs) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Presence of DNA in Human Blood Plasma Small Extracellular Vesicles

Lichá

Pastorek

Repiská

et al. 2023

IJMS

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Extracellular DNA (ecDNA) is DNA outside of cells, which is a result of various mechanisms. EcDNA is believed to be a cause of various pathogeneses as well as their potential biomarker. EcDNA is believed to also be part of small extracellular vesicles (sEVs) from cell cultures. If ecDNA is present in sEVs in plasma, their membrane may protect it from degradation by deoxyribonucleases. Moreover, sEVs play a role in the intercellular communication, and they can therefore transfer ecDNA between cells. The aim of this study was to investigate the presence of ecDNA in sEVs isolated from fresh human plasma by the ultracentrifugation and density gradient, which serves to exclude the co-isolation of non-sEVs compartments. The novelty of the current study is the investigation of the localization and subcellular origin of the ecDNA associated with sEVs in plasma, as well as the estimation of the approximate concentration. The cup-shaped sEVs were confirmed by transmission electron microscopy. The highest concentration of particles was in the size of 123 nm. The presence of the sEVs markers CD9 and TSG101 was confirmed by western blot. It was found that 60–75% of DNA is on the surface of sEVs, but a part of the DNA is localized inside the sEVs. Moreover, both nuclear and mitochondrial DNA were present in plasma EVs. Further studies should focus on the potential harmful autoimmune effect of DNA carried by plasma EVs or specifically sEVs.

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Pro‐inflammatory role of cell‐free mitochondrial DNA in cardiovascular diseases

Cited by 22 publications

References 114 publications

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Investigation of the Presence of DNA in Human Blood Plasma Small Extracellular Vesicles

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