Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

Ciccarelli, Giovanni; Conte, Stefano; Cimmino, Giovanni; Maiorano, Patrizia; Morrione, Andrea; Giordano, Antonio

doi:10.3390/ijms24021086

Cited by 38 publications

(24 citation statements)

References 113 publications

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“…Interestingly, a decrease of mtDNA copy number is proven to lead to endothelial cell dysfunction, which is a characteristic of early events occurring in the pathogenesis of atherosclerosis. 57 Although we established an infection model with viable P. gingivalis and found that P. gingivalis induced mitochondrial dysfunction, we did not further confirm which virulence factor of P. gingivalis was responsible. It is well-accepted that gingipains, LPS, peptidoglycan and flagellin are fundamental virulence factors for P. gingivalis.…”

Section: Discussionmentioning

confidence: 85%

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RhoA/ROCK1 regulates the mitochondrial dysfunction through Drp1 induced by Porphyromonas gingivalis in endothelial cells

Qin

Ying

Yin

et al. 2023

J Cellular Molecular Medi

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Porphyromonas gingivalis (P. gingivalis) is a pivotal pathogen of periodontitis. Our previous studies have confirmed that mitochondrial dysfunction in the endothelial cells caused by P. gingivalis was dependent on Drp1, which may be the mechanism of P. gingivalis causing endothelial dysfunction. Nevertheless, the signalling pathway induced the mitochondrial dysfunction remains unclear. The purpose of this study was to investigate the role of the RhoA/ROCK1 pathway in regulating mitochondrial dysfunction caused by P. gingivalis. P. gingivalis was used to infect EA.hy926 cells (endothelial cells). The expression and activation of RhoA and ROCK1 were assessed by western blotting and pull‐down assay. The morphology of mitochondria was observed by mitochondrial staining and transmission electron microscopy. Mitochondrial function was measured by ATP content, mitochondrial DNA and mitochondrial permeability transition pore openness. The phosphorylation and translocation of Drp1 were evaluated using western blotting and immunofluorescence. The role of the RhoA/ROCK1 pathway in mitochondrial dysfunction was investigated using RhoA and ROCK1 inhibitors. The activation of RhoA/ROCK1 pathway and mitochondrial dysfunction were observed in P. gingivalis‐infected endothelial cells. Furthermore, RhoA or ROCK1 inhibitors partly prevented mitochondrial dysfunction caused by P. gingivalis. The increased phosphorylation and mitochondrial translocation of Drp1 induced by P. gingivalis were both blocked by RhoA and ROCK1 inhibitors. In conclusion, we demonstrate that the RhoA/ROCK1 pathway was involved in mitochondrial dysfunction caused by P. gingivalis by regulating the phosphorylation and mitochondrial translocation of Drp1. Our research illuminated a possible new mechanism by which P. gingivalis promotes endothelial dysfunction.

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Section: Discussionmentioning

confidence: 85%

“…mtDNA is more vulnerable to ROS attack when exposed to oxidative damage than nuclear DNA. Interestingly, a decrease of mtDNA copy number is proven to lead to endothelial cell dysfunction, which is a characteristic of early events occurring in the pathogenesis of atherosclerosis 57 …”

Section: Discussionmentioning

confidence: 99%

RhoA/ROCK1 regulates the mitochondrial dysfunction through Drp1 induced by Porphyromonas gingivalis in endothelial cells

Qin

Ying

Yin

et al. 2023

J Cellular Molecular Medi

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show abstract

“…This accumulation of reactive oxygen species likely plays a prominent role in the development of atherosclerosis, as demonstrated by numerous studies. [52][53][54][55][56][57] Another phenomenon could have an impact, which is the release by activated monocytes of free mitochondria and microvesicles containing mitochondrial elements, as demonstrated by Puhm et al 58 The development of therapeutic interventions to limit this mitochondrial dysfunction and its impact on cardiovascular risk could be contemplated in patients with T2D, as is already the case in psychiatric 59 or neurological diseases. 60 Nevertheless, our study puts monocytes at the core of the equation for the heightened risk in patients with T2D and advocates for further research on antiatherosclerotic treatments targeting monocytes and mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Blood Monocyte Phenotype Is A Marker of Cardiovascular Risk in Type 2 Diabetes

Julla,

Girard,

Diedisheim

et al. 2024

Circulation Research

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Background: Diabetes is a major risk factor for atherosclerotic cardiovascular diseases with a 2-fold higher risk of cardiovascular events in people with diabetes compared with those without. Circulating monocytes are inflammatory effector cells involved in both type 2 diabetes (T2D) and atherogenesis. Methods: We investigated the relationship between circulating monocytes and cardiovascular risk progression in people with T2D, using phenotypic, transcriptomic, and metabolomic analyses. cardiovascular risk progression was estimated with coronary artery calcium score in a cohort of 672 people with T2D. Results: Coronary artery calcium score was positively correlated with blood monocyte count and frequency of the classical monocyte subtype. Unsupervised k-means clustering based on monocyte subtype profiles revealed 3 main endotypes of people with T2D at varying risk of cardiovascular events. These observations were confirmed in a validation cohort of 279 T2D participants. The predictive association between monocyte count and major adverse cardiovascular events was validated through an independent prospective cohort of 757 patients with T2D. Integration of monocyte transcriptome analyses and plasma metabolomes showed a disruption of mitochondrial pathways (tricarboxylic acid cycle, oxidative phosphorylation pathway) that underlined a proatherogenic phenotype. Conclusions: In this study, we provide evidence that frequency and monocyte phenotypic profile are closely linked to cardiovascular risk in patients with T2D. The assessment of monocyte frequency and count is a valuable predictive marker for risk of cardiovascular events in patients with T2D. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04353869

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“…Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, so called mitochondrial dynamic, which is fundamental for the organelle function 75 . We found that MTF2, mitochondrial protein responsible for fusion process, expression was reduced by ethanol consumption with no difference in DRP1 (mitochondria fission inducer), interestingly losartan prevented these changes, suggesting ethanol decreases mitochondria fusion via RASS activation.…”

Section: Discussionmentioning

confidence: 99%

Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction

Awata,

Alves,

Costa

et al. 2023

Preprint

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Background: Renin angiotensin (Ang II) aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS). Methods: Male C57/BL6J or mt-keima mice (6 to 8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg). Results: Ethanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1a; (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mtkeima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H2O2 bioavailability. These responses were prevented by losartan. Conclusion: AT1 receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H2O2 bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking.

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Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

Cited by 38 publications

References 113 publications

RhoA/ROCK1 regulates the mitochondrial dysfunction through Drp1 induced by Porphyromonas gingivalis in endothelial cells

RhoA/ROCK1 regulates the mitochondrial dysfunction through Drp1 induced by Porphyromonas gingivalis in endothelial cells

Blood Monocyte Phenotype Is A Marker of Cardiovascular Risk in Type 2 Diabetes

Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction

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