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1.
Biomedicines ; 9(9)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34572406

RESUMO

Atherosclerosis is still one of the main causes of death around the globe. This condition leads to various life-threatening cardiovascular complications. However, no effective preventive measures are known apart from lifestyle corrections, and no cure has been developed. Despite numerous studies in the field of atherogenesis, there are still huge gaps in already poor understanding of mechanisms that underlie the disease. Inflammation and lipid metabolism violations are undoubtedly the key players, but many other factors, such as oxidative stress, endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. This overview is focusing on the role of macrophages in atherogenesis, which are at the same time a part of the inflammatory response, and also tightly linked to the foam cell formation, thus taking part in both crucial for atherogenesis processes. Being essentially involved in atherosclerosis development, macrophages and foam cells have attracted attention as a promising target for therapeutic approaches.

2.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445084

RESUMO

Atherosclerosis is the major cause of the development of cardiovascular disease, which, in turn, is one of the leading causes of mortality worldwide. From the point of view of pathogenesis, atherosclerosis is an extremely complex disease. A huge variety of processes, such as violation of mitophagy, oxidative stress, damage to the endothelium, and others, are involved in atherogenesis; however, the main components of atherogenesis are considered to be inflammation and alterations of lipid metabolism. In this review, we want to focus on inflammation, and more specifically on the cellular elements of adaptive immunity, T and B cells. It is known that various T cells are widely represented directly in atherosclerotic plaques, while B cells can be found, for example, in the adventitia layer. Of course, such widespread and well-studied cells have attracted attention as potential therapeutic targets for the treatment of atherosclerosis. Various approaches have been developed and tested for their efficacy.


Assuntos
Aterosclerose/imunologia , Linfócitos B/imunologia , Imunidade , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Aterosclerose/patologia , Linfócitos B/patologia , Humanos , Imunidade Celular , Inflamação/imunologia , Inflamação/patologia , Linfócitos T/patologia
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206708

RESUMO

Atherosclerosis has complex pathogenesis, which involves at least three serious aspects: inflammation, lipid metabolism alterations, and endothelial injury. There are no effective treatment options, as well as preventive measures for atherosclerosis. However, this disease has various severe complications, the most severe of which is cardiovascular disease (CVD). It is important to note, that CVD is among the leading causes of death worldwide. The renin-angiotensin-aldosterone system (RAAS) is an important part of inflammatory response regulation. This system contributes to the recruitment of inflammatory cells to the injured site and stimulates the production of various cytokines, such as IL-6, TNF-a, and COX-2. There is also an association between RAAS and oxidative stress, which is also an important player in atherogenesis. Angiotensin-II induces plaque formation at early stages, and this is one of the most crucial impacts on atherogenesis from the RAAS. Importantly, while stimulating the production of ROS, Angiotensin-II at the same time decreases the generation of NO. The endothelium is known as a major contributor to vascular function. Oxidative stress is the main trigger of endothelial dysfunction, and, once again, links RAAS to the pathogenesis of atherosclerosis. All these implications of RAAS in atherogenesis lead to an explicable conclusion that elements of RAAS can be promising targets for atherosclerosis treatment. In this review, we also summarize the data on treatment approaches involving cytokine targeting in CVD, which can contribute to a better understanding of atherogenesis and even its prevention.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Suscetibilidade a Doenças , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Aterosclerose/diagnóstico , Aterosclerose/terapia , Biomarcadores , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Avaliação Pré-Clínica de Medicamentos , Endotélio/metabolismo , Humanos , Terapia de Alvo Molecular , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
4.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209109

RESUMO

Atherosclerosis is a well-known global health problem. Despite the high prevalence of the disease, numerous aspects of pathogenesis remain unclear. Subsequently, there are still no cure or adequate preventive measures available. Atherogenesis is now considered a complex interplay between lipid metabolism alterations, oxidative stress, and inflammation. Inflammation in atherogenesis involves cellular elements of both innate (such as macrophages and monocytes) and adaptive immunity (such as B-cells and T-cells), as well as various cytokines cascades. Because inflammation is, in general, a well-investigated therapeutic target, and strategies for controlling inflammation have been successfully used to combat a number of other diseases, inflammation seems to be the preferred target for the treatment of atherosclerosis as well. In this review, we summarized data on targeting the most studied inflammatory molecular targets, CRP, IL-1ß, IL-6, IFN-γ, and TNF-α. Studies in animal models have shown the efficacy of anti-inflammatory therapy, while clinical studies revealed the incompetence of existing data, which blocks the development of an effective atheroprotective drug. However, all data on cytokine targeting give evidence that anti-inflammatory therapy can be a part of a complex treatment.


Assuntos
Imunidade Adaptativa , Anti-Inflamatórios/uso terapêutico , Aterosclerose , Citocinas/imunologia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Aterosclerose/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia
5.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946649

RESUMO

COVID-19 is a highly contagious new infection caused by the single-stranded RNA Sars-CoV-2 virus. For the first time, this infection was recorded in December 2019 in the Chinese province of Wuhan. The virus presumably crossed the interspecies barrier and passed to humans from a bat. Initially, the disease was considered exclusively in the context of damage to the respiratory system, but it quickly became clear that the disease also entails serious consequences from various systems, including the cardiovascular system. Among these consequences are myocarditis, myocardial damage, subsequent heart failure, myocardial infarction, and Takotsubo syndrome. On the other hand, clinical data indicate that the presence of chronic diseases in a patient aggravates the course and outcome of coronavirus infection. In this context, the relationship between COVID-19 and atherosclerosis, a condition preceding cardiovascular disease and other disorders of the heart and blood vessels, is particularly interesting. The renin-angiotensin system is essential for the pathogenesis of both coronavirus disease and atherosclerosis. In particular, it has been shown that ACE2, an angiotensin-converting enzyme 2, plays a key role in Sars-CoV-2 infection due to its receptor activity. It is noteworthy that this enzyme is important for the normal functioning of the cardiovascular system. Disruptions in its production and functioning can lead to various disorders, including atherosclerosis.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Aterosclerose/metabolismo , COVID-19/metabolismo , Animais , Aterosclerose/patologia , COVID-19/patologia , Humanos , Sistema Renina-Angiotensina , SARS-CoV-2/fisiologia
6.
Cells ; 10(2)2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669743

RESUMO

Cardiovascular disease (CVD) is one of the greatest health problems affecting people worldwide. Atherosclerosis, in turn, is one of the most common causes of cardiovascular disease. Due to the high mortality rate from cardiovascular diseases, prevention and treatment at the earliest stages become especially important. This requires developing a deep understanding of the mechanisms underlying the development of atherosclerosis. It is well-known that atherogenesis is a complex multi-component process that includes lipid metabolism disorders, inflammation, oxidative stress, autophagy disorders and mitochondrial dysfunction. Autophagy is a cellular control mechanism that is critical to maintaining health and survival. One of the specific forms of autophagy is mitophagy, which aims to control and remove defective mitochondria from the cell. Particularly defective mitophagy has been shown to be associated with atherogenesis. In this review, we consider the role of autophagy, focusing on a special type of it-mitophagy-in the context of its role in the development of atherosclerosis.


Assuntos
Aterosclerose/genética , Autofagia/genética , Doenças Cardiovasculares/genética , Mitofagia/genética , Humanos
7.
Cells ; 10(2)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33671887

RESUMO

It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local senescence of the endothelial cells of the arteries in places with either low or multidirectional oscillatory wall shear stress. The process of regeneration of the artery surface that has begun does not lead to success for several reasons. Atherosclerotic plaques are formed, which, when developed, lead to fatal consequences, which are the leading causes of death in the modern world. The pronounced age dependence of the manifestations of atherosclerosis pushes scientists to try to link the development of atherosclerosis with telomere length. The study of the role of telomere shortening in atherosclerosis is mainly limited to measuring the telomeres of blood cells, and only in rare cases (surgery or post-mortem examination) are the telomeres of local cells available for measurement. The review discusses the basic issues of cellular aging and the interpretation of telomere measurement data in atherosclerosis, as well as the prospects for the prevention and possible treatment of atherosclerosis.


Assuntos
Aterosclerose/genética , Telomerase/metabolismo , Encurtamento do Telômero/genética , Telômero/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Humanos
8.
Curr Pharm Des ; 27(2): 276-292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33045961

RESUMO

BACKGROUND: The aim of the elucidation of mechanisms implicated in the chronification of inflammation is to shed light on the pathogenesis of disorders that are responsible for the majority of the incidences of diseases 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 response to 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.


Assuntos
Aterosclerose , DNA Mitocondrial , Aterosclerose/genética , DNA Mitocondrial/genética , Humanos , Inflamação/genética , Mitocôndrias/genética , Mutação
9.
Am J Cardiovasc Dis ; 10(2): 62-71, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685264

RESUMO

Non-contagious diseases such as atherosclerosis, diabetes, cardiovascular disease, cancer, chronic respiratory diseases, and mental disorders hold responsibility for major health losses worldwide. Atherosclerosis was found to be the leading cause of deaths due to the major consequences, such as cardiovascular disease, stroke, ischemic heart disease, myocardial infarction, and others. The number of patients with atherosclerosis increases with every passing year. If treatment is not started on time, every second patient dies within 10 years. Moreover, the disease leads to persistent disability of patients, most of whom are of active working age. Atherosclerosis is a metabolic disorder characterized by hyperlipidemia and chronic inflammation. Although this disease annually kills a huge number of people, patients are now offered various therapeutic techniques, however, with different efficiencies. The scientific community is working to develop more effective means for treatment and precaution of the disease, regardless of the difficulties in understanding the causes of the health problem and the characteristics of its course. There are numerous strategies in the treatment and prevention of atherosclerosis, focusing on different aspects of the disease, such as inflammation, lipid metabolism alterations, or others, but none of them, unfortunately, is absolutely effective. In this review, we focused on the treatment approaches aimed at remedy the disruptions of lipid metabolism that are currently used in clinical practice.

10.
Biology (Basel) ; 9(6)2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32630516

RESUMO

The role of mitochondria in cardiovascular diseases is receiving ever growing attention. As a central player in the regulation of cellular metabolism and a powerful controller of cellular fate, mitochondria appear to comprise an interesting potential therapeutic target. With the development of DNA sequencing methods, mutations in mitochondrial DNA (mtDNA) became a subject of intensive study, since many directly lead to mitochondrial dysfunction, oxidative stress, deficient energy production and, as a result, cell dysfunction and death. Many mtDNA mutations were found to be associated with chronic human diseases, including cardiovascular disorders. In particular, 17 mtDNA mutations were reported to be associated with ischemic heart disease in humans. In this review, we discuss the involvement of mitochondrial dysfunction in the pathogenesis of atherosclerosis and describe the mtDNA mutations identified so far that are associated with atherosclerosis and its risk factors.

11.
Biomedicines ; 8(7)2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645916

RESUMO

People exposed to chronic stress age rapidly. The telomeres in their cells of all types shorten faster. Inflammation is another important feature of stress that, along with aging, accounts for the phenomenon of inflammaging. In addition to aging itself, inflammaging can contribute to the development of several pathologies, including atherosclerosis, diabetes, hypertension, and others. Oxidative stress is one of the main mechanisms related to stress. Oxidative stress is caused by the over-production of reactive oxygen species (ROS) that can damage various tissues. The main source of ROS is mitochondria. Being suppressed by mitochondrial mutations, mitophagy can aggravate the situation. In this case, the aging-specific pro-inflammatory changes are amplified. It happens because of the inability of cells to maintain the normal state of mitochondria. Macrophages are the crucial element of the innate immunity associated with the chronic inflammation and, subsequently, with the inflammaging. In this review, we focus on the therapy approaches potentially reducing the deleterious effects of oxidative stress. These include stimulation of mitophagy, activation of mitochondrial uncoupling, induction of the expression of the telomerase catalytic component gene, and use of antioxidants. Any method reducing oxidative stress should improve post-traumatic stress disorder.

12.
Biomedicines ; 8(7)2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664349

RESUMO

Atherosclerosis is a serious disorder, with numerous potential complications such as cardiovascular disease, ischemic stroke, and myocardial infarction. The origin of atherosclerosis is related to chronic inflammation, lipid metabolism alterations, and oxidative stress. Inflammasomes are the cytoplasmic multiprotein complex triggering the activation of inflammatory response. NLRP3 inflammasomes have a specific activation pathway that involves numerous stimuli, including a wide range of PAMPs and DAMPs. Recent studies of atherosclerotic pathology are focused on the mitochondria that appear to be a promising target for therapeutic approach development. Mitochondria are the main source of reactive oxygen species (ROS) associated with oxidative stress. It was previously shown that NLRP3 inflammasome activation results in mitochondrial damage, but the exact mechanisms of this need to be specified. In this review, we focused on the features of NLRP3 inflammasomes and their significance for atherosclerosis, especially concerning mitochondria.

13.
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.

14.
Minerva Cardioangiol ; 68(4): 359-364, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32472985

RESUMO

Atherosclerosis is a major cause of disease-related mortality around the globe. The main characteristic of the disease is an accumulation of plaque on the arterial wall and subsequent erosion or rupture of some plaques. Atherosclerosis often leads to cardiovascular disease and such acute complications as myocardial infarction or ischemic stroke due to thrombus formation. Most recent advances in atherosclerotic research state that the modifications of low-density lipoprotein (LDL) are one of the most significant stages in the disease initiation, and among these modifications desialylation is of particular interest. Sialic acids are widely expressed on all types of cells of many organisms and participate in numerous biological processes. Regarding atherosclerosis, sialidases that are responsible for the regulation of the sialic component of different molecules, are probably one of the most crucial enzymatic families. Sufficient sialylation of vascular endothelium defines its susceptibility to an atherogenic plaque formation. Moreover, the desialylation of LDL provokes an accumulation of cholesterol and lipids in the arterial walls. According to the multiple involvements of sialic acids and related enzymes, sialidases, in the initiation and development of atherosclerosis, the deeper understanding of their exact role, as well as cellular and molecular mechanisms, will allow creating more targeted and effective therapeutic and diagnostic approaches.


Assuntos
Aterosclerose , Infarto do Miocárdio , Ácidos Siálicos , Endotélio Vascular , Humanos , Lipoproteínas LDL
15.
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.

16.
Pharmacol Res Perspect ; 8(2): e00584, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32237116

RESUMO

Atherosclerosis with associated cardiovascular diseases remains one of the main causes of disability and death worldwide, requiring development of new solutions for prevention and treatment. Macrophages are the key effectors of a series of events involved in atherogenesis, such as inflammation, plaque formation, and changes in lipid metabolism. Some of these events were shown to be associated with mitochondrial dysfunction and excessive mitochondrial DNA (mtDNA) damage. Moreover, macrophages represent a promising target for novel therapeutic approaches that are based on the expression of various receptors and nanoparticle uptake. Lipid-based gene delivery to mitochondria is considered to be an interesting strategy for mtDNA damage correction. To date, several nanocarriers and their modifications have been developed that demonstrate high transfection efficiency and low cytotoxicity. This review discusses the possibilities of lipid-based gene delivery to macrophage mitochondria for atherosclerosis therapy.


Assuntos
Doenças Cardiovasculares/terapia , Técnicas de Transferência de Genes , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Animais , Dano ao DNA , DNA Mitocondrial , Humanos , Lipídeos/administração & dosagem , Nanotecnologia
17.
Int J Mol Sci ; 21(8)2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32295185

RESUMO

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is 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. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.


Assuntos
Colesterol/metabolismo , Células Espumosas/metabolismo , Metabolismo dos Lipídeos , Transdução de Sinais , Biomarcadores , Suscetibilidade a Doenças , Células Espumosas/patologia , Perfilação da Expressão Gênica , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Modelos Biológicos
18.
Int J Mol Sci ; 21(6)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197550

RESUMO

Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr-/-), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE-/-) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr-/- mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets.


Assuntos
Aterosclerose , Dislipidemias , Regulação da Expressão Gênica , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , Dislipidemias/genética , Dislipidemias/metabolismo , Humanos , Camundongos , Camundongos Knockout
19.
Cells ; 9(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32121535

RESUMO

Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.


Assuntos
Aterosclerose/imunologia , Doenças Cardiovasculares/imunologia , Células Espumosas/imunologia , Doenças Cardiovasculares/patologia , Humanos , Lipoproteínas LDL/metabolismo , Transdução de Sinais
20.
Curr Neuropharmacol ; 18(11): 1064-1075, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31744449

RESUMO

BACKGROUND: Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques. OBJECTIVES: Despite the high priority of atherosclerosis research for global health and the numerous preclinical and clinical studies conducted, currently, there is no effective pharmacological treatment that directly impacts atherosclerotic plaques. Many knowledge gaps exist in our understanding of the mechanisms of plaque formation. In this review, we discuss the role of mitochondria in different cell types involved in atherogenesis and provide information about mtDNA mutations associated with the disease. RESULTS: Mitochondria of blood and arterial wall cells appear to be one of the important factors in disease initiation and development. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction and vascular disease. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers. Further study of mtDNA damage and associated dysfunction may open new perspectives for atherosclerosis treatment. CONCLUSION: Mitochondria can be considered as important disease-modifying factors in several chronic pathologies. Deletions and mutations of mtDNA may be used as potential disease markers. Mitochondria-targeting antioxidant therapies appear to be promising for the development of treatment of atherosclerosis and other diseases associated with oxidative stress and chronic inflammation.


Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/terapia , Inflamação/patologia , Mitocôndrias/efeitos dos fármacos , Animais , LDL-Colesterol , DNA Mitocondrial , Humanos , Mitocôndrias/metabolismo , Mitofagia , Músculo Liso Vascular , Mutação , Estresse Oxidativo , Placa Aterosclerótica
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