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Previous reports suggest an association between the development of atherosclerosis and alterations in the aortic sympathetic nervous system, but there is no agreement on whether atherosclerotic plaques are accompanied by increased or decreased sympathetic innervation in the arterial wall. In the present study, the aortic transcriptional profile of mice with different predisposition to atherosclerosis was investigated to clarify how the expression of genes involved in sympathetic neurotransmission varied. Eight-week-old C57Bl/6J control mice, Apoe knockout mice (EKO), EKO mice overexpressing human apoA-I (EKO/hA-I) and double Apoe/Apoa1 knockout mice (DKO) mice were fed either a standard rodent diet or a Western-type diet for 22 weeks. Atherosclerosis was quantified, and the aortic transcriptome was analyzed by RNAseq. Western-type diet administration deeply modified the aortic transcriptome. In the genetically modified atherosclerosis-prone mouse lines, an upregulated expression of genes associated with the immunomodulatory response was observed, paralleled by a downregulated expression of the genes related to sympathetic nervous system. Functional enrichment analysis indicated that the presence of advanced atherosclerosis was accompanied by reduced neuronal generation, modulation of synapse chemical transmission, and catecholamine biosynthesis, supporting a relationship between atherosclerosis, dyslipidemia, and sympathetic neurotransmission.
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The molecular mechanism by which lipid/lipoprotein biosynthesis is regulated in mammals involves a very large number of genes that are subject to multiple levels of regulation. miRNAs are recognized contributors to lipid homeostasis at the post-transcriptional level, although the elucidation of their role is made difficult by the multiplicity of their targets and the ability of more miRNAs to affect the same mRNAs. In this study, an evaluation of how miRNA expression varies in organs playing a key role in lipid/lipoprotein metabolism was conducted in control mice and in two mouse models carrying genetic ablations which differently affect low-density lipoprotein metabolism. Mice were fed a lipid-poor standard diet and a diet enriched in cholesterol and saturated fat. The results obtained showed that there are no miRNAs whose expression constantly vary with dietary or genetic changes. Furthermore, it appears that diet, more than genotype, impacts on organ-specific miRNA expression profiles.
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AIMS: In view of the consolidating evidence on the causal role of Lp(a) in cardiovascular disease, the Italian Society for the Study of Atherosclerosis (SISA) has assembled a consensus on Lp(a) genetics and epidemiology, together with recommendations for its measurement and current and emerging therapeutic approaches to reduce its plasma levels. Data on the Italian population are also provided. DATA SYNTHESIS: Lp(a) is constituted by one apo(a) molecule and a lipoprotein closely resembling to a low-density lipoprotein (LDL). Its similarity with an LDL, together with its ability to carry oxidized phospholipids are considered the two main features making Lp(a) harmful for cardiovascular health. Plasma Lp(a) concentrations vary over about 1000 folds in humans and are genetically determined, thus they are quite stable in any individual. Mendelian Randomization studies have suggested a causal role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis and observational studies indicate a linear direct correlation between cardiovascular disease and Lp(a) plasma levels. Lp(a) measurement is strongly recommended once in a patient's lifetime, particularly in FH subjects, but also as part of the initial lipid screening to assess cardiovascular risk. The apo(a) size polymorphism represents a challenge for Lp(a) measurement in plasma, but new strategies are overcoming these difficulties. A reduction of Lp(a) levels can be currently attained only by plasma apheresis and, moderately, with PCSK9 inhibitor treatment. CONCLUSIONS: Awaiting the approval of selective Lp(a)-lowering drugs, an intensive management of the other risk factors for individuals with elevated Lp(a) levels is strongly recommended.
Assuntos
Estenose da Valva Aórtica , Aterosclerose , Humanos , Lipoproteína(a)/genética , Pró-Proteína Convertase 9 , Consenso , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/genéticaRESUMO
SCOPE: Specific lipid molecules circulating in plasma at low concentrations have emerged as biomarkers of atherosclerotic risk. The aim of the present study is that of evaluating, in an athero-prone mouse model, how different diets can affect plasma and aorta lipidome. METHODS AND RESULTS: Thirty-six apoE knockout mice are divided in three groups and feed 12 weeks with diets differing for cholesterol and fatty acid content. Atherosclerosis is measured at the aortic sinus and aorta. Lipids are quantified in plasma and aorta with mass spectrometry. The cholesterol content of the diets is the main driver of lipid accumulation in plasma and aorta. The fatty acid composition of the diets affects plasma levels both of essential (linoleic acid) and nonessential (myristic and arachidonic acid) ones. Lipidomics show a comparable distribution, in plasma and aorta, of the main lipid components of oxidized LDL, including cholesteryl esters and lysophosphatidylcholines. Interestingly, lactosylceramide, glucosyl/galactosylceramide, and individual ceramide species are found to accumulate in diseased aortic segments. CONCLUSION: Both the cholesterol and fatty acid content of the diets profoundly affect plasma lipidome. Aorta lipidome is likewise affected with the accumulation of specific lipids known as markers of atherosclerosis.
Assuntos
Aorta , Aterosclerose , Colesterol na Dieta , Dieta , Ácidos Graxos , Lipidômica , Animais , Camundongos , Aorta/metabolismo , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/metabolismo , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Camundongos Knockout , Colesterol na Dieta/sangue , Colesterol na Dieta/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismoRESUMO
BACKGROUND: HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions. METHODS: ApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses. RESULTS: DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development. CONCLUSIONS: HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.
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Aterosclerose , Doença da Artéria Coronariana , Hiperlipidemias , Xantomatose , Animais , Apolipoproteína A-I , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Hiperlipidemias/complicações , Hiperlipidemias/genética , Inflamação/complicações , Inflamação/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Functional enrichment analysis is an analytical method to extract biological insights from gene expression data, popularized by the ever-growing application of high-throughput techniques. Typically, expression profiles are generated for hundreds to thousands of genes/proteins from samples belonging to two experimental groups, and after ad-hoc statistical tests, researchers are left with lists of statistically significant entities, possibly lacking any unifying biological theme. Functional enrichment tackles the problem of putting overall gene expression changes into a broader biological context, based on pre-existing knowledge bases of reference: database collections of known expression regulation, relationships and molecular interactions. STRING is among the most popular tools, providing both protein-protein interaction networks and functional enrichment analysis for any given set of identifiers. For complex experimental designs, manually retrieving, interpreting, analyzing and abridging functional enrichment results is a daunting task, usually performed by hand by the average wet-biology researcher. We have developed reString, a cross-platform software that seamlessly retrieves from STRING functional enrichments from multiple user-supplied gene sets, with just a few clicks, without any need for specific bioinformatics skills. Further, it aggregates all findings into human-readable table summaries, with built-in features to easily produce user-customizable publication-grade clustermaps and bubble plots. Herein, we outline a complete reString protocol, showcasing its features on a real use-case.
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Análise por Conglomerados , Biologia Computacional/métodos , Mineração de Dados/métodos , Regulação da Expressão Gênica , Reconhecimento Automatizado de Padrão , Animais , Aorta/metabolismo , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Humanos , Internet , Camundongos , Reação em Cadeia da Polimerase , Linguagens de Programação , Mapas de Interação de Proteínas , Proteínas , RNA-Seq , Transdução de Sinais , Software , Interface Usuário-ComputadorRESUMO
In any research field, data access and data integration are major challenges that even large, well-established consortia face. Although data sharing initiatives are increasing, joint data analyses on nutrition and microbiomics in health and disease are still scarce. We aimed to identify observational studies with data on nutrition and gut microbiome composition from the Intestinal Microbiomics (INTIMIC) Knowledge Platform following the findable, accessible, interoperable, and reusable (FAIR) principles. An adapted template from the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) consortium was used to collect microbiome-specific information and other related factors. In total, 23 studies (17 longitudinal and 6 cross-sectional) were identified from Italy (7), Germany (6), Netherlands (3), Spain (2), Belgium (1), and France (1) or multiple countries (3). Of these, 21 studies collected information on both dietary intake (24 h dietary recall, food frequency questionnaire (FFQ), or Food Records) and gut microbiome. All studies collected stool samples. The most often used sequencing platform was Illumina MiSeq, and the preferred hypervariable regions of the 16S rRNA gene were V3-V4 or V4. The combination of datasets will allow for sufficiently powered investigations to increase the knowledge and understanding of the relationship between food and gut microbiome in health and disease.
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Microbioma Gastrointestinal , Inquéritos Nutricionais , Ciências da Nutrição , Estudos Observacionais como Assunto , Inquéritos sobre Dietas/métodos , Ingestão de Alimentos , Europa (Continente) , Humanos , Disseminação de Informação , Metadados , Inquéritos Nutricionais/métodos , Ciências da Nutrição/métodosRESUMO
OBJECTIVE: HDL (high-density lipoprotein) particles are known to possess several antiatherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant, and anti-inflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Approach and Results: Eight-week-old EKO mice, EKO mice overexpressing human apoA-I, and wild-type mice as controls were fed either normal laboratory or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated, and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyze the transcriptome of the aorta of the 3 genotypes in each experimental condition. In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system, and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway. CONCLUSIONS: ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response.
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Aorta/metabolismo , Doenças da Aorta/genética , Apolipoproteína A-I/metabolismo , Aterosclerose/genética , Inflamação/genética , Lisossomos/genética , Esfingolipídeos/metabolismo , Transcriptoma , Animais , Aorta/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/metabolismo , Inflamação/patologia , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Mapas de Interação de Proteínas , Transdução de Sinais , Esfingolipídeos/sangue , Fatores de Tempo , Triglicerídeos/sangueRESUMO
Lipidomic analyses address the problem of characterizing the lipid components of given cells, tissues and organisms by means of chromatographic separations coupled to high-resolution, tandem mass spectrometry analyses. A number of software tools have been developed to help in the daunting task of mass spectrometry signal processing and cleaning, peak analysis and compound identification, and a typical finished lipidomic dataset contains hundreds to thousands of individual molecular lipid species. To provide researchers without a specific technical expertise in mass spectrometry the possibility of broadening the exploration of lipidomic datasets, we have developed liputils, a Python module that specializes in the extraction of fatty acid moieties from individual molecular lipids. There is no prerequisite data format, as liputils extracts residues from RefMet-compliant textual identifiers and from annotations of other commercially available services. We provide three examples of real-world data processing with liputils, as well as a detailed protocol on how to readily process an existing dataset that can be followed with basic informatics skills.
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SCOPE: Protein malnutrition is characterized by stunted growth, hepatic steatosis and a damaged gut mucosal architecture. Since high-fat shaped gut microbiota (HFM) has an increased ability in providing nutrients and energy from food to the host, the aim of this study is to determine whether such a microbiota could beneficially impact on the consequences of malnutrition. METHODS AND RESULTS: The cecal content of specific pathogen free C57Bl/6J mice fed a high-fat diet or a low-protein diet is transplanted in two groups of germ-free C57Bl/6J recipient mice, which are subsequently fed a low-protein diet for 8 weeks. Body weight gain is comparable between the two groups of microbiota-recipient mice. The HFM led to a worsening of microvesicular steatosis and a decrease of plasma lipids compared to the low-protein shaped microbiota. In the small intestine of mice receiving the HFM, although significant histological differences are not observed, the expression of antimicrobial genes promoting oxidative stress and immune response at the ileal epithelium (Duox2, Duoxa2, Saa1, Ang4, Defa5) is increased. CONCLUSION: The transplant of HFM in mice fed a low-protein diet represents a noxious stimulus for the ileal mucosa and impairs hepatic lipoprotein secretion, favoring the occurrence of hepatic microvesicular steatosis.
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Dieta Hiperlipídica , Dieta com Restrição de Proteínas/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Animais , Ceco/microbiologia , Colesterol/sangue , Disbiose/genética , Disbiose/microbiologia , Ingestão de Alimentos , Fezes/microbiologia , Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Tamanho do Órgão , Triglicerídeos/sangue , Aumento de PesoRESUMO
BACKGROUND AND PURPOSE: Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that fenretinide may have an anti-atherosclerotic action. EXPERIMENTAL APPROACH: To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.1% w/w) fenretinide. As a reference, wild-type (WT) mice were treated similarly. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses. KEY RESULTS: Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, fenretinide remarkably reduced hepatic glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary haematopoiesis. Severe renal hemosiderin deposition was observed in treated EKO mice. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was markedly increased at the aortic arch, thoracic and abdominal aorta of fenretinide-treated mice. CONCLUSIONS AND IMPLICATIONS: We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may enhance the development of atherosclerosis.
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Antineoplásicos/toxicidade , Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Metabolismo Energético/efeitos dos fármacos , Fenretinida/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Ocidental , Modelos Animais de Doenças , Progressão da Doença , Feminino , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Redução de Peso/efeitos dos fármacosRESUMO
AIMS: Increased Ankyrin Repeat Domain 1 (ANKRD1) levels linked to gain of function mutations have been associated to total anomalous pulmonary venous return and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease is not understood. To get insight into this problem, we have generated a gain of function ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium. METHODS AND RESULTS: Ankrd1 is expressed non-homogeneously in the embryonic myocardium, with a dynamic nucleo-sarcomeric localization in developing cardiomyocytes. ANKRD1 transgenic mice present sinus venosus defect, which originates during development by impaired remodelling of early embryonic heart. Adult transgenic hearts develop diastolic dysfunction with preserved ejection fraction, which progressively evolves into heart failure, as shown histologically and haemodynamically. Transgenic cardiomyocyte structure, sarcomeric assembly, and stability are progressively impaired from embryonic to adult life. Postnatal transgenic myofibrils also present characteristic functional alterations: impaired compliance at neonatal stage and impaired lusitropism in adult hearts. Altogether, our combined analyses suggest that impaired embryonic remodelling and adult heart dysfunction in ANKRD1 transgenic mice present a common ground of initial cardiomyocyte defects, which are exacerbated postnatally. Molecular analysis showed transient activation of GATA4-Nkx2.5 transcription in early transgenic embryos and subsequent dynamic transcriptional modulation within titin gene. CONCLUSIONS: ANKRD1 is a fine mediator of cardiomyocyte response to haemodynamic load in the developing and adult heart. Increased ANKRD1 levels are sufficient to initiate an altered cellular phenotype, which is progressively exacerbated into a pathological organ response by the high ventricular workload during postnatal life. Our study defines for the first time a unifying picture for ANKRD1 role in heart development and disease and provides the first mechanistic link between ANKRD1 overexpression and cardiac disease onset.
Assuntos
Comunicação Interatrial/metabolismo , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Animais , Diástole , Feminino , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Comunicação Interatrial/fisiopatologia , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Masculino , Camundongos Transgênicos , Proteínas Musculares/genética , Miocárdio/patologia , Proteínas Nucleares/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Repressoras/genética , Regulação para Cima , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND: Among strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic high-density lipoprotein (sHDL). METHODS: New Zealand rabbits underwent a perivascular injury at both carotids and were randomly allocated into 2 protocols: (1) a single-dose study, where rabbits were treated with a single infusion of sHDL containing a trimeric form of human apoA-I (TN-sHDL, 200 mg/kg) or with Placebo; (2) a multiple-dose study, where 4 groups of rabbits were treated 5 times with Placebo or TN-sHDL at different doses (8, 40, 100 mg/kg). Plaque changes were analysed in vivo by intravascular ultrasound. Blood was drawn from rabbits for biochemical analyses and cholesterol efflux capacity evaluation. RESULTS: In both protocols, atheroma volume in the Placebo groups increased between the first and the second intravascular ultrasound evaluation. A stabilization or a slight regression was instead observed vs baseline in the TN-sHDL-treated groups (P < 0.005 vs Placebo after infusion). TN-sHDL treatment caused a sharp rise of plasma-free cholesterol levels and a significant increase of total cholesterol efflux capacity. Histologic analysis of carotid plaques showed a reduced macrophage accumulation in TN-sHDL-treated rabbits compared with Placebo (P < 0.05). CONCLUSIONS: Our results demonstrate that acute and subacute treatments with TN-sHDL are effective in stabilizing atherosclerotic plaques in a rabbit model. This effect appears to be related to a reduced intraplaque accumulation of inflammatory cells. Besides recent failures in proving its efficacy, sHDL treatment remains a fascinating therapeutic option for the reduction of cardiovascular risk.
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Apolipoproteína A-I/administração & dosagem , Lipoproteínas HDL/administração & dosagem , Placa Aterosclerótica/prevenção & controle , Animais , Hipercolesterolemia/complicações , Infusões Intravenosas , Masculino , Preparações Farmacêuticas , Placa Aterosclerótica/etiologia , Coelhos , Distribuição AleatóriaRESUMO
Topiramate is an anticonvulsant drug also prescribed for migraine prophylaxis that acts through several mechanisms of action. Several studies indicate that topiramate induces weight loss and a moderate reduction of plasma lipids and glucose. Based on these favourable metabolic effects, aim of this study was to evaluate if topiramate could modulate atherosclerosis development and protect target organs of dysmetabolic conditions. Thirty apoE-deficient mice were divided into three groups and fed for 12 weeks a high fat diet (Control) or the same diet containing topiramate at 0.125% and 0.250%. Body weight, water and food intake were monitored throughout the study. Plasma lipids and glucose levels were measured and a glucose tolerance test was performed. Atherosclerosis development was evaluated in the whole aorta and at the aortic sinus. Histological analysis of liver, kidney and adipose tissue was performed. Topiramate did not affect weight gain and food intake. Glucose tolerance and plasma lipids were not changed and, in turn, atherosclerosis development was not different among groups. Topiramate did not modify liver and adipose tissue histology. Conversely, in the kidneys, the treatment reduced the occurrence of glomerular lipidosis by decreasing foam cells accumulation and reducing the expression of inflammatory markers. Blood urea nitrogen levels were also reduced by treatment. Our results indicate that topiramate does not affect atherosclerosis development, but preserves kidney structure and function. The study suggests that topiramate could be investigated in drug repurposing studies for the treatment of glomerular lipidosis.
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Rim/efeitos dos fármacos , Lipidoses/prevenção & controle , Substâncias Protetoras/farmacologia , Topiramato/farmacologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Glicemia/análise , Dieta Hiperlipídica , Feminino , Rim/metabolismo , Rim/patologia , Lipidoses/metabolismo , Lipidoses/patologia , Lipídeos/sangue , Camundongos Knockout para ApoERESUMO
It is widely recognized that the microorganisms inhabiting our gastrointestinal tract-the gut microbiota-deeply affect the pathophysiology of the host. Gut microbiota composition is mostly modulated by diet, and gut microorganisms communicate with the different organs and tissues of the human host by synthesizing hormones and regulating their release. Herein, we will provide an updated review on the most important classes of gut microbiota-derived hormones and their sensing by host receptors, critically discussing their impact on host physiology. Additionally, the debated interplay between microbial hormones and the development of cardiovascular disease will be thoroughly analysed and discussed.
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Doenças Cardiovasculares/fisiopatologia , Glândulas Endócrinas , Microbioma Gastrointestinal/fisiologia , Hormônios/biossíntese , Animais , Aterosclerose/fisiopatologia , Ácidos e Sais Biliares/metabolismo , Colina/metabolismo , Dieta , Ácidos Graxos Voláteis/metabolismo , Humanos , Neurotransmissores/fisiologia , Fatores de RiscoRESUMO
Risk assessment tools, i.e., validated risk prediction algorithms, to estimate the patient's 10-year risk of developing cardiovascular disease (CVD) should be used to identify high-risk people for primary prevention. Current evidence confirms that appropriate monitoring and control of risk factors either reduces the likelihood of CVD or slows down its progression. It is thus crucial that all health professionals make appropriate use of all the available intervention strategies to control risk factors: from dietary improvement and adequate physical activity to the use of functional foods, food supplements, and drugs. The gut microbiota, which encompasses 1 × 1014 resident microorganisms, has been recently recognized as a contributing factor in the development of human disease. This review examines the effect of both some vegetable food components belong to the "protein food group" and the underexploited protein-rich hempseed on cholesterolemia and gut microbiota composition.
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Doenças Cardiovasculares/prevenção & controle , Dieta Saudável , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Hipercolesterolemia/dietoterapia , Valor Nutritivo , Proteínas de Vegetais Comestíveis/administração & dosagem , Verduras , Animais , Biomarcadores/sangue , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Colesterol/sangue , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/epidemiologia , Estado Nutricional , Proteínas de Vegetais Comestíveis/metabolismo , Fatores de Proteção , Recomendações Nutricionais , Fatores de Risco , Comportamento de Redução do RiscoRESUMO
LPP3 is an integral membrane protein belonging to a family of enzymes (LPPs) that display broad substrate specificity and catalyse dephosphorylation of several lipid substrates, including lysophosphatidic acid and sphingosine-1-phosphate. In mammals, the LPP family consists of three enzymes named LPP1, LPP2 and LPP3, which are encoded by three independent genes, PLPP1, PLPP2 and PLPP3, respectively (formerly known as PPAP2A, PPAP2C, PPAP2B). These three enzymes, in vitro, do not seem to differ for catalytic activities and substrate preferences. However, in vivo targeted inactivation of the individual genes has indicated that the enzymes do not have overlapping functions and that LPP3, specifically, plays a crucial role in vascular development. In 2011, two genome-wide association studies have identified PLPP3 as a novel locus associated with coronary artery disease susceptibility. Shortly after these reports, tissue specific inactivation of PLPP3 in mice highlighted a specific role for LPP3 in vascular pathophysiology and, more recently, in atherosclerosis development. This review is aimed at providing an updated overview on the function of LPP3 in embryonic cardiovascular development and on the experimental and clinical evidences relating this enzyme to vascular cell functions and cardiovascular disease.
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Doença da Artéria Coronariana/enzimologia , Vasos Coronários/enzimologia , Fosfatidato Fosfatase/metabolismo , Animais , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Humanos , Fosfatidato Fosfatase/química , Fosfatidato Fosfatase/genética , Polimorfismo Genético , Conformação Proteica , Fatores de Risco , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
SCOPE: Antarctic krill is a great source of n-3 fatty acids and high-quality proteins. Aim of the study was to evaluate the effect of Antarctic krill components on plasma lipids and atherosclerosis development. METHODS AND RESULTS: Sixty apoEKO mice were divided into four groups and fed Western diet (CONTROL) or Western-like diets, differing for protein or fat content. Specifically, casein or fat in CONTROL was partially replaced by krill proteins (PRO), krill oil (KRILL OIL), or both (KRILL OIL+PRO). In KRILL OIL+PRO and KRILL OIL, cholesterol levels were significantly lower than in CONTROL group. Atherosclerosis in aorta of PRO, KRILL OIL and KRILL OIL+PRO was lower than in CONTROL, whereas, at the aortic sinus, atherosclerosis reduction was only observed in KRILL OIL. Liver steatosis, commonly present in CONTROL and PRO animals, was sporadic in KRILL OIL+PRO and KRILL OIL mice. Krill oil containing diets affected the expression of genes involved in cholesterol metabolism, mainly HMG-CoA reductase. No reduced systemic inflammation was found in all groups. CONCLUSION: Krill oil containing diets were able to reduce cholesterol levels, inhibit plaque development and prevent liver damage. Krill proteins also reduced atherosclerosis development through mechanisms not involving lipid metabolism.
Assuntos
Aterosclerose/dietoterapia , Gorduras Insaturadas na Dieta/farmacologia , Proteínas Alimentares/farmacologia , Euphausiacea/química , Animais , Regiões Antárticas , Antioxidantes/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Colesterol/genética , Dieta Ocidental , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/fisiologia , Camundongos Knockout para ApoERESUMO
The PLPP3 gene encodes for a ubiquitous enzyme that dephosphorylates several lipid substrates. Genome-wide association studies identified PLPP3 as a gene that plays a role in coronary artery disease susceptibility. The aim of the study was to investigate the effect of Plpp3 deletion on atherosclerosis development in mice. Because the constitutive deletion of Plpp3 in mice is lethal, conditional Plpp3 hepatocyte-specific null mice were generated by crossing floxed Plpp3 mice with animals expressing Cre recombinase under control of the albumin promoter. The mice were crossed onto the athero-prone apoE-/- background to obtain Plpp3f/fapoE-/-Alb-Cre+ and Plpp3f/fapoE-/-Alb-Cre- offspring, the latter of which were used as controls. The mice were fed chow or a Western diet for 32 or 12 weeks, respectively. On the Western diet, Alb-Cre+ mice developed more atherosclerosis than Alb-Cre- mice, both at the aortic sinus and aorta. Lipidomic analysis showed that hepatic Plpp3 deletion significantly modified the levels of several plasma lipids involved in atherosclerosis, including lactosylceramides, lysophosphatidic acids, and lysophosphatidylinositols. In conclusion, Plpp3 ablation in mice worsened atherosclerosis development. Lipidomic analysis suggested that the hepatic Plpp3 deletion may promote atherosclerosis by increasing plasma levels of several low-abundant pro-atherogenic lipids, thus providing a molecular basis for the observed results.