Key Role In Cardiovascular Diseases Research Articles

Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy.

Ischemic heart disease (IHD) is a major cause of mortality and morbidity worldwide, with novel therapeutic strategies urgently needed. Endothelial dysfunction is a hallmark of IHD, contributing to its development and progression. Hypoxia-inducible factors (HIFs) are transcription factors activated in response to low oxygen levels, playing crucial roles in various pathophysiological processes related to cardiovascular diseases. Among the HIF isoforms, HIF2α is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFβ, also known as ARNT, is the obligate binding partner of HIFα subunits and is necessary for HIFα's transcriptional activity. ARNT itself plays an essential role in the development of the cardiovascular system, regulating angiogenesis, limiting inflammatory cytokine production, and protecting against cardiomyopathy. This review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cell function and dysfunction and their involvement in IHD pathogenesis. We highlight their roles in inflammation and maintaining the integrity of the endothelial barrier, as well as their potential as therapeutic targets for IHD.

The role of ROS-induced pyroptosis in CVD.

Cardiovascular disease (CVD) is the number one cause of death in the world and seriously threatens human health. Pyroptosis is a new type of cell death discovered in recent years. Several studies have revealed that ROS-induced pyroptosis plays a key role in CVD. However, the signaling pathway ROS-induced pyroptosis has yet to be fully understood. This article reviews the specific mechanism of ROS-mediated pyroptosis in vascular endothelial cells, macrophages, and cardiomyocytes. Current evidence shows that ROS-mediated pyroptosis is a new target for the prevention and treatment of cardiovascular diseases such as atherosclerosis (AS), myocardial ischemia-reperfusion injury (MIRI), and heart failure (HF).

Ticagrelor Can Regulate the Ion Channel Characteristics of Superior Cervical Ganglion Neurons after Myocardial Infarction.

The superior cervical ganglion (SCG) plays a key role in cardiovascular diseases. The aim of this study was to determine the changes in the ion channel characteristics of the SCG following myocardial infarction (MI) and the role of pretreatment with the P2Y12 receptor antagonist ticagrelor (TIC). A total of 18 male rabbits were randomly divided into a control group, MI group, and P2Y12 receptor antagonist (TIC) group (abbreviated as the TIC group). Rabbit MI was performed via two abdominal subcutaneous injections of 150 mg·kg-1·d-1 of isoproterenol (ISO) with an interval of 24 h. TIC pretreatment at 20 mg·kg-1·d-1 was administered via gavage for two consecutive days. The cardiac function of each group was evaluated with echocardiography. ADP receptor P2Y12 expressions in SCGs were determined using RT-PCR and immunofluorescence staining. Ion channel characteristics of SCG neurons were measured using a whole-cell patch clamp. Intracellular calcium concentrations for SCG neurons were measured using confocal microscopy. Cardiac function was reduced in the rabbits of the MI group, the sympathetic nerve activity of SCGs was increased, and the current amplitude of the neuron ion channel was increased. MI led to alterations in the activation and inactivation characteristics of INa channels accompanied by increased expression of P2Y12 in SCGs. Most of these abnormalities were prevented by TIC pretreatment in the TIC group. TIC pretreatment could attenuate the increase in P2Y12 expression in SCGs and the changes to the ion channel characteristics of SCG neurons after MI. This may be the mechanism underlying the cardiac protective effects of TIC.

Effect of regular exercise training on platelet function in patients with cardiovascular disease and healthy individuals: A systematic review

IntroductionRegular exercise training is essential in prevention and treatment of cardiovascular disease (CVD), yet the beneficial effects of exercise remain only partly explained. Platelets play a key role in CVD and may be affected by regular exercise training. We aimed to systematically summarise studies investigating the effect of regular exercise training on platelet function in patients with CVD and in healthy individuals. MethodsStudies were identified by PubMed, Embase and Web of Science May 16, 2022. We selected studies investigating markers of platelet function in relation to regular exercise training in patients with CVD and in healthy individuals. Regular exercise was defined as exercise training for four weeks or more. ResultsOf the included studies, 11 investigated patients with CVD and 29 were on healthy individuals. Studies were heterogeneous regarding design, study population and methodology, and the results were ambiguous. In total, 52 different markers of platelet function were investigated with platelet aggregation, soluble P-selectin, and thromboxane B2 (TXB2) as the most frequently examined. When evaluating between-group changes after regular exercise, two studies found a reduced platelet aggregation in the exercise group whilst three studies did not find a difference between groups. With respect to TXB2, three studies reported a reduction and two studies an increase in the exercise group. There were no between-group differences in the seven studies examining soluble P-selectin. ConclusionRegular exercise training has no clear impact on platelet function in patients with CVD or healthy individuals. Prospero registrationCRD42022350539.

Identification of hub biomarkers of myocardial infarction by single-cell sequencing, bioinformatics, and machine learning.

BackgroundMyocardial infarction (MI) is one of the first cardiovascular diseases endangering human health. Inflammatory response plays a significant role in the pathophysiological process of MI. Messenger RNA (mRNA) has been proven to play a key role in cardiovascular diseases. Single-cell sequencing (SCS) technology is a new technology for high-throughput sequencing analysis of genome, transcriptome, and epigenome at the single-cell level, and it also plays an important role in the diagnosis and treatment of cardiovascular diseases. Machine learning algorithms have a wide scope of utilization in biomedicine and have demonstrated superior efficiency in clinical trials. However, few studies integrate these three methods to investigate the role of mRNA in MI. The aim of this study was to screen the expression of mRNA, investigate the function of mRNA, and provide an underlying scientific basis for the diagnosis of MI.MethodsIn total, four RNA microarray datasets of MI, namely, GSE66360, GSE97320, GSE60993, and GSE48060, were downloaded from the Gene Expression Omnibus database. The function analysis was carried out by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) enrichment analysis. At the same time, inflammation-related genes (IRGs) were acquired from the GeneCards database. Then, 52 co-DEGs were acquired from differentially expressed genes (DEGs) in differential analysis, IRGs, and genes from SCS, and they were used to construct a protein-protein interaction (PPI) network. Two machine learning algorithms, namely, (1) least absolute shrinkage and selection operator and (2) support vector machine recursive feature elimination, were used to filter the co-DEGs. Gene set enrichment analysis (GSEA) was performed to screen the hub-modulating signaling pathways associated with the hub genes. The results were validated in GSE97320, GSE60993, and GSE48060 datasets. The CIBERSORT algorithm was used to analyze 22 infiltrating immune cells in the MI and healthy control (CON) groups and to analyze the correlation between these immune cells. The Pymol software was used for molecular docking of hub DEGs and for potential treatment of MI drugs acquired from the COREMINE.ResultsA total of 126 DEGs were in the MI and CON groups. After screening two machine learning algorithms and key co-DEGs from a PPI network, two hub DEGs (i.e., IL1B and TLR2) were obtained. The diagnostic efficiency of IL1B, TLR2, and IL1B + TLR2 showed good discrimination in the four cohorts. GSEA showed that KEGG enriched by DEGs were mainly related to inflammation-mediated signaling pathways, and GO biological processes enriched by DEGs were linked to biological effects of various inflammatory cells. Immune analysis indicated that IL1B and TLR2 were correlated with various immune cells. Dan shen, san qi, feng mi, yuan can e, can sha, san qi ye, san qi hua, and cha shu gen were identified as the potential traditional Chinese medicine (TCM) for the treatment of MI. 7-hydroxyflavone (HF) had stable combinations with IL1B and TLR2, respectively.ConclusionThis study identified two hub DEGs (IL1B and TLR2) and illustrated its potential role in the diagnosis of MI to enhance our knowledge of the underlying molecular mechanism. Infiltrating immune cells played an important role in MI. TCM, especially HF, was a potential drug for the treatment of MI.

Fluorescent Nanodiamonds for Detecting Free-Radical Generation in Real Time during Shear Stress in Human Umbilical Vein Endothelial Cells.

Free-radical generation is suspected to play a key role in cardiovascular diseases. Another crucial factor is shear stress. Human umbilical vein endothelial cells (HUVECS), which form the lining of blood vessels, require a physiological shear stress to activate many vasoactive factors. These are needed for maintaining vascular cell functions such as nonthrombogenicity, regulation of blood flow, and vascular tone. Additionally, blood clots form at regions of high shear stress within a blood vessel. Here, we use a new method called diamond magnetometry which allows us to measure the dynamics of free-radical generation in real time under shear stress. This quantum sensing technique allows free-radical detection with nanoscale resolution at the single-cell level. We investigate radical formation in HUVECs in a microfluidic environment under different flow conditions typically found in veins and arteries. Here, we looked into free-radical formation before, during, and after flow. We found that the free-radical production varied depending on the flow conditions. To confirm the magnetometry results and to differentiate between radicals, we performed conventional fluorescent reactive oxygen species (ROS) assays specific for superoxide, nitric oxide, and overall ROS.

DNMT3A R882 Mutation in Human Haematopoietic Stem Cells Alters Differentiation Towards Neutrophils and Monocytes

Age related clonal haematopoiesis (ARCH) is defined as the clonal expansion of hematopoietic stem cells (HSCs), driven by recurrent mutations. Many of these are also commonly seen in haematological malignancies, hence termed pre-leukemic mutations (pLM). ARCH carries an increased risk of haematological malignancies and cardiometabolic disease. Further understanding of the role of pLMs in HSC function is necessary to predict and possibly prevent leukemia. DNMT3A R882 is the most common pLM observed in ARCH and is associated with poor outcomes in acute myeloid leukemia (AML). It is acquired early in life and is positively selected in HSCs. HSCs of Dnmt3a knock-out or knock-in mouse models have increased self-renewal capacity and can differentiate towards all lineages. DNMT3A R882 mutation is observed in all mature blood lineages in ARCH individuals, indicating their multipotential differentiation capacity, but the dynamics of differentiation are not known. We hypothesise that DNMT3A R882 mutation affects the differentiation dynamics of HSCs, potentially contributing to disease risk.We characterised the functional changes in HSC differentiation driven by DNMT3A R882 at single cell resolution. Single phenotypic HSCs (CD33-/CD34+/CD45dim/CD38-/CD45RA-) from 9 individuals (Table 1) were cultured in media supporting differentiation into all major blood lineages. To assess changes in differentiation capacity between DNMT3A R882 and wild-type (WT) HSCs within each individual, each single-cell colony was genotyped by targeted DNA sequencing and scored by high-throughput flow cytometry. Flow cytometry data was analysed using a novel unbiased analytical pipeline, which we have named ‘FlowPAC’, allowing generation of a two-dimensional representation of the global output of HSC differentiation by identifying clusters based on fluorochrome intensity. Four samples were underpowered for either DNMT3A R882 or WT colonies and were excluded from this analysis.We did not observe any difference in erythroid versus myeloid or lymphoid (NK) differentiation capacity between DNMT3A R882 and WT HSC. DNMT3A R882 and WT HSCs also produced similar proportions of monocytic and neutrophil colonies. However, FlowPAC analysis identified differences in their level of maturity. CD15 (neutrophil marker) expression was significantly increased in myeloid clusters of DNMT3A R882 colonies compared to WT (p=0.0043), whereas CD14 (monocyte marker) expression was decreased compared to WT (p=0.0645). We further analysed mature neutrophil differentiation using CD66b expression. Consistent with promotion of neutrophil differentiation, CD66b median fluorescence intensity was significantly increased in the CD15+ population of DNMT3A R882 colonies compared to WT. To further investigate monocyte differentiation, we performed RNAseq on colonies containing only monocytes from 1 ARCH sample. Analysis of transcriptional profiles confirmed less mature monocytes in DNMT3A R882 colonies compared to WT. Overall, our data indicate that DNMT3A R882 mutation in HSCs alters neutrophil and monocyte production.Additionally, we observed that in contrast to samples with high LSC content leading to leukemic engraftment in mice, in samples where DNMT3A R882 HSCs were able to reconstitute normal blood production, the expression of the cell surface marker CD49f, a marker of the most potent HSCs, was significantly increased in DNMT3A R882 HSCs compared to WT at the time of sorting. This may suggest unequal distribution of this pLM within the preserved normal HSC pool prior to leukemic transformation.In conclusion, DNMT3A R882 alters the dynamics of human HSC myeloid differentiation. The propensity of DNMT3A R882 derived monocytes to retain an immature phenotype relative to WT cells could represent an early change later facilitating the complete differentiation block seen in AML, driven by the acquisition of additional mutations such as NPM1. DNMT3A R882 also promoted neutrophil maturation. Altered neutrophil differentiation has been observed in patients with germline DNMT3A mutation. As altered neutrophil function plays a key role in cardiovascular disease, future studies are required to investigate whether the effect of DNMT3A R882 on neutrophil differentiation may contribute to the increased cardiovascular disease risk associated with this mutation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Compositional and functional alterations of gut microbiota in patients with stroke

Background and aimsThere is accumulating evidence that gut microbiota plays a key role in cardiovascular diseases. Gut bacteria can transform dietary choline, l-carnitine, and trimethylamine N-oxide (TMAO) into trimethylamine, which can be oxidized into TMAO again in the liver. However, the alterations of the gut microbiota in large artery atherosclerotic (LAA) stroke and cardioembolic (CE) stroke have been less studied. Methods and resultsWe performed a case–control study in patients with LAA and CE types of strokes. We profiled the gut microbiome using Illumina sequencing of the 16S ribosomal RNA gene (V4–V5 regions), and TMAO was determined via liquid chromatography–tandem mass spectrometry. Our results showed that the TMAO levels in the plasma of patients with LAA and CE strokes were significantly higher than those in controls (LAA stroke, 2931 ± 456.4 ng/mL; CE stroke, 4220 ± 577.6 ng/mL; healthy control, 1663 ± 117.8 ng/mL; adjusted p < 0.05). The TMAO level in the plasma of patients with LAA stroke was positively correlated with the carotid plaque area (rho = 0.333, 95% CI = 0.08–0.55, p = 0.0093). Notably, the composition and the function of gut microbiota in the LAA stroke group were significantly different from those in the control group (FDR-adjusted p-value < 0.05). There was no significant association between gut microbiota and CE stroke in our study. ConclusionThis study provides evidence for significant compositional and functional alterations of the gut microbiome in patients with LAA stroke. Gut microbiota might serve as a potential biomarker for patients with LAA stroke.

Nature versus Number: Monocytes in Cardiovascular Disease.

Monocytes play a key role in cardiovascular disease (CVD) as their influx into the vessel wall is necessary for the development of an atherosclerotic plaque. Monocytes are, however, heterogeneous differentiating from classical monocytes through the intermediate subset to the nonclassical subset. While it is recognized that the percentage of intermediate and nonclassical monocytes are higher in individuals with CVD, accompanying changes in inflammatory markers suggest a functional impact on disease development that goes beyond the increased proportion of these ‘inflammatory’ monocyte subsets. Furthermore, emerging evidence indicates that changes in monocyte proportion and function arise in dyslipidemia, with lipid lowering medication having some effect on reversing these changes. This review explores the nature and number of monocyte subsets in CVD addressing what they are, when they arise, the effect of lipid lowering treatment, and the possible implications for plaque development. Understanding these associations will deepen our understanding of the clinical significance of monocytes in CVD.

Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and CYP2C19 polymorphisms. On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x109/L for clopidogrel and ticagrelor, respectively; p < .001) or following cessation of clopidogrel (7.23 (1.97) x109/L, at 6 months vs 7.56 (2.28) x109/L after treatment cessation; P < .001). This occurred independently of baseline biomarkers and CYP2C19 genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC. Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and CYP2C19 genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel’s efficacy as well as therapeutic interaction with anti-inflammatory drugs.

Heritability of haemodynamics in the ascending aorta

Blood flow in the vasculature can be characterised by dimensionless numbers commonly used to define the level of instabilities in the flow, for example the Reynolds number, Re. Haemodynamics play a key role in cardiovascular disease (CVD) progression. Genetic studies have identified mechanosensitive genes with causal roles in CVD. Given that CVD is highly heritable and abnormal blood flow may increase risk, we investigated the heritability of fluid metrics in the ascending aorta calculated using patient-specific data from cardiac magnetic resonance (CMR) imaging. 341 participants from 108 British Caucasian families were phenotyped by CMR and genotyped for 557,124 SNPs. Flow metrics were derived from the CMR images to provide some local information about blood flow in the ascending aorta, based on maximum values at systole at a single location, denoted max, and a ‘peak mean’ value averaged over the area of the cross section, denoted pm. Heritability was estimated using pedigree-based (QTDT) and SNP-based (GCTA-GREML) methods. Estimates of Reynolds number based on spatially averaged local flow during systole showed substantial heritability ({hbox {h}}^{2}_{Ped} = 41% ,[hbox {P}=0.001], {hbox {h}}^{2}_{SNP} = 39%, [hbox {P}=0.002]), while the estimated heritability for Reynolds number calculated using the absolute local maximum velocity was not statistically significant (12–13%; hbox {P}>0.05). Heritability estimates of the geometric quantities alone; e.g. aortic diameter ({hbox {h}}^{2}_{Ped} = 29%, [hbox {P}=0.009], {hbox {h}}^{2}_{SNP} = 30%, [hbox {P}=0.010]), were also substantially heritable, as described previously. These findings indicate the potential for the discovery of genetic factors influencing haemodynamic traits in large-scale genotyped and phenotyped cohorts where local spatial averaging is used, rather than instantaneous values. Future Mendelian randomisation studies of aortic haemodynamic estimates, which are swift to derive in a clinical setting, will allow for the investigation of causality of abnormal blood flow in CVD.

Mitoquinone (MitoQ) Inhibits Platelet Activation Steps by Reducing ROS Levels.

Platelet activation plays a key role in cardiovascular diseases. The generation of mitochondrial reactive oxygen species (ROS) has been described as a critical step required for platelet activation. For this reason, it is necessary to find new molecules with antiplatelet activity and identify their mechanisms of action. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces mitochondrial overproduction of ROS. In this work, the antiplatelet effect of MitoQ through platelet adhesion and spreading, secretion, and aggregation was evaluated. Thus MitoQ, in a non-toxic effect, decreased platelet adhesion and spreading on collagen surface, and expression of P-selectin and CD63, and inhibited platelet aggregation induced by collagen, convulxin, thrombin receptor activator peptide-6 (TRAP-6), and phorbol 12-myristate 13-acetate (PMA). As an antiplatelet mechanism, we showed that MitoQ produced mitochondrial depolarization and decreased ATP secretion. Additionally, in platelets stimulated with antimycin A and collagen MitoQ significantly decreased ROS production. Our findings showed, for the first time, an antiplatelet effect of MitoQ that is probably associated with its mitochondrial antioxidant effect.

The Effect of Aerobic Training and Tribulus terrestris Extract on Some Oxidative Stress Indices in the Heart Tissue of Male Wistar Rats Poisoned with Hydrogen Peroxide

Background: Oxidative stress plays a key role in cardiovascular diseases. Hydrogen peroxide poisoning also increases oxidative stress. In contrast, aerobic exercise and the use of Tribulus terrestris (Tt) extract can individually play an antioxidant defense balance. Objectives: The aim of this study was to investigate the simultaneous effect of aerobic training (AT), and alcoholic extract of Tt on some oxidative stress indices in the heart tissue of hydrogen peroxide poisoned male Wistar rats. Methods: Forty-two male Wistar rats were randomly divided into seven groups, including (1) healthy-control, (2) H2O2, (3) H2O2 + AT, (4) H2O2 + Tt 1 (5 mg/kg), (5) H2O2 + Tt 2 (10 mg/kg), (6) H2O2 + AT + Tt 1, and (7) H2O2 + AT + Tt 2. The AT protocol consisted of eight weeks (5 sessions per week) of treadmill running at 20 m/min for 60 minutes per session. Tissue samples were collected to measure oxidative stress indices. Two-way analysis of variance was used for statistical analysis. Results: A significant decrease in tissue concentration of cytochrome C (ng/mL), MDA (Pmol/mL), PAB index (HK), while an increase in tissue concentration of ATP (µM) was observed in the H2O2 + AT + Tt 2 group compared to other groups (P ≤ 0.05). Conclusions: Combining AT and Tt can be a good strategy to reduce the complications of hydrogen peroxide poisoning. Because the observed changes were far from complete improvement compared to the healthy control group, it is likely that longer treatment periods and higher drug doses should be used. Future studies should use Tribulus terrestris (Tt) supplementation in addition to Tribulus terrestris (Tt) intake prior to training sessions.

ALK7 Promotes Vascular Smooth Muscle Cells Phenotypic Modulation by Negative Regulating PPARγ Expression.

As a receptor for transforming growth factor-β, nodal and activin, activin receptor-like kinase 7 (ALK7) previously acts as a suppressor of tumorigenesis and metastasis, which has emerged to play a key role in cardiovascular diseases. However, the potential effect and molecular mechanism of ALK7 on vascular smooth muscle cells' (VSMCs) phenotypic modulation have not been investigated. Using cultured mouse VSMCs with platelet-derived growth factor-BB administration, we observed that ALK7 showed a significantly increased expression in VSMCs accompanied by decreased VSMCs differentiation marker genes. Loss-of-function study demonstrated that ALK7 knockdown inhibited platelet-derived growth factor-BB-induced VSMCs phenotypic modulation characterized by increased VSMCs differentiation markers, reduced proliferation, and migration of VSMCs. Such above effects were reversed by ALK7 overexpression. Notably, we noticed that ALK7 silencing dramatically enhanced PPARγ expression, which was required for the attenuated effect of ALK7 knockdown on VSMCs phenotypic modulation. Collected, we identified that ALK7 acted as a novel and positive regulator for VSMCs phenotypic modulation partially through inactivation of PPARγ, which suggested that neutralization of ALK7 might act as a promising therapeutic strategy of intimal hyperplasia.

Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions.

Cardiovascular diseases (CVD) represent one of the biggest causes of death globally, and their prevalence, aetiology, and outcome are related to genetic, metabolic, and environmental factors, among which sex- and age-dependent differences may play a key role. Among CVD risk factors, platelet hyperactivity deserves particular mention, as it is involved in the pathophysiology of main cardiovascular events (including stroke, myocardial infarction, and peripheral vascular injury) and is closely related to sex/age differences. Several determinants (e.g., hormonal status and traditional cardiovascular risk factors), together with platelet-related factors (e.g., plasma membrane composition, receptor signaling, and platelet-derived microparticles) can elucidate sex-related disparity in platelet functionality and CVD onset and outcome, especially in relation to efficacy of current primary and secondary interventional strategies. Here, we examined the state of the art concerning sex differences in platelet biology and their relationship with specific cardiovascular events and responses to common antiplatelet therapies. Moreover, as healthy nutrition is widely recognized to play a key role in CVD, we also focused our attention on specific dietary components (especially polyunsaturated fatty acids and flavonoids) and patterns (such as Mediterranean diet), which also emerged to impact platelet functions in a sex-dependent manner. These results highlight that full understanding of gender-related differences will be useful for designing personalized strategies, in order to prevent and/or treat platelet-mediated vascular damage.

Hypoxia Enhances Endothelial Intercellular Adhesion Molecule 1 Protein Level Through Upregulation of Arginase Type II and Mitochondrial Oxidative Stress.

Hypoxia plays a crucial role in the pathogenesis of cardiovascular diseases. Mitochondrial enzyme arginase type II (Arg-II) is reported to lead to endothelial dysfunction and enhance the expression of endothelial inflammatory adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, we investigate the role of Arg-II in hypoxia-induced endothelial activation and the potential underlying mechanisms. Exposure of the human endothelial cells to hypoxia induced a time-dependent increase in Arg-II, HIF1α, HIF2α, and ICAM-1 protein level, whereas no change in the protein level of VCAM-1 and E-selectin was observed. Similar effects were obtained in cells treated with a hypoxia mimetic Dimethyloxaloylglycine (DMOG). Silencing HIF1α, but not HIF2α, reversed hypoxia-induced upregulation of Arg-II. Moreover, silencing Arg-II prevented the ICAM-1 upregulation induced by hypoxia or DMOG. Furthermore, the endothelial cells incubated under hypoxic condition or treated with DMOG or hypoxia enhanced monocyte adhesion, which was inhibited by silencing Arg-II. Lastly, silencing Arg-II prevented hypoxia-induced mitochondrial superoxide production in endothelial cells, and hypoxia-induced ICAM-1 upregulation was reversed by mitochondrial electron transport inhibitor rotenone. These data demonstrate that hypoxia enhances ICAM-1 protein level and monocyte-endothelial interaction through HIF1α-mediated increase in Arg-II protein level on leading to increased mitochondrial reactive oxygen species production. These effects of hypoxia on endothelial cells may play a key role in cardiovascular diseases. Our results suggest that Arg-II could be a promising therapeutic target to prevent hypoxia-induced vascular damage/dysfunction.

High Incidence of Diabetes in People with Extremely High High-Density Lipoprotein Cholesterol: Results of the Kanagawa Investigation of Total Checkup Data from the National Database-1 (KITCHEN-1).

Background: It is unknown whether extremely high high-density lipoprotein cholesterol (HDL-C) has a protective effect against diabetes, which plays a key role in cardiovascular disease. Methods: In a community-based cohort study of 387,642 subjects (40–68 years old) without diabetes, the incidence of diabetes 6 years later was determined according to baseline HDL-C (≤39, 40–49, 50–59, 60–69, 70–79, 80–89, 90–99, 100–109, or ≥110 mg/dL). Results: At baseline, HDL-C ≥100 mg/dL was present in 12,908 subjects (3.3%), who had a better lipid profile and a high prevalence of heavy alcohol consumption and habitual exercise. The incidences of diabetes according to baseline HDL-C were 14.7, 11.2, 7.7, 5.3, 3.8, 2.8, 2.7, 2.5, and 3.5 per 1000 person-years, respectively. The adjusted relative risks (ARRs) for diabetes showed concave relationships with HDL-C, with minima at 80–89 mg/dL. The ARR (95% CI) of the lowest HDL-C category was 1.56 (1.40–1.74) and of the highest HDL-C category was 1.46 (1.18–1.81) (both p < 0.001), regardless of alcohol consumption. The latter ARR was higher in men (n = 219,047) (2.45 (1.70–3.53), p < 0.0001) after adjustment for baseline glycemic index. Conclusion: Both extremely high and low HDL-C represent risks for diabetes, which deserves further study.

Abstract # 3142 Association between complicated grief and inflammation among bereaved adults

The loss of a spouse is a highly stressful life event and bereavement is associated with an increased risk of death from cardiovascular disease (CVD). Given inflammation’s key role in CVD, it is an essential mechanism through which bereaved individuals may experience heightened risk for CVD. Complicated grief symptoms are prognostic of both mental and physical health issues, including cardiovascular problems, and engender negative emotions that may amplify inflammation. This study explored the mechanisms linking inflammation and CVD to complicated grief among 100 bereaved participants using the Inventory of Complicated Grief to assess ”caseness” of complicated grief (CG). Inflammation was measured using in vitro stimulated cytokine secretion by T cells. After controlling for medication use income, alcohol use, time since bereavement, BMI, age, and comorbid conditions, bereaved individuals with CG had higher levels of several pro-inflammatory cytokines. Specifically, complicated grief was associated with higher levels of the pro-inflammatory cytokines IL-6 ( M CG = 5.07, SD CG = 0.38, M NCG = 4.25, SD NCG = 0.24, p =.03), TNF-alpha ( M CG = 6.89, SD CG = 0.43, M NCG = 6.24, SD NCG = 0.22, p =.03), and IFN-gamma ( M CG = 8.50, SD CG = 0.49, M NCG = 7.76, SD NCG = 0.27, p =.03). CG did not significantly predict IL17-A, IL-2, or any other chemokines (CCL5, CXCL10, CCL2). This is the first study to demonstrate the association between CG and inflammation. .

Towards more specific treatment for diabetic dyslipidemia.

Treatment of diabetic dyslipidemia is necessary because of its impact on cardiovascular disease, which is the leading cause of death in patients with diabetes. In the past, standard treatment of diabetic dyslipidemia focused only on correcting lipids. Although this remains the mainstay of treatment, because new antihyperglycemic treatments reduce cardiovascular events with minimal effect on dyslipidemia, a new approach is both timely and relevant. LDL-lowering remains the focus of treatment for diabetic dyslipidemia, especially in patients with both diabetes and cardiovascular disease (CVD). Higher intensity statin therapy or lower LDL cholesterol goals are recommended in these patients. Combination therapy, especially with ezetimibe, fibrates, bile acid sequestrants, PCSK9 inhibitors and omega 3 fatty acids should be considered along with selected new agents to reduce glycemia. As diabetic dyslipidemia plays a key role in CVD, aggressive treatment is indicated. New research targets include apo-CIII and lipoprotein(a) [Lp(a)]. In addition, new antihyperglycemic therapy is changing diabetes care and altering treatment guidelines. The most recent American Diabetes Association Standards of Care has expanded its recommendations for people with CVD and diabetes, suggesting that medications validated to improve cardiac health should be strongly considered.

Inhibition of 5-Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β-Arrestin2-Mammalian Target of Rapamycin/p70S6K Pathway.

BackgroundAs a monoamine neurotransmitter, 5‐hydroxytryptamine (5‐HT) or serotonin modulates mood, appetite, and sleep. Besides, 5‐HT also has important peripheral functions. 5‐HT receptor 2B (5‐HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5‐HT2BR in neointimal hyperplasia, a key pathological process in restenosis.Methods and ResultsThe expression of 5‐HT2BR was upregulated in wire‐injured mouse femoral arteries. In addition, BW723C86, a selective 5‐HT2BR agonist, promoted the injury response during restenosis. 5‐HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5‐HT–induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5‐HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a β‐arrestin2–dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5‐HT2BR–mediated smooth muscle cell migration. Mice with deficiency of 5‐HT2BR showed significantly reduced neointimal formation in wire‐injured arteries.ConclusionsThese results demonstrated that activation of 5‐HT2BR and β‐arrestin2–biased downstream signaling are key pathological processes in neointimal formation, and 5‐HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.