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1.
Biomol Concepts ; 12(1): 55-67, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115932

RESUMO

Abdominal aortic aneurysm (AAA) is a complex degenerative vascular disease, with considerable morbidity and mortality rates among the elderly population. The mortality of AAA is related to aneurysm expansion (the enlargement of the aortic diameter up to 30 mm and above) and the subsequent rupture. The pathogenesis of AAA involves several biological processes, including aortic mural inflammation, oxidative stress, vascular smooth muscle cell apoptosis, elastin depletion, and degradation of the extracellular matrix. Mitochondrial dysfunction was also found to be associated with AAA formation. The evidence accumulated to date supports a close relationship between environmental and genetic factors in AAA initiation and progression. However, a comprehensive pathophysiological understanding of AAA formation remains incomplete. The open surgical repair of AAA is the only therapeutic option currently available, while a specific pharmacotherapy is still awaited. Therefore, there is a great need to clarify pathophysiological cellular and molecular mechanisms underlying AAA formation that would help to develop effective pharmacological therapies. In this review, pathophysiological aspects of AAA development with a special focus on mitochondrial dysfunction and genetic associations were discussed.

2.
Am J Cardiovasc Dis ; 10(4): 463-472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224597

RESUMO

Background: It is well-known that the distribution of traditional cardiovascular risk factors (CVRFs) of atherosclerosis, including hypertension, dyslipidemia, smoking, obesity, and diabetes is considerably variable between different countries, however, with some important geographical trends. Thus, CVRFs contribute differently to atherosclerosis development in different countries. Common carotid artery intima-media thickness (CCA IMT) is a validated biomarker of subclinical atherosclerosis that is used in clinical and epidemiological studies to evaluate the impact of CVRFs on atherosclerosis development. Material and methods: This comparative cohort study included a random sample of 1200 participants (n = 600 men and n = 600 women) from Moscow, Russia and Paris, France, aged between 55 and 79 years, and free of clinical symptoms of atherosclerosis. The study was conducted to determine the interpopulation variability of CCA IMT. CCA IMT was measured by ultrasonic scanning at the high-resolution regimen. Statistical analysis was performed using Stata 9.1. For comparison of mean values of continuous variables, Mann-Whitney U-test was used; Chi-square, Pearson's test was used for comparison of categorical variables. To determine to what extent presented differences can be explained by differences in traditional CVRFs, the regression model was applied. Path analysis (plug Passport Litigation Decision Analysis & Optimization Module, Datacert, USA) was used to assess the impact of traditional CVRFs on the CCA IMT in both Moscow and Paris study populations. Results: There was a significant difference in the distribution of most of the traditional CVRFs between the study populations, including blood pressure, lipid profile, statin treatment, hormone replacement therapy in women, and CVD history. The remarkably high level of difference in the mean values of the CCA IMT was found between Moscow and Paris study populations. In women of both Moscow and Paris study populations, the mean value of CCA IMT was 0.78 and 0.63, respectively. In men of both Moscow and Paris study populations, the mean CCA IMT value was 0.84 and 0.67, respectively. In the Moscow study population, the effects (direct and indirect) of traditional CVRs can explain 42% of the CCA IMT variance in women and 30% - in men. In the Paris study population, direct and indirect effects of traditional CVRFs can explain 27% of the CCA IMT variance in men and 14% - in women. Conclusion: The Paris study population significantly differed from the Moscow study population in the distribution and impact of traditional CVRFs. Traditional CVRFs can explain only a small proportion of the interpopulation differences in CCA IMT suggesting the presence of other factors, such as longitude, which can possibly influence these differences. Therefore, this study provided an additional piece of evidence towards the existence of a geographic gradient of carotid IMT.

3.
Int J Mol Sci ; 21(16)2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32781508

RESUMO

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in developed countries predominantly affecting the elderly population therefore posing a large economic burden. It is a gradually progressive condition ranging from mild valve calcification and thickening, without the hemodynamic obstruction, to severe calcification impairing leaflet motion, known as aortic stenosis (AS). The progression of CAVD occurs over many years, and it is extremely variable among individuals. It is also associated with an increased risk of coronary events and mortality. The recent insights into the CAVD pathophysiology included an important role of sex. Accumulating evidence suggests that, in patients with CAVD, sex can determine important differences in the relationship between valvular calcification process, fibrosis, and aortic stenosis hemodynamic severity between men and women. Consequently, it has implications on the development of different valvular phenotypes, left ventricular hypertrophy, and cardiovascular outcomes in men and women. Along these lines, taking into account the sex-related differences in diagnosis, prognosis, and treatment outcomes is of profound importance. In this review, the sex-related differences in patients with CAVD, in terms of pathobiology, clinical phenotypes, and outcomes were discussed.


Assuntos
Estenose da Valva Aórtica/epidemiologia , Valva Aórtica/patologia , Calcinose/epidemiologia , Caracteres Sexuais , Animais , Estenose da Valva Aórtica/patologia , Calcinose/patologia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/patologia , Masculino , Fenótipo , Transdução de Sinais , Resultado do Tratamento
4.
Int J Mol Sci ; 21(8)2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32340284

RESUMO

Atherosclerosis is a lipoprotein-driven inflammatory disorder leading to a plaque formation at specific sites of the arterial tree. After decades of slow progression, atherosclerotic plaque rupture and formation of thrombi are the major factors responsible for the development of acute coronary syndromes (ACSs). In this regard, the detection of high-risk (vulnerable) plaques is an ultimate goal in the management of atherosclerosis and cardiovascular diseases (CVDs). Vulnerable plaques have specific morphological features that make their detection possible, hence allowing for identification of high-risk patients and the tailoring of therapy. Plaque ruptures predominantly occur amongst lesions characterized as thin-cap fibroatheromas (TCFA). Plaques without a rupture, such as plaque erosions, are also thrombi-forming lesions on the most frequent pathological intimal thickening or fibroatheromas. Many attempts to comprehensively identify vulnerable plaque constituents with different invasive and non-invasive imaging technologies have been made. In this review, advantages and limitations of invasive and non-invasive imaging modalities currently available for the identification of plaque components and morphologic features associated with plaque vulnerability, as well as their clinical diagnostic and prognostic value, were discussed.


Assuntos
Aterosclerose/diagnóstico , Diagnóstico por Imagem , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Biomarcadores , Diagnóstico por Imagem/efeitos adversos , Diagnóstico por Imagem/métodos , Suscetibilidade a Doenças , Humanos , Imagem Molecular , Imagem Multimodal/efeitos adversos , Imagem Multimodal/métodos , Placa Aterosclerótica/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
5.
Int J Mol Sci ; 21(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012706

RESUMO

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.


Assuntos
Células Espumosas/metabolismo , Células Espumosas/patologia , Lipoproteínas LDL/metabolismo , Fagocitose , Biomarcadores , Células Espumosas/imunologia , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Metabolismo dos Lipídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Oxirredução , Fagocitose/genética , Fagocitose/imunologia , Transdução de Sinais , Transcriptoma
6.
Am J Transl Res ; 11(8): 4614-4633, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497187

RESUMO

Atherosclerosis is a lipid-driven, chronic inflammatory disease that leads to plaque formation at specific sites of the arterial tree. Being the common cause of many cardiovascular disorders, atherosclerosis makes a tremendous impact on morbidity and mortality rates of cardiovascular diseases (CVDs) in countries with higher income. Animal models of atherosclerosis are utilized as useful tools for studying the aetiology, pathogenesis and complications of atherosclerosis, thus, providing a valuable platform for the efficacy testing of different pharmacological therapies and validation of imaging techniques. To date, a large variety of models is available. Pathophysiological changes can be induced in animals by either an atherogenic diet or genetic manipulations. The discussion of advantages and disadvantages of some murine, rabbit and porcine genetic models currently available for the atherosclerosis research is the scope of the following review.

7.
Int J Mol Sci ; 20(14)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330845

RESUMO

Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs.


Assuntos
Aterosclerose/metabolismo , Metabolismo dos Lipídeos/fisiologia , Animais , Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/metabolismo , Aterosclerose/sangue , Aterosclerose/etiologia , Humanos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo
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