Electronic Cigarettes Induce Mitochondrial DNA Damage and Trigger TLR 9 (Toll-Like Receptor 9)-Mediated Atherosclerosis

Objective: Electronic cigarette (e-cig) use has recently been implicated in promoting atherosclerosis. In this study, we aimed to investigate the mechanism of e-cig exposure accelerated atherosclerotic lesion development. Approach and Results: Eight-week-old ApoE − /− mice fed normal laboratory diet were exposed to e-cig vapor (ECV) for 2 hours/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining and greatly upregulated TLR9 (toll-like receptor 9) expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by enhanced TLR9 expression in human femoral artery atherosclerotic plaques from e-cig smokers. Intriguingly, we found a significant increase of oxidative mitochondria DNA lesion in the plasma of ECV-exposed mice. Administration of TLR9 antagonist before ECV exposure not only alleviated atherosclerosis and the upregulation of TLR9 in plaques but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the plaque accumulation of lipid and macrophages, and decreased the frequency of blood CCR2 + classical monocytes. Surprisingly, we found that cytoplasmic mitochondrial DNA isolated from ECV extract-treated macrophages can enhance TLR9 activation in reporter cells and the induction of inflammatory cytokine could be suppressed by TLR9 inhibitor in macrophages. Conclusions: E-cig increases level of damaged mitochondrial DNA in circulating blood and induces the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacological target of ECV-related inflammation and cardiovascular diseases.

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Electronic cigarettes induce mitochondrial DNA damage and trigger toll-like receptor 9-mediated atherosclerosis

10.1101/2020.08.15.252494 ◽

2020 ◽

Author(s):

Jieliang Li ◽

Do Luong Huynh ◽

Moon-Shong Tang ◽

Hannah Simborio ◽

Jing Huang ◽

...

Keyword(s):

Electronic Cigarettes ◽

Atherosclerotic Lesion ◽

Atherosclerotic Plaques ◽

Chow Diet ◽

Toll Like Receptor ◽

Tlr9 Expression ◽

Mitochondrial Dna Damage ◽

Normal Chow ◽

Classical Monocytes ◽

Tlr9 Activation

AbstractObjectiveBoth electronic cigarette (e-cig) use and toll-like receptor 9 (TLR9) activation have been implicated in promoting atherosclerosis. In this study we aimed to investigate the causative relationship of e-cig exposure on TLR9 activation and atherosclerosis development.Approach and ResultsEight-week-old ApoE-/- mice fed normal chow diet were exposed to e-cig vapor (ECV) for 2 h/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining of aortic root and greatly upregulated TLR9 expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by upregulated TLR9 expression in human femoral artery atherosclerotic plaques in e-cig smokers. Intriguingly, we found a significant increase of damaged mitochondria DNA level in the circulating blood of ECV exposed mice. Furthermore, administration of TLR9 antagonist prior to ECV exposure not only alleviated atherosclerotic lesion and the upregulation of TLR9 in plaques, but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the accumulation of lipid and macrophages, and decreased the frequency of blood CCR2+ classical monocytes. Surprisingly, we found that the cytoplasmic mtDNA isolated from ECV extract-treated cells can greatly enhance the expression of TLR9 in reporter cells.ConclusionE-cig induces mtDNA damage and the mtDNA in circulating blood stimulates the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacologic target of ECV-related inflammation and cardiovascular diseases.

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Toll‐like receptor 4 mediates mitochondrial DNA damage and biogenic responses after heat‐inactivated E. coli

The FASEB Journal ◽

10.1096/fj.04-3500fje ◽

2005 ◽

Vol 19 (11) ◽

pp. 1531-1533 ◽

Cited By ~ 62

Author(s):

Hagir B. Suliman ◽

Karen E. Welty‐Wolf ◽

Martha Sue Carraway ◽

David A. Schwartz ◽

John W. Hollingsworth ◽

...

Keyword(s):

Dna Damage ◽

Mitochondrial Dna ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

E Coli ◽

Mitochondrial Dna Damage

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microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans

Thrombosis and Haemostasis ◽

10.1160/th11-09-0607 ◽

2012 ◽

Vol 107 (04) ◽

pp. 619-625 ◽

Cited By ~ 71

Author(s):

Bernd Denecke ◽

André Rostalsky ◽

Mihail Hristov ◽

Thomas A. Koeppel ◽

Kiril Bidzhekov ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

Mirna Expression ◽

Expression Profiles ◽

Atherosclerotic Lesion ◽

Vascular Diseases ◽

Atherosclerotic Plaques ◽

Monocyte Subset ◽

Monocyte Subsets ◽

Cardiovascular Biology ◽

Classical Monocytes

SummarySmall non-coding microRNAs (miRNAs) have emerged to play critical roles in cardiovascular biology. Monocytes critically drive atherosclerotic lesion formation, and can be subdivided into a classical and non-classical subset. Here we scrutinised the miRNA signature of human classical and non-classical monocytes, and compared miRNA expression profiles of atherosclerotic plaques from human carotid arteries and healthy arteries. We identified miRNAs to be differentially regulated with a two-fold or higher difference between classical and non-classical monocyte subsets. Moreover, comparing miRNA expression in atherosclerotic plaques compared to healthy arteries, we observed several miRNAs to be aberrantly expressed, with the majority of miRNAs displaying a two-fold or higher increase in plaques and only few miRNAs being decreased. To elucidate similarities in miRNA signatures between monocyte subsets and atherosclerotic plaque, expression of miRNAs highly abundant in monocytes and plaque tissues were compared. Several miRNAs were found in atherosclerotic plaques but not in healthy vessels or either monocyte subset. However, we could identify miRNAs co-expressed in plaque tissue and classical monocytes (miR-99b, miR-152), or non-classical monocytes (miR-422a), or in both monocytes subsets. We thus unravelled candidate miRNAs, which may facilitate our understanding of monocyte recruitment and fate during atherosclerosis, and may serve as therapeutic targets for treating inflammatory vascular diseases.Note: The editorial process for this article was fully handled by Prof. G. Y. H. Lip, Editor-in-Chief.

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Do mitochondrial DNA mutations play the key role in chronification of sterile inflammation? Special focus on atherosclerosis

Current Pharmaceutical Design ◽

10.2174/1381612826666201012164330 ◽

2020 ◽

Vol 26 ◽

Author(s):

Alexander N. Orekhov ◽

Elena V. Gerasimova ◽

Vasily N. Sukhorukov ◽

Anastasia V. Poznyak ◽

Nikita G. Nikiforov

Keyword(s):

Innate Immunity ◽

Mitochondrial Dna ◽

Low Density Lipoprotein ◽

Atherosclerotic Lesion ◽

Density Lipoprotein ◽

Sterile Inflammation ◽

Special Focus ◽

Mitochondrial Dysfunctions ◽

Mtdna Mutations ◽

Dna Mutations

Background: The elucidation of mechanisms implicated in the chronification of inflammation is able to shed the light on the pathogenesis of disorders that are responsible for the majority of the incidence of disease and deaths, and also causes of ageing. Atherosclerosis is an example of the most significant inflammatory pathology. The inflammatory response of innate immunity is implicated in the development of atherosclerosis arising locally or focally. Modified low-density lipoprotein (LDL) was regarded as the trigger for this response. No atherosclerotic changes in the arterial wall occur due to the quick decrease in inflammation rate. Nonetheless, the atherosclerotic lesion formation can be a result of the chronification of local inflammation, which, in turn, is caused by alteration of the response of innate immunity. Objective: In this review, we discussed potential mechanisms of the altered response of the immunity in atherosclerosis with a particular emphasis on mitochondrial dysfunctions. Conclusion: A few mitochondrial dysfunctions can be caused by the mitochondrial DNA (mtDNA) mutations. Moreover, mtDNA mutations were found to affect the development of defective mitophagy. Modern investigations have demonstrated the controlling mitophagy function in the response of the immune system. Therefore, we hypothesized that impaired mitophagy, as a consequence of mutations in mtDNA, can raise a disturbed innate immunity response resulting in the chronification of inflammation in atherosclerosis.

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Deficiency of endothelial CD40 induces a stable plaque phenotype and limits inflammatory cell recruitment to atherosclerotic lesions in mice

Thrombosis and Haemostasis ◽

10.1055/a-1397-1858 ◽

2021 ◽

Author(s):

Mark Colin Gissler ◽

Philipp Scherrer ◽

Nathaly Anto Michel ◽

Jan Pennig ◽

Natalie Hoppe ◽

...

Keyword(s):

Adhesion Molecule ◽

Inflammatory Cell ◽

Leukocyte Adhesion ◽

Critical Role ◽

Atherosclerotic Lesion ◽

Intercellular Adhesion Molecule ◽

Atherosclerotic Plaques ◽

Chow Diet ◽

Stable Plaque ◽

Plaque Phenotype

Objectives: The co-stimulatory CD40L-CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis. Approach & Results: Atherosclerotic plaques of Apolipoprotein E deficient (Apoe-/-) mice and humans displayed increased expression of CD40 on ECs compared to controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCreERT2-driven) deficiency of CD40 in Apoe-/- mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs. Conclusions: Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.

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