Francesca De Vito, E. Suraci, R. Marasco, F. Andreozzi, M. Hribal, F. Luzza, G. Sesti, T. V. Fiorentino
Aim: Treatment with the FXR agonist obeticholic acid (OCA) has been found to improve glucose metabolism in type 2 diabetes (T2DM) subjects with mechanisms not completely elucidated. In the gut, FXR is mainly expressed in the ileum where promotes transcription of fibroblast growth factor-19 (FGF19) having positive effects on glucose homeostasis, and maintains gut barrier integrity by regulating tight-junction (TJ) proteins expression. Herein, we evaluate whether subjects with dysglycemic conditions exhibit a down-regulation of the intestinal FXR-FGF19-TJ axis and whether treatment with OCA may revert this aberration. Methods: Levels of FXR, FGF19 and TJ proteins and pro-inflammatory cytokines were assessed in ileal mucosa specimens collected during colonoscopy from 53 subjects subdivided according to their glucose tolerance in: NGT (n=26), prediabetes (n=12) and T2DM (n=15). Effects of OCA treatment was assessed on ileal mucosa specimens of subjects with prediabetes or T2DM cultured in absence or presence of OCA for 6h. Results: Ileal FXR protein and mRNA levels were progressively decreased in prediabetes (-26%) and T2DM (-34%) as compared to the NGT group (both P<0.05). Ileal FXR downregulation was paralleled by lower FGF19 expression and circulating levels (both P<0.05). Additionally, we observed a progressive decrease of proteins and mRNA levels of the TJ zonulin (ZO)-1, occludin and claudin-1 (P<0.05 for all) with an activation of pro-inflammatory pathways in the ileal mucosa of subjects with prediabetes and T2DM as compared to the NGT group. OCA treatment resulted in an up-regulation of FGF19 expression and release (both P<0.01), mRNA and protein levels of the TJ ZO-1, occludin and claudin-1 and in reduced pro-inflammatory cytokines synthesis and release (P<0.05 for all). Conclusion: FXR stimulation by OCA treatment reverts the altered FGF-19/TJ axis in subjects with prediabetes and T2DM, indicating intestinal FXR signaling as a novel target for prevention and/or treatment of T2DM.
{"title":"Exploring the role of FXR signaling in maintaining ileal mucosa integrity in subjects with altered glucose tolerance conditions","authors":"Francesca De Vito, E. Suraci, R. Marasco, F. Andreozzi, M. Hribal, F. Luzza, G. Sesti, T. V. Fiorentino","doi":"10.56095/eaj.v2i1.36","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.36","url":null,"abstract":"Aim: Treatment with the FXR agonist obeticholic acid (OCA) has been found to improve glucose metabolism in type 2 diabetes (T2DM) subjects with mechanisms not completely elucidated. In the gut, FXR is mainly expressed in the ileum where promotes transcription of fibroblast growth factor-19 (FGF19) having positive effects on glucose homeostasis, and maintains gut barrier integrity by regulating tight-junction (TJ) proteins expression. Herein, we evaluate whether subjects with dysglycemic conditions exhibit a down-regulation of the intestinal FXR-FGF19-TJ axis and whether treatment with OCA may revert this aberration. Methods: Levels of FXR, FGF19 and TJ proteins and pro-inflammatory cytokines were assessed in ileal mucosa specimens collected during colonoscopy from 53 subjects subdivided according to their glucose tolerance in: NGT (n=26), prediabetes (n=12) and T2DM (n=15). Effects of OCA treatment was assessed on ileal mucosa specimens of subjects with prediabetes or T2DM cultured in absence or presence of OCA for 6h. Results: Ileal FXR protein and mRNA levels were progressively decreased in prediabetes (-26%) and T2DM (-34%) as compared to the NGT group (both P<0.05). Ileal FXR downregulation was paralleled by lower FGF19 expression and circulating levels (both P<0.05). Additionally, we observed a progressive decrease of proteins and mRNA levels of the TJ zonulin (ZO)-1, occludin and claudin-1 (P<0.05 for all) with an activation of pro-inflammatory pathways in the ileal mucosa of subjects with prediabetes and T2DM as compared to the NGT group. OCA treatment resulted in an up-regulation of FGF19 expression and release (both P<0.01), mRNA and protein levels of the TJ ZO-1, occludin and claudin-1 and in reduced pro-inflammatory cytokines synthesis and release (P<0.05 for all). Conclusion: FXR stimulation by OCA treatment reverts the altered FGF-19/TJ axis in subjects with prediabetes and T2DM, indicating intestinal FXR signaling as a novel target for prevention and/or treatment of T2DM.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129478563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Olmastroni, F. Galimberti, A. Catapano, B. Ference
Background: Inherited predisposition to atherosclerosis leads to higher risk for developing coronary heart disease (CHD). There are mainly two ways to conceptualize inherited risk of CHD: family history and polygenic predisposition. We aimed at assessing the impact of family history of CHD and genetic predisposition in predicting the individual lifetime risk of major coronary events (MCE). Methods: Using adjusted Cox proportional hazard models, we estimated the lifetime risk of MCE associated with parental family history of CHD and individual genetic predisposition (estimated by a polygenic risk score including 350 variants). Results: A total of 445,744 UK-Biobank participants were included in the study (mean age 57 years; 54.3% females). Having one parent with a history of CHD increased the lifetime risk of MCE by 75% (HR 1.75, 95%CI 1.70-1.82). Having both parents with a history of CHD further increased the risk (HR 2.78, 95%CI 2.64-2.92) Similarly, a dose-dependent step-wise increase in MCE risk was observed moving from the lowest to the highest decile of the polygenic score. Compared to subjects without family history of CHD and with average level of the polygenic score, having a parental history of CHD determined an increase in lifetime risk of MCE (HR 1.90, 95%CI 1.82-1.98) comparable to belonging to the highest decile of the polygenic score (HR 1.89, 95%CI 1.76-2.02). However, if subjects present both parents with family history of CHD and a very high polygenic predisposition, the risk was even higher (HR 3.54, 95%CI 3.34-3.75), suggesting an additive contribution to the characterization of the lifetime risk. Conclusions: We described the addictive impact of family history of CHD and individual polygenic predisposition in predicting lifetime risk of MCE. In order to identify subjects at higher risk of having an early event, it is essential to retrieve information about both these hereditary components.
{"title":"Combining family history of coronary heart disease and individual genetic predisposition to predict the risk of major coronary events: Selected Abstract - SITeCS Congress 2022","authors":"E. Olmastroni, F. Galimberti, A. Catapano, B. Ference","doi":"10.56095/eaj.v1i3.17","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.17","url":null,"abstract":"Background: Inherited predisposition to atherosclerosis leads to higher risk for developing coronary heart disease (CHD). There are mainly two ways to conceptualize inherited risk of CHD: family history and polygenic predisposition. We aimed at assessing the impact of family history of CHD and genetic predisposition in predicting the individual lifetime risk of major coronary events (MCE). Methods: Using adjusted Cox proportional hazard models, we estimated the lifetime risk of MCE associated with parental family history of CHD and individual genetic predisposition (estimated by a polygenic risk score including 350 variants). Results: A total of 445,744 UK-Biobank participants were included in the study (mean age 57 years; 54.3% females). Having one parent with a history of CHD increased the lifetime risk of MCE by 75% (HR 1.75, 95%CI 1.70-1.82). Having both parents with a history of CHD further increased the risk (HR 2.78, 95%CI 2.64-2.92) Similarly, a dose-dependent step-wise increase in MCE risk was observed moving from the lowest to the highest decile of the polygenic score. Compared to subjects without family history of CHD and with average level of the polygenic score, having a parental history of CHD determined an increase in lifetime risk of MCE (HR 1.90, 95%CI 1.82-1.98) comparable to belonging to the highest decile of the polygenic score (HR 1.89, 95%CI 1.76-2.02). However, if subjects present both parents with family history of CHD and a very high polygenic predisposition, the risk was even higher (HR 3.54, 95%CI 3.34-3.75), suggesting an additive contribution to the characterization of the lifetime risk. Conclusions: We described the addictive impact of family history of CHD and individual polygenic predisposition in predicting lifetime risk of MCE. In order to identify subjects at higher risk of having an early event, it is essential to retrieve information about both these hereditary components.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127367120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lipoprotein (a) (Lp(a)) attests to be of interest as a new lipoprotein target. However, Lp(a) was discovered in 1963 and since then was recognized as a low-density lipoprotein (LDL)-like lipoprotein with a structurally similar domain to plasminogen. We are increasingly recognizing the importance of Lp(a) and cardiovascular pathologies including atherosclerotic cardiovascular disease, aortic valve stenosis, heart failure, and atrial fibrillation. However, we neither have a standardized measurement method nor an appropriate agent to intervene with this old threat that we have recognized for more than 50 years. Herein, we present an up-to-date review of our knowledge about Lp(a) covering measurement methods, its associates, and summary of the currently available therapies and emerging therapeutic agents for the management of high Lp(a) in the light of recent evidence and guideline recommendations
{"title":"Are we seeing the light at the end of the tunnel for high lipoprotein(a)? Lipoprotein(a)","authors":"M. Kayıkçıoğlu, H. Ozkan, L. Tokgozoglu","doi":"10.56095/eaj.v1i3.21","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.21","url":null,"abstract":"Lipoprotein (a) (Lp(a)) attests to be of interest as a new lipoprotein target. However, Lp(a) was discovered in 1963 and since then was recognized as a low-density lipoprotein (LDL)-like lipoprotein with a structurally similar domain to plasminogen. We are increasingly recognizing the importance of Lp(a) and cardiovascular pathologies including atherosclerotic cardiovascular disease, aortic valve stenosis, heart failure, and atrial fibrillation. However, we neither have a standardized measurement method nor an appropriate agent to intervene with this old threat that we have recognized for more than 50 years. Herein, we present an up-to-date review of our knowledge about Lp(a) covering measurement methods, its associates, and summary of the currently available therapies and emerging therapeutic agents for the management of high Lp(a) in the light of recent evidence and guideline recommendations","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"38 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117119078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Comí, Claudia Giglione, Fationa Tolaj, C. Parolini, C. Olivieri, Marco Ruzza, Valentina Tollemeto, Maria Zurlo, Federico Pialorsi, A. Seneci, P. Magni
The nutraceutical approach to moderate hypercholesterolaemia is an interesting option in the context of appropriate conditions associated with low cardiovascular risk, and red yeast rice (RYR) extract is one of the most utilized products in this field. Monacolin k, its main active component, reduces serum LDL-C levels via inhibition of β-Hydroxy β-methylglutaryl-CoA reductase, similarly to statins. In 2011, EFSA approved the claim regarding monacolin k from RYR extract and maintenance of normal cholesterol levels. However, in 2018, EFSA issued a warning about potential adverse effects of this nutraceutical and, in 2022, the European Commission published a Regulation with several limitations of its use. Therefore, current research and development efforts are aiming at assessing efficacy and safety of other known and novel nutraceutical products which may benefit patients with moderate hypercholesterolaemia. These active agents range from phytosterols, probiotics and berberine to bergamot, cabbage and artichoke extracts and soy protein. Moreover, plant extracts from traditional medicine, for example from African countries, are also a subject of study in this direction. The full clinical exploitation of many of them, however, still requires robust clinical evidence, which should be the objective of future research.
{"title":"Nutraceutical alternatives to red yeast rice extract/monacolin K for moderate hypercholesterolaemia: Current evidence and knowledge gaps: Nutraceuticals and hypercholesterolaemia","authors":"L. Comí, Claudia Giglione, Fationa Tolaj, C. Parolini, C. Olivieri, Marco Ruzza, Valentina Tollemeto, Maria Zurlo, Federico Pialorsi, A. Seneci, P. Magni","doi":"10.56095/eaj.v1i3.20","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.20","url":null,"abstract":"The nutraceutical approach to moderate hypercholesterolaemia is an interesting option in the context of appropriate conditions associated with low cardiovascular risk, and red yeast rice (RYR) extract is one of the most utilized products in this field. Monacolin k, its main active component, reduces serum LDL-C levels via inhibition of β-Hydroxy β-methylglutaryl-CoA reductase, similarly to statins. In 2011, EFSA approved the claim regarding monacolin k from RYR extract and maintenance of normal cholesterol levels. However, in 2018, EFSA issued a warning about potential adverse effects of this nutraceutical and, in 2022, the European Commission published a Regulation with several limitations of its use. Therefore, current research and development efforts are aiming at assessing efficacy and safety of other known and novel nutraceutical products which may benefit patients with moderate hypercholesterolaemia. These active agents range from phytosterols, probiotics and berberine to bergamot, cabbage and artichoke extracts and soy protein. Moreover, plant extracts from traditional medicine, for example from African countries, are also a subject of study in this direction. The full clinical exploitation of many of them, however, still requires robust clinical evidence, which should be the objective of future research.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131297973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Coppi, C. Peri, F. Bonacina, R. Longo, Dalma Cricrí, S. Pedretti, Rui Silva, I. Severi, A. Giordano, G. Norata, A. Catapano, N. Mitro, E. De Fabiani, M. Crestani
Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 diabetes. HDAC3 regulates adipose tissue physiology (WAT), and its genetic inactivation causes metabolic reprogramming of white adipocytes toward browning. The aim of this work is to evaluate the effect of HDAC3 silencing at different stages of differentiation and investigate the influence of adipocyte metabolism on the immunophenotype of WAT. Materials and Methods: Following HDAC3 silencing in mesenchymal stem cells and mature adipocytes, adipocyte function, RNA, DNA and protein levels, and proliferation at the end of differentiation were analyzed. Visceral WAT immunophenotype (vWAT) of Hdac3 KO mice in WAT (Hdac3fatKO) and controls (FL) was performed by FACS. Results: Silencing HDAC3 in precursors amplifies the expression of genes and proteins that regulate differentiation, oxidative metabolism, browning and mitochondrial activity. Following silencing, we found increased 1)phosphorylation of AKT (1.64 fold change, P<0.0001), indicative of increased insulin signaling, and 2)proliferation, characteristic of the early phase of differentiation. Mitochondrial content was unchanged, but increased mitochondrial activity was observed in terms of maximal respiration (1.42 fold change, P=0.0151) and uncoupling of the electron transport chain (+11.6%, P<0.0001). No difference was observed following HDAC3 silencing in mature adipocytes. We hypothesized that the enhancement of oxidative metabolism may cause cellular damage or senescence and, consequently, the immunophenotype of vWAT might be affected by HDAC3 ablation. Analysis reveals an increase of macrophages (2.48 fold change, P=0.0311) in the vWAT of Hdac3fatKO mice polarizing toward the M2 population. Coculture of adipocytes with macrophages from bone marrow indicates that HDAC3 silencing in adipocytes stimulates macrophage activation. Conclusions: HDAC3 is a key factor in the WAT phenotype, and its inactivation triggers mechanisms that support browning. Early epigenetic events mediated by HDAC3 silencing are crucial in directing adipocyte precursors toward the oxidative phenotype. Finally, results obtained from ex vivo and in vitro studies suggest that specific factors produced by KO adipocytes may be involved in determining the observed immunophenotype. [FONDAZIONE CARIPLO 2015-0641]
{"title":"Role of histone deacetylase 3 (HDAC3) in adipose tissue metabolism and immunophenotype: Selected Abstract - SITeCS Congress 2022","authors":"L. Coppi, C. Peri, F. Bonacina, R. Longo, Dalma Cricrí, S. Pedretti, Rui Silva, I. Severi, A. Giordano, G. Norata, A. Catapano, N. Mitro, E. De Fabiani, M. Crestani","doi":"10.56095/eaj.v1i3.22","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.22","url":null,"abstract":"Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 diabetes. HDAC3 regulates adipose tissue physiology (WAT), and its genetic inactivation causes metabolic reprogramming of white adipocytes toward browning. The aim of this work is to evaluate the effect of HDAC3 silencing at different stages of differentiation and investigate the influence of adipocyte metabolism on the immunophenotype of WAT. Materials and Methods: Following HDAC3 silencing in mesenchymal stem cells and mature adipocytes, adipocyte function, RNA, DNA and protein levels, and proliferation at the end of differentiation were analyzed. Visceral WAT immunophenotype (vWAT) of Hdac3 KO mice in WAT (Hdac3fatKO) and controls (FL) was performed by FACS. Results: Silencing HDAC3 in precursors amplifies the expression of genes and proteins that regulate differentiation, oxidative metabolism, browning and mitochondrial activity. Following silencing, we found increased 1)phosphorylation of AKT (1.64 fold change, P<0.0001), indicative of increased insulin signaling, and 2)proliferation, characteristic of the early phase of differentiation. Mitochondrial content was unchanged, but increased mitochondrial activity was observed in terms of maximal respiration (1.42 fold change, P=0.0151) and uncoupling of the electron transport chain (+11.6%, P<0.0001). No difference was observed following HDAC3 silencing in mature adipocytes. We hypothesized that the enhancement of oxidative metabolism may cause cellular damage or senescence and, consequently, the immunophenotype of vWAT might be affected by HDAC3 ablation. Analysis reveals an increase of macrophages (2.48 fold change, P=0.0311) in the vWAT of Hdac3fatKO mice polarizing toward the M2 population. Coculture of adipocytes with macrophages from bone marrow indicates that HDAC3 silencing in adipocytes stimulates macrophage activation. Conclusions: HDAC3 is a key factor in the WAT phenotype, and its inactivation triggers mechanisms that support browning. Early epigenetic events mediated by HDAC3 silencing are crucial in directing adipocyte precursors toward the oxidative phenotype. Finally, results obtained from ex vivo and in vitro studies suggest that specific factors produced by KO adipocytes may be involved in determining the observed immunophenotype. [FONDAZIONE CARIPLO 2015-0641]","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131503981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manuela Casula, A. Aronica, M. Averna, S. Carugo, A. Poli, A. Catapano
No abstract available
没有摘要
{"title":"The XVI National Congress of the Società Italiana di Terapia Clinica e Sperimentale (SITeCS): Conference report","authors":"Manuela Casula, A. Aronica, M. Averna, S. Carugo, A. Poli, A. Catapano","doi":"10.56095/eaj.v1i3.25","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.25","url":null,"abstract":"No abstract available","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123982139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Colombo, M. Busnelli, S. Manzini, E. Franchi, Mariel Garcia Rivera, J. Kirwan, G. Chiesa
TMAO, a metabolite of dietary choline, is considered a pro-atherogenic molecule for its ability to interfere with the reverse cholesterol transport, in which apolipoprotein A-I and HDL play a key role. In the present work it was evaluated how TMAO impacts on the development of atherosclerosis in mice with different levels of apoA-I/HDL. Mice deficient in both murine apoA-I and apoE (DKO) and DKO mice overexpressing human apoA-I (DKO/hA-I), characterized by extremely low or high plasma HDL levels respectively, were fed for 16 weeks two standard rodent diets, differing only in their choline content (0.09% or 1.2%). At the end of the dietary treatment, atherosclerosis development was quantified at the aortic sinus, targeted plasma metabolomics was performed, and gene expression was evaluated in liver, duodenum, jejunum and ileum. With both diets, DKO mice developed much larger plaques than DKO/hA-I mice. High-choline diet increased plasma TMAO levels in both genotypes. Interestingly, a worsening of plaque development by high choline diet occurred in DKO/hA-I mice only (0.057±0.048 mm2 vs 0.0988±0.064 mm2, p<0.01). Plasma metabolomics indicated that choline supplementation, only in the presence of HDL, significantly increased the concentration of some ceramide species in addition to several markers of impaired kidney function. High-choline diet increased the hepatic gene expression of Fmo1 and Fmo2 in DKO/hA-I, whereas the expression of Scarb1 was lower in DKO/hA-I compared to DKO mice, regardless of the dietary treatment. Intestinal expression of genes involved in inflammatory response and in lipid metabolism was comparable between genotypes and was not modified by choline supplementation. In conclusion, high choline diet increased plasma TMAO concentration in both genotypes, but affected atherosclerosis development, plasma metabolome and hepatic gene expression only in high HDL mice. Intestinal gene expression was not affected neither by genotype nor by dietary choline content.
氧化三甲胺是膳食胆碱的代谢物，被认为是一种促动脉粥样硬化分子，因为它能够干扰胆固醇的逆向运输，其中载脂蛋白a - i和高密度脂蛋白起关键作用。本研究评估了氧化三甲胺对不同apoA-I/HDL水平小鼠动脉粥样硬化的影响。小鼠apoA-I和apoE缺乏(DKO)和DKO小鼠过度表达人apoA-I (DKO/hA-I)，分别以极低或高血浆HDL水平为特征，饲喂两种标准啮齿动物饮食16周，仅胆碱含量(0.09%或1.2%)不同。在饮食治疗结束时，量化主动脉窦动脉粥样硬化的发展，进行靶向血浆代谢组学研究，并评估肝脏、十二指肠、空肠和回肠的基因表达。在这两种饮食中，DKO小鼠的斑块都比DKO/ ha - 1小鼠大得多。高胆碱饮食增加了两种基因型的血浆TMAO水平。有趣的是，高胆碱饮食仅在DKO/hA-I小鼠中发生斑块发展恶化(0.057±0.048 mm2 vs 0.0988±0.064 mm2, p<0.01)。血浆代谢组学表明，仅在HDL存在的情况下，胆碱的补充显著增加了一些神经酰胺种类的浓度，以及一些肾功能受损的标志物。无论何种饮食处理，高胆碱日粮增加了DKO/ ha - 1小鼠肝脏中Fmo1和Fmo2基因的表达，而与DKO小鼠相比，DKO/ ha - 1小鼠中Scarb1的表达较低。肠道中参与炎症反应和脂质代谢的基因表达在基因型之间是相似的，并且没有被补充胆碱改变。由此可见，高胆碱饮食增加了两种基因型小鼠的血浆TMAO浓度，但仅影响高HDL小鼠的动脉粥样硬化发展、血浆代谢组和肝脏基因表达。肠道基因表达不受基因型和饲粮胆碱含量的影响。
{"title":"Impact of dietary choline on lipid metabolism and atherosclerosis development in apoEKO mice deficient or overexpressing apolipoprotein A-I: Selected Abstract - XVI SITeCS Congress","authors":"A. Colombo, M. Busnelli, S. Manzini, E. Franchi, Mariel Garcia Rivera, J. Kirwan, G. Chiesa","doi":"10.56095/eaj.v1i3.23","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.23","url":null,"abstract":"TMAO, a metabolite of dietary choline, is considered a pro-atherogenic molecule for its ability to interfere with the reverse cholesterol transport, in which apolipoprotein A-I and HDL play a key role. In the present work it was evaluated how TMAO impacts on the development of atherosclerosis in mice with different levels of apoA-I/HDL. Mice deficient in both murine apoA-I and apoE (DKO) and DKO mice overexpressing human apoA-I (DKO/hA-I), characterized by extremely low or high plasma HDL levels respectively, were fed for 16 weeks two standard rodent diets, differing only in their choline content (0.09% or 1.2%). At the end of the dietary treatment, atherosclerosis development was quantified at the aortic sinus, targeted plasma metabolomics was performed, and gene expression was evaluated in liver, duodenum, jejunum and ileum. With both diets, DKO mice developed much larger plaques than DKO/hA-I mice. High-choline diet increased plasma TMAO levels in both genotypes. Interestingly, a worsening of plaque development by high choline diet occurred in DKO/hA-I mice only (0.057±0.048 mm2 vs 0.0988±0.064 mm2, p<0.01). Plasma metabolomics indicated that choline supplementation, only in the presence of HDL, significantly increased the concentration of some ceramide species in addition to several markers of impaired kidney function. High-choline diet increased the hepatic gene expression of Fmo1 and Fmo2 in DKO/hA-I, whereas the expression of Scarb1 was lower in DKO/hA-I compared to DKO mice, regardless of the dietary treatment. Intestinal expression of genes involved in inflammatory response and in lipid metabolism was comparable between genotypes and was not modified by choline supplementation. In conclusion, high choline diet increased plasma TMAO concentration in both genotypes, but affected atherosclerosis development, plasma metabolome and hepatic gene expression only in high HDL mice. Intestinal gene expression was not affected neither by genotype nor by dietary choline content.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"76 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130787614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Amadio, C. Banfi, M. Zarà, M. Brioschi, S. Ghilardi, L. Sandrini, S. Barbieri
Prenylcysteine-oxidase1 (PCYOX1) enzyme, involved in the degradation of prenylated proteins, is expressed in different types of cells, among which vascular and blood cells. Previous studies demonstrated that the secretome of cells silenced for PCYOX1 reduced platelet adhesion on both fibrinogen and endothelial cells, suggesting its possible involvement in thrombotic mechanisms. In this study we analyzed the role of PCYOX1 in arterial thrombosis by the use of an animal model. All the procedures have been carried on mice knock-out for PCYOX1 (Pcyox1KO) that were compared with wild-type (WT) mice. Arterial thrombosis was induced by Ferric chloride application on carotid artery, while pulmonary thromboembolism was induced by the injection of collagen-epinephrine. The phenotype and the functionality of platelets were analyzed by cytofluorimetry and functional tests. The expression of PCYOX1 on platelets was evaluated by mass spectrometry. Thrombus formation induced by Ferric Chloride was reduced in Pcyox1KO mice, that were also protected from pulmonary thromboembolism. No differences were identified in blood cells count, vascular pro-coagulant activity and functional fibrinogen. Interestingly, Pcyox1KO mice displayed a marked reduction in the number of platelets-leukocytes aggregates, in the release of alpha granules, in the activation of receptor αIIbβ3 and in platelets aggregation induced by ADP e TRAP (analyzed on whole blood or platelets rich plasma). Mass spectrometry showed that PCYOX1 was highly expressed in WT platelets. However, the deletion of PCYOX1 did not alter platelets phosphorylation pathways, and platelets adhesion and aggregation (analyzed on washed platelets), in respect of WT mice. Of note, when platelets aggregation was performed on washed platelets isolated from WT mice in the presence of plasma derived from Pcyox1KO mice, we observed a strong impairment in comparison with the aggregation obtained on the same platelets resuspended in plasma derived from WT mice. In conclusion, our results, showing an ipo-reactivity of platelets and a reduced arterial and pulmonary thrombosis in Pcyox1KO mice, suggest that this protein could represent a new potential target in antithrombotic therapy.
前戊酰半胱氨酸氧化酶1 (PCYOX1)酶参与前戊酰化蛋白的降解，在不同类型的细胞中表达，其中包括血管细胞和血细胞。先前的研究表明，PCYOX1沉默的细胞分泌组降低了血小板对纤维蛋白原和内皮细胞的粘附，提示其可能参与血栓形成机制。在本研究中，我们通过动物模型分析了PCYOX1在动脉血栓形成中的作用。所有程序均在小鼠PCYOX1基因(Pcyox1KO)敲除中进行，并与野生型(WT)小鼠进行比较。颈动脉应用三氯化铁诱发动脉血栓形成，注射胶原-肾上腺素诱发肺血栓栓塞。通过细胞荧光法和功能试验分析血小板的表型和功能。质谱法检测PCYOX1在血小板上的表达。在Pcyox1KO小鼠中，氯化铁诱导的血栓形成减少，也可以防止肺血栓栓塞。在血细胞计数、血管促凝活性和功能性纤维蛋白原方面没有发现差异。有趣的是，Pcyox1KO小鼠在血小板-白细胞聚集的数量、α颗粒的释放、受体αIIbβ3的激活和ADP e TRAP诱导的血小板聚集方面表现出显著的减少(在全血或富血小板血浆中分析)。质谱分析显示PCYOX1在WT血小板中高表达。然而，PCYOX1的缺失并没有改变WT小鼠的血小板磷酸化途径，以及血小板的粘附和聚集(在洗涤后的血小板上分析)。值得注意的是，在Pcyox1KO小鼠血浆存在的情况下，对WT小鼠分离的洗净血小板进行血小板聚集时，我们观察到与在WT小鼠血浆中重悬的相同血小板上获得的聚集相比有强烈的损伤。总之，我们的研究结果显示Pcyox1KO小鼠的血小板具有ipo反应性，动脉和肺部血栓形成减少，这表明该蛋白可能代表抗血栓治疗的新潜在靶点。
{"title":"Effect of the deletion of prenylcysteine-oxidase 1 (PCYOX1) on arterial thrombosis in an animal model: Selected Abstract - SITeCS Congress 2022","authors":"P. Amadio, C. Banfi, M. Zarà, M. Brioschi, S. Ghilardi, L. Sandrini, S. Barbieri","doi":"10.56095/eaj.v1i3.19","DOIUrl":"https://doi.org/10.56095/eaj.v1i3.19","url":null,"abstract":"Prenylcysteine-oxidase1 (PCYOX1) enzyme, involved in the degradation of prenylated proteins, is expressed in different types of cells, among which vascular and blood cells. Previous studies demonstrated that the secretome of cells silenced for PCYOX1 reduced platelet adhesion on both fibrinogen and endothelial cells, suggesting its possible involvement in thrombotic mechanisms. In this study we analyzed the role of PCYOX1 in arterial thrombosis by the use of an animal model. All the procedures have been carried on mice knock-out for PCYOX1 (Pcyox1KO) that were compared with wild-type (WT) mice. Arterial thrombosis was induced by Ferric chloride application on carotid artery, while pulmonary thromboembolism was induced by the injection of collagen-epinephrine. The phenotype and the functionality of platelets were analyzed by cytofluorimetry and functional tests. The expression of PCYOX1 on platelets was evaluated by mass spectrometry. Thrombus formation induced by Ferric Chloride was reduced in Pcyox1KO mice, that were also protected from pulmonary thromboembolism. No differences were identified in blood cells count, vascular pro-coagulant activity and functional fibrinogen. Interestingly, Pcyox1KO mice displayed a marked reduction in the number of platelets-leukocytes aggregates, in the release of alpha granules, in the activation of receptor αIIbβ3 and in platelets aggregation induced by ADP e TRAP (analyzed on whole blood or platelets rich plasma). Mass spectrometry showed that PCYOX1 was highly expressed in WT platelets. However, the deletion of PCYOX1 did not alter platelets phosphorylation pathways, and platelets adhesion and aggregation (analyzed on washed platelets), in respect of WT mice. Of note, when platelets aggregation was performed on washed platelets isolated from WT mice in the presence of plasma derived from Pcyox1KO mice, we observed a strong impairment in comparison with the aggregation obtained on the same platelets resuspended in plasma derived from WT mice. In conclusion, our results, showing an ipo-reactivity of platelets and a reduced arterial and pulmonary thrombosis in Pcyox1KO mice, suggest that this protein could represent a new potential target in antithrombotic therapy.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"77 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115145102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Current clinical guidelines on lipid metabolism disorders are represented by the integration of relevant multicenter observational studies and registries aimed to identify best strategies in cardiovascular risk stratification, diagnostics and treatment of dyslipidemias. The approaches outlined in the European, Russian and American clinical guidelines look relevant to each other despite a range slightly different postulates, as they all demonstrate a general tendency to the importance of accurate risk stratification of patients and timely action on low-density lipoprotein cholesterol (LDL-C) levels when using effective lipid-lowering therapy.
{"title":"European, Russian and American Clinical Guidelines on dyslipidemias management – where do we stand? European, Russian, and US guidelines on dyslipidemias","authors":"A. Alieva, E. Usova, O. Reutova","doi":"10.56095/eaj.v1i2.14","DOIUrl":"https://doi.org/10.56095/eaj.v1i2.14","url":null,"abstract":"Current clinical guidelines on lipid metabolism disorders are represented by the integration of relevant multicenter observational studies and registries aimed to identify best strategies in cardiovascular risk stratification, diagnostics and treatment of dyslipidemias. The approaches outlined in the European, Russian and American clinical guidelines look relevant to each other despite a range slightly different postulates, as they all demonstrate a general tendency to the importance of accurate risk stratification of patients and timely action on low-density lipoprotein cholesterol (LDL-C) levels when using effective lipid-lowering therapy.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"55 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126712714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Stevens, A. Lyons, Kanika I Dharmayat, J. Brandts, A. Vallejo-Vaz, Magdalena Daccord, K. Ray
Information available on lipid clinics and patient support and advocacy groups, such as location and services provided, is limited or unknown to patients with dyslipidaemia and their family members who may also be affected, and non-specialist clinicians, hindering accessibility to appropriate healthcare. To overcome this, the European Atherosclerosis Society Familial Hypercholesterolemia Study Collaboration (EAS FHSC) led by Imperial College London has, in collaboration with the European FH Patient Network (FH Europe), developed FindMyLipidClinic.com, a global Directory of lipid clinics and patient support groups in 29 languages. Since its launch in 2020, around 4,000 visitors have conducted 12,000 searches across 1,100 locations, which may have retrieved up to 124 lipid clinics and 29 patient groups currently listed in 39 and 28 countries, respectively. Clinics and patient organisations not currently listed are encouraged to join this directory, and it would also benefit further from collaborations with other existing directories able to contribute.
{"title":"FindMyLipidClinic.com: A global Directory of lipid clinics and patient organisations to improve dyslipidemia care: FindMyLipidClinic.com","authors":"C. Stevens, A. Lyons, Kanika I Dharmayat, J. Brandts, A. Vallejo-Vaz, Magdalena Daccord, K. Ray","doi":"10.56095/eaj.v1i2.11","DOIUrl":"https://doi.org/10.56095/eaj.v1i2.11","url":null,"abstract":"Information available on lipid clinics and patient support and advocacy groups, such as location and services provided, is limited or unknown to patients with dyslipidaemia and their family members who may also be affected, and non-specialist clinicians, hindering accessibility to appropriate healthcare. To overcome this, the European Atherosclerosis Society Familial Hypercholesterolemia Study Collaboration (EAS FHSC) led by Imperial College London has, in collaboration with the European FH Patient Network (FH Europe), developed FindMyLipidClinic.com, a global Directory of lipid clinics and patient support groups in 29 languages. Since its launch in 2020, around 4,000 visitors have conducted 12,000 searches across 1,100 locations, which may have retrieved up to 124 lipid clinics and 29 patient groups currently listed in 39 and 28 countries, respectively. Clinics and patient organisations not currently listed are encouraged to join this directory, and it would also benefit further from collaborations with other existing directories able to contribute. ","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130980397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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