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1.
Biomedicines ; 9(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34440119

RESUMO

Atherosclerosis is a multifactorial chronic disease that has a prominent inflammatory component. Currently, atherosclerosis is regarded as an active autoimmune process that involves both innate and adaptive immune pathways. One of the drivers of this process is the presence of modified low-density lipoprotein (LDL). For instance, lipoprotein oxidation leads to the formation of oxidation-specific epitopes (OSE) that can be recognized by the immune cells. Macrophage response to OSEs is recognized as a key trigger for initiation and a stimulator of progression of the inflammatory process in the arteries. At the same time, the role of oxidized LDL components is not limited to pro-inflammatory stimulation, but includes immunoregulatory effects that can have protective functions. It is, therefore, important to better understand the complexity of oxidized LDL effects in atherosclerosis in order to develop new therapeutic approaches to correct the inflammatory and metabolic imbalance associated with this disorder. In this review, we discuss the process of oxidized LDL formation, mechanisms of OSE recognition by macrophages and the role of these processes in atherosclerosis.

2.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201756

RESUMO

Diabetes mellitus and related disorders significantly contribute to morbidity and mortality worldwide. Despite the advances in the current therapeutic methods, further development of anti-diabetic therapies is necessary. Mitochondrial dysfunction is known to be implicated in diabetes development. Moreover, specific types of mitochondrial diabetes have been discovered, such as MIDD (maternally inherited diabetes and deafness) and DAD (diabetes and Deafness). Hereditary mitochondrial disorders are caused by certain mutations in the mitochondrial DNA (mtDNA), which encodes for a substantial part of mitochondrial proteins and mitochondrial tRNA necessary for mitochondrial protein synthesis. Study of mtDNA mutations is challenging because the pathogenic phenotype associated with such mutations depends on the level of its heteroplasmy (proportion of mtDNA copies carrying the mutation) and can be tissue-specific. Nevertheless, modern sequencing methods have allowed describing and characterizing a number of mtDNA mutations associated with human disorders, and the list is constantly growing. In this review, we provide a list of mtDNA mutations associated with diabetes and related disorders and discuss the mechanisms of their involvement in the pathology development.


Assuntos
Diabetes Mellitus/genética , Genoma Mitocondrial/genética , Inflamação/genética , Mutação , Animais , Doença Crônica , DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Camundongos , Doenças Mitocondriais/genética
3.
Life (Basel) ; 10(9)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842589

RESUMO

The search for markers of predisposition to atherosclerosis development is very important for early identification of individuals with a high risk of cardiovascular disease. The aim of the present study was to investigate the association of mitochondrial DNA mutations with carotid intima-media thickness and to determine the impact of mitochondrial heteroplasmy measurements in the prognosis of atherosclerosis development. This cross-sectional, population-based study was conducted in 468 subjects from the Novosibirsk region. It was shown that the mean (carotid intima-media thickness) cIMT correlated with the following mtDNA mutations: m.15059G>A (r = 0.159, p = 0.001), m.12315G>A (r = 0.119; p = 0.011), m.5178C>A (r = 0.114, p = 0.014), and m.3256C>T (r = 0.130, p = 0.011); a negative correlation with mtDNA mutations m.14846G>A (r = -0.111, p = 0.042) and m.13513G>A (r = -0.133, p = 0.004) was observed. In the linear regression analysis, the addition of the set of mtDNA mutations to the conventional cardiovascular risk factors increased the ability to predict the cIMT variability from 17 to 27%. Multi-step linear regression analysis revealed the most important predictors of mean cIMT variability: age, systolic blood pressure, blood levels of total cholesterol, LDL and triglycerides, as well as the mtDNA mutations m.13513G>A, m.15059G>A, m.12315G>A, and m.3256C>T. Thus, a high predictive value of mtDNA mutations for cIMT variability was demonstrated. The association of mutation m.13513G>A and m.14846G>A with a low value of cIMT, demonstrated in several studies, represents a potential for the development of anti-atherosclerotic gene therapy.

4.
Biomedicines ; 8(7)2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664404

RESUMO

The current view on atherosclerosis positions it as a multifactorial disorder that results from the interplay between lipid metabolism disturbances and inflammatory processes. Oxidative stress is proven to be one of the initiating factors in atherosclerosis development, being implicated both in the inflammatory response and in atherogenic modifications of lipoproteins that facilitate lipid accumulation in the arterial wall. The hallmark of oxidative stress is the elevated level of reactive oxygen species (ROS). Correspondingly, the activity of major ROS-generating enzymes, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, and cyclooxygenases, is an important element in atherosclerosis development. In particular, the role of NADPH oxidases in atherosclerosis development has become a subject of intensive research. Aberrant activity of NADPH oxidases was shown to be associated with cardiovascular disease in humans. With regard to atherosclerosis, several important pathological components of the disease development, including endothelial dysfunction, inflammation, and vascular remodeling, involve aberrations in NADPH oxidases functioning. In humans, NADPH oxidases are represented by four isoforms expressed in vascular tissues, where they serve as the main source of ROS during atherogenesis. Moreover, recent studies have demonstrated their impact on vascular remodeling processes. Interestingly, one of the NADPH oxidase isoforms, NOX4, was shown to have an atheroprotective effect. Despite the growing evidence of the crucial involvement of NADPH oxidases in atherosclerosis pathogenesis, the available data still remains controversial. In this narrative review, we summarize the current knowledge of the role of NADPH oxidases in atherosclerosis and outline the future directions of research.

5.
Biology (Basel) ; 9(3)2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32245238

RESUMO

Atherosclerosis can be regarded as chronic inflammatory disease affecting the arterial wall. Despite the recent progress in studying the pathogenesis of atherosclerosis, some of the pathogenic mechanisms remain to be fully understood. Among these mechanisms is oxidative stress, which is closely linked to foam cells formation and other key events in atherosclerosis development. Two groups of enzymes are involved in the emergence of oxidative stress: Pro-oxidant (including NADPH oxidases, xanthine oxidases, and endothelial nitric oxide synthase) and antioxidant (such as superoxide dismutase, catalases, and thioredoxins). Pro-oxidant enzymes in normal conditions produce moderate concentrations of reactive oxidant species that play an important role in cell functioning and can be fully utilized by antioxidant enzymes. Under pathological conditions, activities of both pro-oxidant and antioxidant enzymes can be modified by numerous factors that can be relevant for developing novel therapies. Recent studies have explored potential therapeutic properties of antioxidant molecules that are capable to eliminate oxidative damage. However, the results of these studies remain controversial. Other perspective approach is to inhibit the activity of pro-oxidant enzymes and thus to slow down the progression of atherosclerosis. In this review we summarized the current knowledge on oxidative stress in atherosclerosis and potential antioxidant approaches. We discuss several important antioxidant molecules of plant origin that appear to be promising for treatment of atherosclerosis.

6.
Biology (Basel) ; 9(3)2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155747

RESUMO

This randomized double-blinded, placebo-controlled clinical trial evaluated the progression of intima-media thickness of common carotid artery (cIMT) and the effect of phytoestrogen therapy on atherosclerosis development in early and late postmenopausal women. The 2-year cIMT progression was evaluated in 315 early postmenopausal women aged 40-55 years and in 231 late postmenopausal women aged 60-69 years free of cardiovascular disease. B-mode ultrasound was done at baseline and after 12 and 24 months of follow-up. The study revealed no significant changes in the rate of cIMT progression in 315 early postmenopausal women. By contrast, a statistically significant difference in the rate of atherosclerosis development was observed in late postmenopausal women treated with phytoestrogens compared to placebo (p = 0.008). The rate of cIMT progression in the placebo group was 0.019 mm/year led to a significant increase of cIMT during the observation period (p = 0.012), while the rate of cIMT progression in phytoestrogen late postmenopausal recipients was 0.011 mm/year, and total change did not reach statistical significance during the follow-up period (p = 0.101). These results suggest that late postmenopausal women can be a suitable cohort for trials assessing the anti-atherosclerosis effects of phytoestrogen preparations. In particular, the beneficial effect of phytoestrogens on cIMT progression was demonstrated in late postmenopausal women.

7.
Data Brief ; 29: 105136, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32016144

RESUMO

The search for variants of mitochondrial genome associated with atherosclerosis, in particular, with carotid intima-media thickness (cIMT), is necessary to understand the role of the damage of mitochondrial genome in the development of atherosclerosis. Such data can be useful to provide novel genetic markers of predisposition to atherosclerosis and molecular targets for further development of technologies aimed to prevent age-related degenerative pathologies. Data presented in this article demonstrate the association of several heteroplasmic variants of mitochondrial DNA (mtDNA) previously described as proatherogenic ones with cIMT in 251 participants (190 participants from Novosibirsk, Russia, and 61 participant from Almaty, Kazakhstan). It was shown that the occurrence of some variants of mitochondrial genome is different in samples derived from Russian and Kazakh populations; the level of mitochondrial heteroplasmy m.13513G > A correlates negatively with mean cIMT in both Russian and Kazakh participants.

8.
Curr Pharm Des ; 25(3): 213-217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30892154

RESUMO

Macrophages are key players in human innate immunity that protect the organism from pathologic agents, including infection and malignant cells. The spectrum of their functions includes initiation and maintaining of inflammation, cleaning of pathogens and cell debris, as well as inflammation resolution and tissue remodeling and repair. Such a wide spectrum is reflected by the great variety of macrophage phenotypes based on the activation of distinct transcription patterns in response to different stimuli. Studying this complexity requires an integrated approach, such as transcriptome studies. For many genes, the exact role in macrophage biology remains unknown, although clear associations with pro- or anti-inflammatory macrophage polarization could be demonstrated. These findings reveal the novel directions for future research. In this review, we describe the known mechanisms of macrophage polarization and the new insights available from transcriptome studies.


Assuntos
Ativação de Macrófagos , Macrófagos/citologia , Transcriptoma , Humanos , Inflamação , Fenótipo
9.
Data Brief ; 18: 16-21, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29896485

RESUMO

Despite the fact that the role of mitochondrial genome mutations in a number of human diseases is widely studied, the effect of mitochondrial heteroplasmy in the development of cardiovascular disease has not been adequately investigated. In this study, we compared the heteroplasmy levels of mtDNA from leukocytes for m.3256C>T, m.3336T>C, m.12315G>A, m.5178C>A, m.13513G>A, m.14459G>A, m.14846G>A, m.15059G>A, m.652insG and m.1555A>G mutations in CVD-free subjects and CVD patients in samples derived from Russian and Mexican populations. It was demonstrated that heteroplasmy level of m.5178C>A was associated with CVD in Russian men, and m.14459G>A - in Russian women. Mitochondrial heteroplasmy level of m.13513G>A and m.652insG were associated with CVD in Mexican men, and only m.652insG- in Mexican women. The levels of heteroplasmy for mitochondrial mutations m.3336T>C, m.5178C>A, m.14459G>A, m.14846G>A and m.1555A>G were significantly higher in CVD-free Mexican men, and for m.3256C>T, m.3336T>C, and m.14459G>A - in CVD-free Mexican women.

10.
Int J Mol Sci ; 17(8)2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27529226

RESUMO

The risk of cardiovascular disease and atherosclerosis progression is significantly increased after menopause, probably due to the decrease of estrogen levels. The use of hormone replacement therapy (HRT) for prevention of cardiovascular disease in older postmenopausal failed to meet expectations. Phytoestrogens may induce some improvements in climacteric symptoms, but their effect on the progression of atherosclerosis remains unclear. The reduction of cholesterol accumulation at the cellular level should lead to inhibition of the atherosclerotic process in the arterial wall. The inhibition of intracellular lipid deposition with isoflavonoids was suggested as the effective way for the prevention of plaque formation in the arterial wall. The aim of this double-blind, placebo-controlled clinical study was to investigate the effect of an isoflavonoid-rich herbal preparation on atherosclerosis progression in postmenopausal women free of overt cardiovascular disease. One hundred fifty-seven healthy postmenopausal women (age 65 ± 6) were randomized to a 500 mg isoflavonoid-rich herbal preparation containing tannins from grape seeds, green tea leaves, hop cone powder, and garlic powder, or placebo. Conventional cardiovascular risk factors and intima-media thickness of common carotid arteries (cIMT) were evaluated at the baseline and after 12 months of treatment. After 12-months follow-up, total cholesterol decreased by 6.3% in isoflavonoid-rich herbal preparation recipients (p = 0.011) and by 5.2% in placebo recipients (p = 0.020); low density lipoprotein (LDL) cholesterol decreased by 7.6% in isoflavonoid-rich herbal preparation recipients (p = 0.040) and by 5.2% in placebo recipients (non-significant, NS); high density lipoprotein (HDL) cholesterol decreased by 3.4% in isoflavonoid-rich herbal preparation recipients (NS) and by 4.5% in placebo recipients (p = 0.038); triglycerides decreased by 6.0% in isoflavonoid-rich herbal preparation recipients (NS) and by 7.1% in placebo recipients (NS). The differences between lipid changes in the isoflavonoid-rich herbal preparation and placebo recipients did not reach statistical significance (p > 0.05). Nevertheless, the mean cIMT progression was significantly lower in isoflavonoid-rich herbal preparation recipients as compared to the placebo group (6 µm, or <1%, versus 100 µm, or 13%; p < 0.001 for the difference). The growth of existing atherosclerotic plaques in isoflavonoid-rich herbal preparation recipients was inhibited by 1.5-fold (27% versus 41% in the placebo group). The obtained results demonstrate that the use of isoflavonoid-rich herbal preparation in postmenopausal women may suppress the formation of new atherosclerotic lesions and reduce the progression of existing ones, thus promising new drug for anti-atherosclerotic therapy. Nevertheless, further studies are required to confirm these findings.


Assuntos
Fitoestrógenos/uso terapêutico , Preparações de Plantas/uso terapêutico , Pós-Menopausa/efeitos dos fármacos , Idoso , Aterosclerose/sangue , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Isoflavonas/uso terapêutico , Pessoa de Meia-Idade , Triglicerídeos/sangue
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