Susceptibility of monocytes to activation correlates with atherogenic mitochondrial DNA mutations

Orekhov, Alexander N.; Zhelankin, Andrey V.; Kolmychkova, K.I.; Mitrofanov, Konstantin Y.; Kubekina, M.; Ivanova, Ekaterina A.; Sobenin, Igor A.

doi:10.1016/j.yexmp.2015.11.006

Cited by 20 publications

(12 citation statements)

References 21 publications

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“…A study conducted by our group has shown that mtDNA mutations are related to the degree of monocyte activation [133]. In this study, pro-inflammatory activation of monocytes isolated from the blood of subjects with asymptomatic atherosclerosis correlated with atherosclerosis-associated mtDNA mutations, in particular, homoplasmic m.1811A>G and m.9477G>A.…”

Section: Innate Immunity and Mtdna Mutationsmentioning

confidence: 51%

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

Orekhov

Nikiforov

Ivanova

et al. 2020

JCM

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Chronification of inflammation is the process that lies at the basis of several human diseases that make up to 80% of morbidity and mortality worldwide. It can also explain a great deal of processes related to aging. Atherosclerosis is an example of the most important chronic inflammatory pathology in terms of public health impact. Atherogenesis is based on the inflammatory response of the innate immunity arising locally or focally. The main trigger for this response appears to be modified low-density lipoprotein (LDL), although other factors may also play a role. With the quick resolution of inflammation, atherosclerotic changes in the arterial wall do not occur. However, a violation of the innate immunity response can lead to chronification of local inflammation and, as a result, to atherosclerotic lesion formation. In this review, we discuss possible mechanisms of the impaired immune response with a special focus on mitochondrial dysfunction. Some mitochondrial dysfunctions may be due to mutations in mitochondrial DNA. Several mitochondrial DNA mutations leading to defective mitophagy have been identified. The regulatory role of mitophagy in the immune response has been shown in recent studies. We suggest that defective mitophagy promoted by mutations in mitochondrial DNA can cause innate immunity disorders leading to chronification of inflammation.

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Section: Innate Immunity and Mtdna Mutationsmentioning

confidence: 51%

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

Orekhov

Nikiforov

Ivanova

et al. 2020

JCM

Self Cite

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“…A recent study has revealed an association of mitochondrial gene mutations with monocyte susceptibility to activation [ 49 ]. At least three heteroplasmic mutations of mtDNA, G14459A, A1555G, and G12315A, associated with atherosclerosis development in humans correlated with facilitated proinflammatory activation of circulating monocytes.…”

Section: Individual Difference In Macrophage Activation and Transcmentioning

confidence: 99%

Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

Bobryshev

Ivanova

Chistiakov

et al. 2016

BioMed Research International

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203

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Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances.

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“…Lipopolysaccharide (LPS), as one of the risk factors of AS, can activate the innate immunity of monocyte/macrophage (M/MΦ), resulting in VECs damage. Recently there have been considerable studies focusing on exosomes, which are released by M/MΦ and regulate the receptor cells function ( Moore and Tabas, 2011 ; Orekhov et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223

Liu

et al. 2018

Front. Pharmacol.

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Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with paeonol’ effects are still not clear.Objective: Our study aimed to explain whether paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results: In vivo experiments confirmed that paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.

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Susceptibility of monocytes to activation correlates with atherogenic mitochondrial DNA mutations

Cited by 20 publications

References 21 publications

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223

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