The Role of Mutagenesis in Atherosclerosis

Kutikhin, Anton G.; Синицкий, М. Ю.; Понасенко, А. В.

doi:10.17802/2306-1278-2017-1-92-101

Cited by 19 publications

(4 citation statements)

References 67 publications

(56 reference statements)

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“…В настоящее время создание комплексных моделей прогнозирования отдаленных исходов становится акту-ОРИГИНАЛЬНЫЕ СТАТЬИ § альной задачей, а учет генетических факторов риска расширяет возможности прогнозирования риска и влияет на выбор лечебной стратегии [21]. В 2017 г. была опубликована математическая модель прогнозирования риска развития НКС в течение года после ОКСбпSТ, включающая, помимо клинических факторов риска, такие факторы, как концентрация С-реактивного протеина в сыворотке крови и носительство генотипа С / Т rs1376251 гена TAS2R50, что позволяет повысить ее прогностическую ценность [22].…”

Section: Discussionunclassified

Predicting the development of adverse events in patients with acute coronary syndrome including genetics in the long-term follow-up

et al. 2020

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Aim To study a relationship of several factors (clinical and genetical markers) with unfavorable outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in long-term follow-up.Material and methods This full-design, prospective study included 415 patients with NSTE-ACS. 266 patients were evaluated for the presence of multifocal atherosclerosis (MFA). Typing of polymorphic variants rs1041981 LTA, rs1800629 TNF, rs4986790, and rs498679 TLR4, and also rs3024491 and rs1800872 IL10 was performed. Follow-up period lasted for 67±4 months. By the end of this period, information about clinical outcomes for 396 patients became available.Results During the entire follow-up period, unfavorable outcomes were observed in 239 (57.5 %) patients with NSTE-ACS. The following clinical signs were associated with unfavorable outcomes: history of myocardial infarction, age >56 years, left ventricular ejection fraction (LV EF) ≤50 % and GRACE score ≥100, significant stenosis of brachiocephalic arteries, MFA, carriage of genotype А / А rs1041981 LTA (OR, 6.1; р=0.02) and allele А (OR, 1.9; р=0.01). According to results of a multifactorial analysis, the most significant predictors included LV EF <50 %, MFA, and carriage of genotype А / А rs1041981 LTA.Conclusion Stratification of patients with NSTE-ACS into groups of high or low risk for having an unfavorable outcome within the next 6 years is possible using the prognostic model developed and presented in this study. The model includes the following signs: LV EF <50 %, MFA, and carriage of genotype А / А rs1041981 LTA.

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Section: Discussionunclassified

Predicting the development of adverse events in patients with acute coronary syndrome including genetics in the long-term follow-up

et al. 2020

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“…Genotoxic stress in mammalian cells is defined as a situation that initiates DNA damage compromising the cell's genomic integrity leading to replication and transcription arrest [1] and underlies many pathological conditions including cellular senescence [2][3][4][5], cancer [6][7][8][9] and cardiovascular diseases [10][11][12][13][14]. Recent experimental data suggest that the genotoxic stress in vitro induced by alkylating mutagen mitomycin C (MMC) is associated with the proinflammatory activation of primary human endothelial cells and the endothelial-to-mesenchymal transition [15][16][17], the key pathways underlying endothelial disfunction [18]-an initial stage of atherosclerosis [19,20], a leading cause of cardiovascular morbidity and mortality worldwide [21,22].…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Endothelial Cells Exposed to Mitomycin C: Key Proteins and Pathways Underlying Genotoxic Stress-Induced Endothelial Dysfunction

Sinitsky,

Repkin,

Sinitskaya

et al. 2024

IJMS

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Mitomycin C (MMC)-induced genotoxic stress can be considered to be a novel trigger of endothelial dysfunction and atherosclerosis—a leading cause of cardiovascular morbidity and mortality worldwide. Given the increasing genotoxic load on the human organism, the decryption of the molecular pathways underlying genotoxic stress-induced endothelial dysfunction could improve our understanding of the role of genotoxic stress in atherogenesis. Here, we performed a proteomic profiling of human coronary artery endothelial cells (HCAECs) and human internal thoracic endothelial cells (HITAECs) in vitro that were exposed to MMC to identify the biochemical pathways and proteins underlying genotoxic stress-induced endothelial dysfunction. We denoted 198 and 71 unique, differentially expressed proteins (DEPs) in the MMC-treated HCAECs and HITAECs, respectively; only 4 DEPs were identified in both the HCAECs and HITAECs. In the MMC-treated HCAECs, 44.5% of the DEPs were upregulated and 55.5% of the DEPs were downregulated, while in HITAECs, these percentages were 72% and 28%, respectively. The denoted DEPs are involved in the processes of nucleotides and RNA metabolism, vesicle-mediated transport, post-translation protein modification, cell cycle control, the transport of small molecules, transcription and signal transduction. The obtained results could improve our understanding of the fundamental basis of atherogenesis and help in the justification of genotoxic stress as a risk factor for atherosclerosis.

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“…Recently, it was reported that genotoxic stress induced by 6 h of exposure of endothelial cells to 500 ng/mL MMC is associated with proinflammatory activation of endothelium and endothelial dysfunction [ 17 , 18 , 19 ] underlying atherosclerosis [ 20 , 21 ], a leading cause of cardiovascular morbidity and mortality worldwide [ 22 , 23 ]. HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, also known as statins, are small molecules that are the rate-controlling enzyme of the mevalonate pathway.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Can Modulate DNA Damage Repair in Endothelial Cells Exposed to Mitomycin C

Sinitsky

Asanov

Цепокина

et al. 2023

IJMS

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HMG-CoA reductase inhibitors (statins) are widely used in the therapy of atherosclerosis and have a number of pleiotropic effects, including DNA repair regulation. We studied the cytogenetic damage and the expression of DNA repair genes (DDB1, ERCC4, and ERCC5) in human coronary artery (HCAEC) and internal thoracic artery endothelial cells (HITAEC) in vitro exposed to mitomycin C (MMC) (positive control), MMC and atorvastatin (MMC+Atv), MMC followed by atorvastatin treatment (MMC/Atv) and 0.9% NaCl (negative control). MMC/Atv treated HCAEC were characterized by significantly decreased micronuclei (MN) frequency compared to the MMC+Atv group and increased nucleoplasmic bridges (NPBs) frequency compared to both MMC+Atv treated cells and positive control; DDB1, ERCC4, and ERCC5 genes were upregulated in MMC+Atv and MMC/Atv treated HCAEC in comparison with the positive control. MMC+Atv treated HITAEC were characterized by reduced MN frequency compared to positive control and decreased NPBs frequency in comparison with both the positive control and MMC/Atv group. Nuclear buds (NBUDs) frequency was significantly lower in MMC/Atv treated cells than in the positive control. The DDB1 gene was downregulated in the MMC+Atv group compared to the positive control, and the ERCC5 gene was upregulated in MMC/Atv group compared to both the positive control and MMC+Atv group. We propose that atorvastatin can modulate the DNA damage repair response in primary human endothelial cells exposed to MMC in a cell line- and incubation scheme-dependent manner that can be extremely important for understanding the fundamental aspects of pleoitropic action of atorvastatin and can also be used to correct the therapy of patients with atherosclerosis characterized by a high genotoxic load.

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The Role of Mutagenesis in Atherosclerosis

Abstract: Федеральное государственное бюджетное научное учреждение «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний»,

Cited by 19 publications

References 67 publications

Predicting the development of adverse events in patients with acute coronary syndrome including genetics in the long-term follow-up

Predicting the development of adverse events in patients with acute coronary syndrome including genetics in the long-term follow-up

Proteomic Profiling of Endothelial Cells Exposed to Mitomycin C: Key Proteins and Pathways Underlying Genotoxic Stress-Induced Endothelial Dysfunction

Atorvastatin Can Modulate DNA Damage Repair in Endothelial Cells Exposed to Mitomycin C

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