Atherosclerosis-related Diseases Research Articles

Macrophage-derived FGFR1 drives atherosclerosis through PLCγ-mediated activation of NF-κB inflammatory signaling pathway.

Atherosclerosis is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signaling in atherosclerosis are not known. In the present study, we investigated FGFR1 signaling in atherosclerosis development and progression. Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Safety evaluation of saffron extracts in early and established atherosclerotic New Zealand white rabbits.

Previous research has shown that natural medications pose health risks, especially in subjects with comorbidities. This study aimed to evaluate the safety of saffron ethanolic extract (SEE) administration in early and established atherosclerotic rabbits. Rabbits were given a high-cholesterol diet (HCD) for 4 and 8 weeks to induce early and established atherosclerosis respectively, and then they were treated with 50 and 100 mg/kg/day SEE. The body weight of the animals was recorded. Blood samples were collected at baseline, pre-treatment, and post-treatment for hematological studies, lipid profiles, and biochemical profiles. Tissue specimens of the vital organs were subjected to histological examination. The above parameters were significantly altered post-intervention with 4 and 8 weeks of HCD. No significant differences in body weight were observed in all the groups post-treatment with 50 and 100mg/kg of SEE compared to pre-treatment. However, low-density lipoprotein cholesterol, total cholesterol, serum urea, and glucose significantly decreased post-treatment with 50 and 100mg/kg/day SEE compared to pre-treatment in early and established atherosclerosis groups. Hematological parameters that were affected post-intervention with HCD returned to their baseline values post-treatment with 50 and 100mg/kg/day SEE. There was a significant improvement in the vital organs post-treatment with 50 and 100mg/kg SEE. SEE can safely be administered without causing harmful effects on the hematological, biochemical profiles, and vital organs. Notably, SEE exerts hypolipidemic and hypoglycemic effects on atherosclerotic conditions. Further clinical trials are warranted to ensure the safety of saffron administration in patients with atherosclerosis-related diseases.

Trait anxiety and health self-esteem of as one of the causes of atherosclerosis related diseases of the cardiovascular system among young age people

The aim of the study was to conduct an associative analysis between trait anxiety and selfdetermination of one’s cardiovascular health among young people.Material and methods. In a typical area of a large industrial and scientific center (Novosibirsk) in 2013–2016 a study of a random sample of young people aged 25–44 was performed, which included 975 participants, 427 of which 427 are men. To assess trait anxiety, a form of Spielberger self-assessment scales was proposed.Results. Men and women with a high level of trait anxiety (HTA) in 57.1 and 64.9 % cases, respectively, believed that they could not classify themselves as healthy people, especially since a third of the respondents complained about their health status; almost 30 % of participants with HTA did not take care of their health (p < 0.001). Persons of both sexes in 41 % cases and 38.6% women with HTA admitted a high probability of a severe illness soon (p < 0.01). However, even pronounced pain sensations in persons of both sexes with HTA in 60.3 % cases was not the reason for seeking medical help, especially since they did not have confidence in the routine examination of a doctor (47.4 % persons of both sexes and 57.1 % men). Only 5.1 % of both sexes examined with HTA would go to the doctor if they were unwell at work (p < 0.05). If they had the flu or had a temperature, then 44.9 % people with HTA worked as usual, with low TA – 26.6 % (p < 0.01).Conclusions. Personal anxiety contributes to a lower health self-esteem, especially cardiovascular, and does not encourage timely seeking medical help.

Serum anti-PCK1 antibody levels are a prognostic factor for patients with diabetes mellitus

BackgroundAutoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM), and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy.MethodsSerological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples.ResultsPhosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular disease than in healthy donors, but not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients.ConclusionsSerum anti-PCK1 antibody levels were found to be associated with DM. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM.

Influence of the Type of Disability and Sporting Discipline on Lipid Profile in a Cohort of Italian Paralympic Athletes

Dyslipidemia is the most frequent cardiovascular (CV) risk factor in able-bodied athletes and is frequently undertreated, resulting in an underestimated risk of atherosclerosis-related diseases. Data on lipid profile in Paralympic athletes are lacking. Our study aimed to identify the prevalence of dyslipidemia and the influence of disability type and sporting discipline in Paralympic athletes. We evaluated 289 athletes who participated in the Paralympic Games from London 2012 to Beijing 2022. All athletes underwent clinical/physical evaluation, blood tests, and body composition analysis. They were divided into different groups based on sports disciplines and disability type (spinal cord injuries [SCIs] and non-SCIs [NSCIs]). Among the Paralympic athletes, 34.6% had a low-density lipoprotein (LDL) level ≥115mg/100ml. They were older (38.1 ± 9.2 vs 30.6 ± 9.6, p=0.001) and had a higher CV risk. Athletes with SCI showed similar total cholesterol and triglycerides, higher LDL (110.9 ± 35.2 vs 102.7 ± 30.6mg/100ml, p=0.03) and lower high-density lipoprotein (HDL) (53.6 ± 13.6 vs 60.5 ± 15.4mg/100ml, p=0.001) than those with NSCI. Endurance athletes had lower LDL, the highest HDL, and the lowest triglycerides and LDL/HDL ratio compared with other sports disciplines. A mean follow-up of 61.5 ± 30.5months was available in 47% athletes, and 72.7% of the athletes with dyslipidemia continued to present altered LDL values at follow-up. In conclusion, dyslipidemia is the most common CV risk factor in the Paralympics, affecting 35% of athletes, with only mild lipid changes over a medium-term time. The type of disability and sporting discipline has an impact on lipids, improving HDL and reducing LDL, with a better profile observed in NSCI and endurance athletes.

Global and national burden of atherosclerosis from 1990 to 2019: trend analysis based on the Global Burden of Disease Study 2019.

Atherosclerosis-related diseases represent significant health issues among adults globally. Despite their widespread impact, comprehensive data concerning the global and national burden and trends of these diseases remain sparse. Our objective is to examine the trends in the burden of atherosclerosis among adults from 1990 to 2019 at both global and national levels. We reported the average annual percentage changes (AAPCs) in prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of atherosclerosis-related diseases (ischemic heart disease [IHD], ischemic stroke, and peripheral arterial disease [PAD]) at the global and national levels among individuals based on a trend analysis of the Global Burden of Diseases Study (GBD) 2019. We further analyzed these global trends as a function of age, gender, and the social development index. We also used joinpoint regression analysis to identify the year with the most substantial changes in global trends. Globally, the AAPC of IHD incidence rose from 1990 to 2019 (0.20; 95% confidence interval [CI], 0.12-0.28), with substantial surges in 1995, 2001, 2005, 2010, and 2017. Conversely, AAPC of IHD mortality rates exhibited a different trend until a rise in 2014. The AAPC of incidence rates of ischemic stroke and PAD also escalated during the same period, with respective 0.43 (95% CI, 0.39-0.48) and 0.13 (95% CI, 0.06-0.21). For ischemic stroke, both incidence and mortality soared in 2014, while PAD incidence declined in 1994 and 1998, then sharply climbed in 2016. Nationally, the Northern Mariana Islands experienced the steepest increase in IHD and PAD incidence and mortality between 1990 and 2019. China saw a significant rise in ischemic stroke incidence, whereas the highest mortality rate increase occurred in Timor-Leste. By sociodemographic index (SDI) quintile, low-middle-, middle-, and high-middle-SDI countries all showed upward trends in IHD, ischemic stroke, and PAD incidence. Simultaneously, IHD and ischemic stroke mortality rates, as well as DALYs, dropped in the low-, high-middle-, and high-SDI nations. However, PAD mortality rates and DALYs saw an uptick across all SDI quintiles. Regarding age demographics, a global decrease in the AAPC IHD incidence as noted in individuals above 55 years old, in contrast to an increase in the 20-55 age group during this period. AAPC of mortality rates for IHD, ischemic stroke, and PAD decreased across all ages. The AAPC showed an increase in IHD incidence in both genders. Conversely, IHD's DALYs saw a reduction in both males and females. Ischemic stroke patterns mirrored these trends, whereas all measures for PAD exhibited growth for both sexes. From 1990 to 2019, there was an overall increasing trend in the global incidence of all three clinical manifestations of atherosclerosis. Between 1990 and 2019, both the mortality rate and DALYs for IHD and ischemic stroke declined across all age groups. Overall, the burden of atherosclerosis-related diseases has not significantly decreased and even shows signs of trending upward. These findings strongly suggest that despite some progress made, efforts to control atherosclerosis diseases globally need to be intensified.

Evaluation of Atherosclerotic Risk by Oxidative Contributors in Alcohol Use Disorder.

Alcohol Use Disorder (AUD) is a condition described as the inability to control or stop alcohol consumption. The patients with AUD have an increased risk of developing atherosclerosis-related diseases. The present study aimed to evaluate oxidative contributors of atherosclerotic risk factors in patients with AUD. The male subjects diagnosed with AUD (n = 45) and the male subjects as control (n = 35) were enrolled in this study. All participants were undergone psychiatric evaluation and sociodemographic tests. Also, serum oxidative contributors of atherosclerosis including myeloperoxidase (MPO), ferroxidase, catalase (CAT), and lipid hydroperoxides (LOOH) were measured. Additionally, serum lipid profile tests and atherogenic indicators including atherogenic index of plasma (AIP) and non-high-density lipoprotein (HDL) cholesterol were also analyzed. The AUD subject had significantly elevated MPO activity and LOOH levels with decreased antioxidant capacity. AIP and non-HDL cholesterol levels, the atherogenic indicators, were also higher in AUD group compared to the control group. We found the MPO activity and LOOH levels were positively correlated with AIP, non-HDL cholesterol levels, and amount of alcohol consumption. Additionally, CAT activity was negatively correlated with duration of alcohol consumption. Our results revealed that MPO and LOOH levels were elevated by severe alcohol intake and the atherogenic indicators, AIP and non-HDL cholesterol, were significantly correlated alcohol induced elevated oxidative risk factors. Therefore, it can be suggested that MPO activity and LOOH levels may be useful to determine jeopardy of atherosclerotic and the therapeutic interventions that reduce oxidative load could be taken into account to prevent atherosclerotic diseases before clinical manifestation.

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.

In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β=0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

Familial Hypercholesterolaemia in Children and Adolescents: Current and Future Perspectives.

Familial hypercholesterolemia (FH) is a genetic disease, the underlying cause of which is represented by mutations capable of influencing the metabolism of low-density lipoproteins (LDL). The distinguishing characteristic of FH has increased LDL cholesterol blood levels since birth, triggering early development of atherosclerosis-related diseases. Diagnosis of FH is frequently either missed or made with a considerable delay. Prompt identification of the disease is pivotal in implementing early prevention measures. Safe and effective drugs have been approved for use in children and adolescents, with statins, with or without ezetimibe, representing first-line therapy. At times, however, these medications may not be sufficient to achieve the therapeutic target, particularly in homozygous FH patients. Lipoprotein apheresis, which has proved safe and efficient, is strongly suggested in such cases. New drugs still at the investigational stage may represent a promising and personalised therapy. Lowering cholesterol levels in childhood hampers the formation of arterial atherosclerotic plaques, thus reducing cardiovascular events later in life. Accordingly, early detection, diagnosis, and therapy in FH subjects are priority aims.

LncRNA RP4-639F20.1 interacts with THRAP3 to attenuate atherosclerosis by regulating c-FOS in vascular smooth muscle cells proliferation and migration

Background and aimsThe aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) play an essential role in the pathogenesis of atherosclerosis (AS). Long noncoding RNAs (lncRNAs) have been reported as important regulators in a number of diseases. However, very little is known regarding the functional role of lncRNAs in governing proliferation and migration of VSMCs and AS development. MethodsBoth in vitro and in vivo assays were performed to investigate the role of lncRNA in the pathophysiology of AS. Our previous lncRNA arrays revealed that lncRNA RP4-639F20.1 was significantly decreased in atherosclerotic plaques. Lentivirus overexpressing RP4-639F20.1 and lncRNA RP4-639F20.1 silencing vectors (Si-lnc-RP4-639F20.1) were constructed and transfected in VSMCs. The in vitro functions of lncRNA were analyzed by CCK-8 assays, EdU assays, scratch wound assays, transwell assays, qRT-PCR and Western blot analyses. RNA fluorescence in situ hybridization, immunoprecipitation and mRNA microarrays were used to explore the underlying mechanism. Adeno-associated-virus-9 (AAV9) overexpressing RP4-639F20.1 was constructed and injected intravenously into ApoE−/− mice to explore the role of lncRNA in vivo. ResultsIn vitro experiments showed that lncRNA RP4-639F20.1 interacted with THRAP3 and downregulated c-FOS expression. Both increase of lncRNA RP4-639F20.1 expression and knockdown of c-FOS inhibited the expression of MMP10 and VEGF-α in VSMCs and suppressed VSMCs proliferation and migration. In vivo experiments using ApoE−/− mice fed a high-fat diet demonstrated that lncRNA RP4-639F20.1 overexpression deterred atherosclerosis and decreased lipid levels in atherosclerotic lesions. Patients with coronary artery disease were found to have higher c-FOS levels than healthy individuals and c-FOS expression was positively correlated with the SYNTAX score of patients. ConclusionsOverall, these data indicated that lncRNA RP4-639F20.1/THRAP3/c-FOS pathway protects against the development of atherosclerosis by suppressing VSMCs proliferation and migration. LncRNA RP4-639F20.1 and c-FOS could represent potential therapeutic targets to ameliorate atherosclerosis-related diseases.

Scaffold-free human vascular calcification model using a bio-three-dimensional printer

Morbidity and mortality rates associated with atherosclerosis-related diseases are increasing. Therefore, developing new research models is important in furthering our understanding of atherosclerosis and investigate novel treatments. Here, we designed novel vascular-like tubular tissues from multicellular spheroids composed of human aortic smooth muscle cells, endothelial cells, and fibroblasts using a bio-3D printer. We also evaluated their potential as a research model for Mönckeberg’s medial calcific sclerosis. The tubular tissues were sufficiently strong to be handled 1 week after printing and could still be cultured for 3 weeks. Histological assessment showed that calcified areas appeared in the tubular tissues within 1 week after culture in a medium containing inorganic phosphate (Pi) or calcium chloride as the calcification-stimulating factors. Calcium deposition was confirmed using micro-computed tomography imaging. Real-time quantitative reverse transcription polymerase chain reaction analysis revealed that the expression of osteogenic transcription factors increased in calcified tubular tissues. Furthermore, the administration of Pi and rosuvastatin enhanced tissue calcification. The bio-3D printed vascular-like tubular structures, which are composed of human-derived cells, can serve as a novel research model for Mönckeberg’s medial calcific sclerosis.

Macrophage Gpx4 deficiency aggravates foam cell formation by regulating the expression of scavenger receptors, ABCA1, and ABCG1.

Macrophage-derived foam cell formation is critical for the initiation and development of atherosclerosis, which contributes to atherosclerotic cardiovascular disease (ASCVD). Glutathione peroxidase 4 (GPX4), a crucial ferroptosis regulator, protects cells from excessive oxidative stress by neutralizing lipid peroxidation. However, the role of macrophage GPX4 in foam cell formation remains unknown. We reported that oxidized low-density lipoprotein (oxLDL) upregulated GPX4 expression in macrophages. Using the Cre-loxP system, we generated myeloid cell-specific Gpx4 knockout (Gpx4myel-KO ) mice. Bone marrow-derived macrophages (BMDMs) were isolated from WT and Gpx4myel-KO mice and incubated with modified low-density lipoprotein (LDL). We found that Gpx4 deficiency promoted foam cell formation and increased the internalization of modified LDL. Mechanistic studies unveiled that Gpx4 knockout upregulated scavenger receptor type A and LOX-1 expression and downregulated ABCA1 and ABCG1 expression. Collectively, our study lends a novel insight into the role of GPX4 in suppressing macrophage-derived foam cell formation and suggests GPX4 as a promising therapeutic target to interfere with atherosclerosis-related diseases.

Transcriptome-wide association study reveals novel susceptibility genes for coronary atherosclerosis.

Genetic risk factors substantially contributed to the development of coronary atherosclerosis. Genome-wide association study (GWAS) has identified many risk loci for coronary atherosclerosis, but the translation of these loci into therapeutic targets is limited for their location in non-coding regions. Here, we aimed to screen the potential coronary atherosclerosis pathogenic genes expressed though TWAS (transcriptome wide association study) and explore the underlying mechanism association. Four TWAS approaches (PrediXcan, JTI, UTMOST, and FUSION) were used to screen genes associated with coronary atherosclerosis. Enrichment analysis of TWAS-identified genes was applied through the Metascape website. The summary-data-based Mendelian randomization (SMR) analysis was conducted to provide the evidence of causal relationship between the candidate genes and coronary atherosclerosis. At last, the cell type-specific expression of the intersection genes was examined by using human coronary artery single-cell RNA-seq, interrogating the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. We identified 19 genes by at least three approaches and 1 gene (NBEAL1) by four approaches. Enrichment analysis enriching the genes identified at least by two TWAS approaches, suggesting that these genes were markedly enriched in asthma and leukocyte mediated immunity reaction. Further, the summary-data-based Mendelian randomization (SMR) analysis provided the evidence of causal relationship between NBEAL1 gene and coronary atherosclerosis, confirming the protecting effects of NBEAL1 gene and coronary atherosclerosis. At last, the single cell cluster analysis demonstrated that NBEAL1 gene has differential expressions in macrophages, plasma cells and endothelial cells. Our study identified the novel genes associated with coronary atherosclerosis and suggested the potential biological function for these genes, providing insightful guidance for further biological investigation and therapeutic approaches development in atherosclerosis-related diseases.

Primary disorders of lipid metabolism: their place in current dyslipidemia guidelines and treatment innovations

According to current guidelines, the selection and intensity of lipid-effective therapies are based on the risk to be treated. The sole clinical categories of primary and secondary prevention of cardiovascular diseases result in over- and under-treatment, which may be acontributory cause of incomplete implementation of current guidelines in everyday practice. For the extent of benefit in cardiovascular outcome studies with lipid-lowering drugs, the importance of dyslipdemia for the pathogenesis of atherosclerosis-related diseases is crucial. Primary lipid metabolism disorders are characterized by life-long increased exposure to atherogenic lipoproteins. This article describes the relevance of new data for low density lipoprotein-effective therapy: inhibition of proprotein convertase subtilisin/kexin type9 (PCSK9), adenosine triphosphate (ATP) citrate lyase with bempedoic acid, and ANGPTL3 with special consideration of primary lipid metabolism disorders, which are insufficiently taken into account, or not taken into account at all, in current guidelines. This is due to their apparently low prevalence rate and thus the lack of large outcome studies. The authors also discuss the consequences of increased lipoprotein(a), which cannot be sufficiently reduced until the ongoing intervention studies examining antisense oligonucleotides and small interfering RNA (siRNA) against apolipoprotein(a) are completed. Another challenge in practice is the treatment of rare, massive hypertriglyceridemia, especially with the aim of preventing pancreatitis. For this purpose, the apolipoprotein C3 (ApoC3) antisense oligonucleotide volenasorsen is available, which binds to the mRNA for ApoC3 and lowers triglycerides by around three quarters.

Tetrandrine alleviates atherosclerosis via inhibition of STING-TBK1 pathway and inflammation in macrophages.

Atherosclerosis (AS) is a chronic inflammatory disease. Recent studies have showed that stimulator of interferon genes (STING), an important protein in innate immunity, mediates pro-inflammatory activation of macrophages in the development of AS. Tetrandrine (TET) is a natural bisbenzylisoquinoline alkaloid isolated from Stepania tetrandra and possesses anti-inflammatory activities, with unknown effects and mechanisms in AS. In this study, we explored the anti-atherosclerotic effects of TET and investigated the underlying mechanisms. Mouse primary peritoneal macrophages (MPMs) are challenged with cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or oxidized LDL (oxLDL). We found that pretreatment with TET dose-dependently inhibited cGAMP- or oxLDL-induced STING/ TANK-binding kinase 1 (TBK1) signaling, then suppressing nuclear factor kappa-B (NF-κB) activation and pro-inflammatory factor expression in MPMs. ApoE-/- mice were fed a high-fat diet (HFD) to develop an atherosclerotic phenotype. Administration of TET at 20mg/kg/day significantly reduced HFD-induced atherosclerotic plaques, accompanied with decreased macrophage infiltration, inflammatory cytokine production, fibrosis, and STING/TBK1 activation in aortic plaque lesions. In summary, we demonstrate that TET inhibits STING/TBK1/NF-κB signaling pathway to reduce inflammation in oxLDL-challenged macrophages and alleviate atherosclerosis in HFD-fed ApoE-/- mice. These findings proved that TET could be a potential therapeutic candidate for the treatment of atherosclerosis-related diseases.

Short-Term Effect of Nutraceutical Fruit Juices on Lipid Metabolism in Patients with Acquired Hypercholesterolemia.

The crucial role of dyslipidaemia, especially hypercholesterolemia, in the development of atherosclerosis-related cardiovascular diseases has been extensively documented in genetic, pathologic, observational and intervention studies. The European guidelines for dyslipidaemia management include the possible use of lipid-lowering nutraceuticals to support a relatively large number of natural compounds. In this context, we have conducted a study to investigate whether dietary supplementation with a functional nutraceutical beverage, containing a standardized polyphenolic fraction from fruit, red yeast rice, phytosterols, and berberine complexed with β-cyclodextrin, could positively affect serum lipid concentration in 14 subjects with hypercholesterolemia. After 12 weeks of treatment, dietary supplementation with this nutraceutical combination was associated with significant improvements in total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, compared to baseline. Compliance was excellent and no adverse effects were reported. In conclusion, this study demonstrates that 100 mL of a functional beverage containing lipid-lowering nutraceuticals safely leads to significant improvements in serum lipids in subjects with moderate hypercholesterolemia. Future research is needed to unravel the role that the polyphenols contained in fruit extracts play in the reduction of cholesterolemia and in cardiovascular disease prevention.

High Interleukin-6 Levels Are Associated With Large-Artery Atherosclerotic Stroke.

Interleukins (ILs) play several critical roles in modulating the occurrence and development of atherosclerosis-related diseases. We aimed to investigate the associations between ILs and the diagnosis, progress, and functional outcome in patients with large-artery atherosclerotic (LAA) stroke. Plasma levels of IL-2, IL-4, IL-6, and IL-10 were measured within 24 hours after stroke in 181 patients with first-time LAA stroke and on admission in 181 age-matched and sex-matched controls. NIHSS scores were recorded at admission and on Day 1, Day 2, Day 3, Day 4, and Day 5 after the stroke. Functional outcome was measured by the modified Rankin Scale at 3 months after stroke. Subgroup analyses were compared based on short-term progress within 5 days (ΔNIHSS ≥3) and 3-month unfavorable outcome (modified Rankin Scale >2). Logistic regression analysis adjusted for relevant confounders was performed. IL-6 levels were higher in patients with LAA stroke than in controls [AOR (95% CI), 0.701 (95% CI 0.651-0.748, P <0.001], with an area under the receiver operating characteristic curve (AUC) of 0.701. Higher IL-6 levels were associated with short-term progression [AOR (95% CI), 1.070 (1.009, 1.135), P =0.025], with an AUC value of 0.720. Higher IL-6 levels were associated with unfavorable outcomes [AOR (95% CI), 1.075 (1.002, 1.153), P =0.040], with an AUC value of 0.658. No difference in IL-2, IL-4, or IL-10 was found between the groups. Plasma levels of IL-6 are higher in patients with LAA stroke and are independently associated with short-term progression and 3-month functional outcomes after stroke.

Endothelial progenitor cells and major adverse cardiovascular events in patients receiving elective coronary angiography

Background and purpose: The association of circulating endothelial progenitor cells (EPCs) with different cardiovascular diseases and their related major adverse cardiovascular events (MACE) remained inconclusive. We aimed to clarify associations between the circulating EPC levels and the risk of MACE concerning different atherosclerosis-related diseases. Methods: This prospective cohort study was conducted from December 2009 to March 2015. Patients who underwent non-emergent coronary angiography (CAG) were included. The circulating EPC levels were measured using flow cytometry prior to the CAG procedure. The study evaluation of circulating EPC levels among patients with obstructive coronary artery disease (CAD) and other comorbidities. Patients were then assigned to tertiles by circulating EPC levels to evaluate the predictive values of the development of MACEs. Results: The study enrolled 1099 patients, of whom, 736 (67%) were men, with a mean age of 66.7 ± 12.5 years old. Overall, 637 (58%) patients were diagnosed with obstructive CAD according to CAG. MACE occurred in 268 (24.4%) patients. Circulating EPC levels were lower in patients with peripheral artery disease (PAD) but not associated with the presence of obstructive CAD, atrial fibrillation, chronic kidney disease (CKD), heart failure, and diabetes mellitus. Higher circulating EPC levels are linked with higher MACE among patients with suspected CAD, regardless of the presence or absence of obstructive CAD or CKD. The association did not present in patients with PAD. Conclusions: Higher circulating EPC levels are associated with a greater risk of MACE, regardless of the presence of obstructive CAD or CKD. This association was not apparent in the patients with PAD, suggesting impaired endothelial repair in these patients.

Hippo/YAP signaling pathway: a new therapeutic target for diabetes mellitus and vascular complications.

Diabetic angiopathy, which includes diabetic kidney disease (DKD), cardio-cerebrovascular disease, and diabetic retinopathy (DR) among other diseases, is one of the most common complications affecting diabetic patients. Among these, DKD, which is a major cause of morbidity and mortality, affects about 40% of diabetic patients. Similarly, DR involves retinal neovascularization and neurodegeneration as a result of chronic hyperglycemia and is the main cause of visual impairment and blindness. In addition, inflammation also promotes atherosclerosis and diabetes, with atherosclerosis-related cardiovascular diseases being often a main cause of disability or death in diabetic patients. Given that vascular diseases caused by diabetes negatively impact human health, it is therefore important to identify appropriate treatments. In this context, some studies have found that the Hippo/Yes-associated protein (YAP) pathway is a highly evolutionarily conserved protein kinase signal pathway that regulates organ growth and size through its effector signaling pathway Transcriptional co-Activator with PDZ-binding motif (TAZ) and its YAP. YAP is a key factor in the Hippo pathway. The activation of YAP regulates gluconeogenesis, thereby regulating glucose tolerance levels; silencing the YAP gene thereby prevents the formation of glomerular fibrosis. YAP can combine with TEA domain family members to regulate the proliferation and migration of retinal vascular endothelial cells (ECs), so YAP plays a prominent role in the formation and pathology of retinal vessels. In addition, YAP/TAZ activation and translocation to the nucleus promote endothelial inflammation and monocyte-EC attachment, which can increase diabetes-induced cardiovascular atherosclerosis. Hippo/YAP signaling pathway provides a potential therapeutic target for diabetic angiopathy, which can prevent the progression of diabetes to DR and improve renal fibrosis and cardio-vascular atherosclerosis.