Role In Atherogenesis Research Articles

Genetics of Arterial-Wall-Specific Mechanisms in Atherosclerosis: Focus on Mitochondrial Mutations.

Mutations in both nuclear and mitochondrial genes are associated with the development of atherosclerotic lesions in arteries and may provide a partial explanation to the focal nature of lesion distribution in the arterial wall. This review is aimed to discuss the genetic aspects of atherogenesis with a special focus on possible pro-atherogenic variants (mutations) of the nuclear and mitochondrial genomes that may be implicated in atherosclerosis development and progression. Mutations in the nuclear genes generally do not cause a phenotype restricted to a specific vascular wall cell and manifest themselves mostly at the organism level. Such mutations can act as important contributors to changes in lipid metabolism and modulate other risk factors of atherosclerosis. By contrast, mitochondrial DNA (mtDNA) mutations occurring locally in the arterial wall cells or in circulating immune cells may play a site-specific role in atherogenesis. The mosaic distribution of heteroplasmic mtDNA mutations in the arterial wall tissue may explain, at least to some extent, the locality and focality of atherosclerotic lesions distribution. The genetic mechanisms of atherogenesis include alterations of both nuclear and mitochondrial genomes. Altered lipid metabolism and inflammatory response of resident arterial wall and circulating immune cells may be related to mtDNA damage and defective mitophagy, which hinders clearance of dysfunctional mitochondria. Mutations of mtDNA can have mosaic distribution and locally affect functionality of endothelial and subendothelial intimal cells in the arterial wall contributing to atherosclerotic lesion development.

The microscopic anatomy of endothelial cells in human atherosclerosis: Focus on ER and mitochondria.

Once regarded merely as a bland lipid storage disease consequence of aging, atherosclerosis is currently considered a slow and continuous inflammatory process (partially controllable by treatment) with complex etiology involving a multitude of genetic and environmental risk factors which ultimately result in the formation of the plaque. The vascular endothelium, a monolayer of endothelial cells (ECs), is an important regulatory "organ" critical for cardiovascular homeostasis in health which also contributes significantly to the pathomechanisms of several disease states, including atherosclerosis. Over the years, there has been evidence highlighting the central role of endoplasmic reticulum (ER) in the maintenance of endothelial function and perturbations in ER biology have been proposed to adversely affect a diverse range of endothelial functions. Of particular interest is the evidence that under certain pathophysiological circumstances, abnormal ER ultrastructure correlates with altered ER function and signaling and can contribute to cell injury and apoptosis. Therefore, the ultrastructural traits of ER membranes can have important implications not only for their functional bearings but also for the etiology and pathophysiology of diverse human disorders. With regard to atherosclerosis, the focus of ER researchhasbeen centered on the molecular signals originated from the ER to manage conditions of stress, leaving the fine structure of this organelle an almost unexplored (but promising) area of studies. There is, also, increasing evidence that mitochondrial dysfunction plays a critical role in promoting cell apoptosis, inflammation, and oxidative stress, thereby contributing to atheroma growth. It is within this context that the present study has been undertaken to investigate the microscopic architecture of ECs in human atherosclerosis and to determine whether the potential structural abnormalities of ER and mitochondria may play a central pathogenic role in atherogenesis or may merely reflect the condition of a tissue whose integrity has already been disturbed or destroyed. For this purpose, transmission electron microscopy (TEM) remains a powerful technique that can not only provide information about the ultrastructural state of cell organelles but also allow the correlation between different subcellular alterations indicative of a certain pathophysiological condition and cellular response. The present study expands the spectrum of ultrastructural defects known to exist in human atherosclerosis and suggests that ER alterations may be of great importance in the pathogenesis of the disease. The architectural changes of ER may be considered early pathological events that precede any overt histologic abnormalities in the vascular endothelium and its subcellular organelles, primarily the mitochondrial pool.

Low Shear Stress Upregulates CX3CR1 Expression by Inducing VCAM-1 via the NF-\u03baB Pathway in Vascular Endothelial Cells

Atherosclerosis is a significant cause of mortality and morbidity. Studies suggest that the chemokine receptor CX3CR1 plays a critical role in atherogenesis. Shear stress is an important mechanical force that affects blood vessel function. In this study, we investigated the effect of shear stress on CX3CR1 expression in vascular endothelial cells (VECs). First, cells were exposed to different shear stress and then CX3CR1 mRNA and protein were measured by quantitative RT-PCR and western blot analysis, respectively. CX3CR1 gene silencing was used to analyze the molecular mechanisms underlying shear stress-mediated effects on CX3CR1 expression. CX3CR1 mRNA and protein expression were significantly increased with 4.14 dyne/cm2 of shear stress compared with other tested levels of shear stress. We observed a significant increase in CX3CR1 mRNA levels at 2 h and CX3CR1 protein expression at 4 h. CX3CR1-induced VCAM-1 expression in response to low shear stress by activating NF-κB signaling pathway in VECs. Our findings demonstrate that low shear stress increases CX3CR1 expression, which increases VCAM-1 expression due to elevated NF-κB activation. The current study provides evidence of the correlation between shear stress and atherosclerosis mediated by CX3CR1.

LOX-1 Regulates P. gingivalis-Induced Monocyte Migration and Adhesion to Human Umbilical Vein Endothelial Cells.

Porphyromonas gingivalis (P. gingivalis) is one of the main periodontal bacteria. This pathogen was reported to enhance monocyte migration and adhesion to endothelial cells in atherosclerosis. The scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays a pivotal role in atherogenesis. The aim of this study was to investigate whether LOX-1 modulates P. gingivalis-mediated monocyte migration and adhesion to endothelial cells and how it works. The results showed that the migration and adhesion of monocytic THP-1 cells to human umbilical vein endothelial cells (HUVECs) were significantly enhanced when HUVECs or THP-1 cells were challenged with P. gingivalis. Meanwhile, the expression level of LOX-1 in both HUVECs and THP-1 cells were also significantly increased by P. gingivalis stimulation. It is well known that ligand/receptor pairs monocyte chemoattractant protein-1 (MCP-1)/CC chemokine receptor 2 (CCR2), selectins/Integrins, and cell adhesion molecules (CAMs)/Integrins mediate monocyte migration and adhesion to endothelial cells. In this study, LOX-1 was demonstrated to be crucially involved in P. gingivalis-induced THP-1 cell migration and adhesion to HUVECs, by regulating expression of ligands MCP-1, intercellular adhesion molecule-1 (ICAM-1) and E-selectin in HUVECs and that of their receptors CCR2 and Integrin αMβ2 in THP-1 cells. The nuclear factor-kappa B (NF-κB) signaling pathway was proved to be involved in this process. In conclusion, LOX-1 plays a crucial role in P. gingivalis-induced monocyte migration and adhesion to endothelial cells. This result implies LOX-1 may act as a bridge in linking periodontitis to atherosclerosis.

Hyperlipidaemia and IFNgamma/TNFalpha Synergism are associated with cholesterol crystal formation in Endothelial cells partly through modulation of Lysosomal pH and Cholesterol homeostasis.

BackgroundInflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation.MethodsWe utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo.FindingsWe detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p < 0.001).InterpretationOur results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis.FundingFunding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB).

Serum LOX-1, ADMA and hs-CRP as Biomarkers of Ischemic Heart Disease in Chronic kidney Disease Patients

Abstracts Background: Ischemic heart disease (IHD) is the main cause of death in patients with chronic kidney disease (CKD)with coronary atherosclerosis , which could be predicted by inflammatory biomarkers , as high sensitive C-reactive protein (hs-CRP), IHD is linked to other independent risk factors as asymmetric dimethylarginine (ADMA) and lectin-like oxidized LDL receptor-1(LOX-1),which have proven roles in atherogenesis .objective to evaluate the clinical significance of ADMA and LOX-1 in addition to hs-CRP as biomarkers of IHD in ESRD patients with regular hemodialysis. Subjects and method: Patients groups included 27 patients under hemodialysis with known IHD (Subgroup Ia), 13 patients under hemodialysis without IHD (Subgroup Ib), 19 patients with CKD under conservative treatment (Subgroup Ic). And A control group of 29 healthy volunteers (group II) serum hs-CRP, ADMA, and LOX-1 were assayed. Results: the value of hs-CRP, ADMA and LOX-1 showed statistically significant increase in subgroup Ia versus subgroup Ib, also between subgroup Ib and subgroup Ic. Furthermore there is a highly statistical significant difference between different subgroups and control group. Correlation studies in subgroup Ia between hs-CRP, ADMA and LOX-1 revealed a statistically significant positive correlation. Conclusion: the combined use of hs-CRP and ADMA or LOX-1 showed to be valid for differentiating ESRD with IHD from ESRD without IHD. Serum levels of ADMA and LOX-1 could be relevant and convenient biomarkers for IHD in patients with CKD and its use beside hs-CRP adds more strength and specification to its known predictive value.

Sleep Duration, Lipid Profile and Insulin Resistance: Potential Role of Lipoprotein(a).

Lipoprotein (a) (Lp(a)) is considered a genetic factor for cardiovascular disease playing an important role in atherogenesis and thrombosis, but the evidence about its association with sleep duration is controversial. We evaluated the relation between self-reported sleep duration and Lp(a). Among 1600 participants of the population-based sample, we selected 1427 subjects without previously known cardiovascular events, who answered the questions about their sleep duration; had valid lipid profile results (total cholesterol, low- and high-density lipoproteins, Lp(a), apolipoprotein AI (ApoAI), ApoB, and ApoB/ApoAI); and did not take lipid-lowering drugs (mean age 46 ± 12 years). We performed a structured interview, which included questions about lifestyle, medical history, complaints, and sleep duration (How long have you been sleeping per night during the last month?). Sleep duration was classified as follows: <6 h/night—short, 6–9 h/night—normal, and ≥10 h/night—long. Overall, 73 respondents (5.2%) were short-sleepers and 69 (4.8%) long-sleepers. Males were slightly more prevalent among short-sleepers. The groups matched by age, body mass index, blood pressure, diabetes mellitus, and hypertension rate. Short-sleepers had lower rates of high total cholesterol (≥5.0 mmol/L), lower Lp(a) levels and lower rates of increased Lp(a) ≥0.5 g/L, and higher insulin and insulin resistance (assessed by the homeostatic model assessment for insulin resistance (HOMA-IR)). ApoAI, ApoB, their ratio, and other lab tests were similar in the groups. The multinomial logistic regression demonstrated that only the short sleep duration was independently (odds ratio (OR) 0.29, 95% confidence interval (CI) (0.09–0.91), p = 0.033) associated with Lp(a) (χ2 = 41.58, p = 0.003). Other influencing factors were smoking and HOMA-IR. Such an association was not found for long-sleepers. In conclusion, a short-sleep duration is associated with Lp(a). The latter might mediate the higher insulin resistance and higher cardiometabolic risks in short-sleepers.

The prognostic value of high-sensitivity C-reactive protein blood level after coronary stenting for the development of stent restenosis

Aim To analyze the relationship between serum concentrations of high-sensitivity C-reactive protein (hsCRP) in dynamics and development of restenosis at 12 months following elective coronary stent placement (CSP).Material and methods The key role in atherogenesis, neointimal proliferation and restenosis belongs to inflammation. This study included 91 patients (median age, 60 [56; 66] years) with stable exertional angina after an elective CSP using second-generation stents. Follow-up coronarography was performed for 60 patients at 12 months. Concentration of hsCRP was measured immediately prior to CSP and at 1, 3, 6, and 12 months after CSP. Restenosis of the stented segment (50% or more narrowing of the stented segment or a 5-mm vessel segment proximally or distally adjacent to the stented segment) was observed in 8 patients.Results According to results of the ROC analysis, the increase in hsCRP concentration &gt;0.9 mg/l (&gt;25%) at one month after CSP had the highest predictive significance with respect of restenosis (area under the ROC curve, 0.89 at 95 % confidence interval (CI) from 0.79 to 0.99; sensitivity, 87.5 %; specificity, 82.8 %; р=0.0005), which was superior to the absolute value of hsCRP concentration &gt;3.0 mg/l (area under the ROC curve, 0.82 at 95 % CI from 0.68 to 0.96; р=0.0007).Conclusion Increased concentration of hsCRP ≥0.9 mg /l (≥25 %) at a month after CSP was associated with restenosis of the coronary artery stented segment.

Hormonal Mechanisms in Atherosclerosis

Abstract Cardiovascular disease is a complex process that includes genetic, inflammatory and endocrine components. During the last decades, much emphasis has been given to cholesterol and lipids as the primary determinants in cardiovascular disease. However, many endocrine and biochemical factors are involved in the atherosclerosis process as well, both systemically and vascular. Multiple obvious data suggest that hormones are responsible for subtle cardiovascular changes long before the development of overt atherosclerotic. Much research remains to be done regarding the interaction between endocrine systems and their role in atherogenesis.

Myocardin-Related Transcription Factor A Mediates LPS-Induced iNOS Transactivation.

Macrophage-dependent inflammation plays a critical role in atherogenesis. Inducible nitric oxide synthase (iNOS) is one of key pro-inflammatory mediators produced in macrophages and its levels can be upregulated by lipopolysaccharide (LPS). The epigenetic mechanism whereby LPS induces iNOS transcription is incompletely understood. We show here myocardin-related transcription factor A (MRTF-A) potentiated iNOS promoter activity in macrophages. There was a decrease in LPS-induced iNOS expression in several cell models due to the lack of MRTF-A. LPS treatment promoted nuclear accumulation of MRTF-A and its interaction with NF-κB/p65 on the iNOS promoter. The absence of MRTF-A prevented the accumulation of active histone marks on the iNOS promoter in response to LPS treatment. Mechanistically, MRTF-A recruited ASH2, a key component of the mammalian histone H3K4 methyltransferase complex, to the iNOS promoter. Silencing of ASH2 attenuated iNOS expression following LPS treatment. Together, our data highlight a role for MRTF-A-dependent recruitment of H3K4 methyltransferase in iNOS induction and as such provide a novel target in the intervention of atherosclerosis.

Local and Systemic Inflammation and Oxidative Stress After a Single Bout of Maximal Walking in Patients With Symptomatic Peripheral Artery Disease.

The aim of this study was to assess the effects of a single bout of maximal walking on blood and muscle nitric oxide (NO) bioavailability, oxidative stress, and inflammation in symptomatic peripheral artery disease (PAD) patients. A total of 35 men with symptomatic PAD performed a graded maximal exercise test on a treadmill (3.2 km/h, 2% increase in grade every 2 minutes). Plasma samples and gastrocnemius muscle biopsies were collected preexercise and postexercise for assessment of NO bioavailability (plasma NO and muscle, endothelial NO synthase), oxidative stress and antioxidant function (lipid peroxidation [LPO], catalase [CAT], and superoxide dismutase), and inflammation (interleukin-6, C-reactive protein, tumor necrosis factor-α, intercellular adhesion molecules, and vascular adhesion molecules). The effects of the walking exercise were assessed using paired t tests or Wilcoxon tests. After maximal walking, plasma NO and LPO were unchanged (P > .05), plasma CAT decreased, and all blood inflammatory markers increased (all P ≤ .05). In the disease-affected skeletal muscle, endothelial NO synthase, CAT, LPO, and all inflammatory markers increased, whereas superoxide dismutase decreased (all P ≤ .05). In patients with symptomatic PAD, maximal exercise induces local and systemic impairments, which may play a key role in atherogenesis. Exercise strategies that avoid maximal effort may be important to reduce local and systemic damage and enhance clinical benefits.

Monocyte CD36 expression associates with atherosclerotic burden in diabetes mellitus

BackgroundBy virtue of its role in oxidized low-density lipoprotein uptake and foam cell transformation, monocyte CD36 (mCD36) is a potential non-invasive tool to detect atherosclerosis (ATH) in patients of type 2 diabetes mellitus (DM). MethodsFlowcytometric expression of mCD36 was evaluated with reference to ankle brachial index (ABI) in 70 patients of type 2 DM [40 with and 30 without coronary artery disease (CAD) respectively] and 30 age and gender matched normoglycemic controls (NGCs). ResultsDM patients had significantly higher mCD36 indices than NGCs (p < 0.001). The mCD36 expression was significantly higher in DM persons with CAD and those with poor glycemia control (glycosylated haemoglobin, HbA1c ≥ 7%) than their respective counterparts (p < 0.001 for both). Thirty subjects had compromised ABI (≤0.9); all were DM persons with CAD. ABI compromised subjects had consistently higher mCD36 indices than all other sub-groups (p < 0.001 for all comparisons). Notably, within the ABI-uncompromised group, mCD36 indices differed significantly and showed progressive increase from NGCs to diabetics without and with CAD respectively. ConclusionsmCD36 plays an important role in atherogenesis. With reference to ABI, mCD36 performed robustly as a marker of ATH. Furthermore, it could stratify subjects within the ‘ABI-uncompromised group’ commensurate with their conventional clinico-pathological ATH risk predisposition.

Cardiovascular Risk in Individuals with Inflammatory Bowel Disease.

BackgroundInflammatory bowel disease (IBD) patients present a higher risk of developing cardiovascular diseases due to the presence of chronic inflammation, which plays an essential role in atherogenesis. Therefore, the aim of the study was to evaluate the cardiovascular risk between patients with IBD and healthy control individuals.Materials and MethodsA total of 52 consecutive IBD outpatients from a tertiary hospital and 37 healthy controls were enrolled. Data collected included age, sex, smoking status, presence of comorbidities, disease activity, ongoing medical treatment, body mass index, arterial blood pressure, and cardiovascular risk. The cardiovascular risk was based on the Framingham risk score and ultrasonography variables, such as the carotid intima-media thickness and the presence of atherosclerotic plaque in the carotid. Multivariate logistic regression or multiple linear regression analysis was performed at a significance level of 5%.ResultsNo differences were observed between groups with regard to age, sex, smoking status, comorbidities, blood pressure, body mass index, lipid profile, and Framingham risk score. In the IBD group, fasting glucose [95 (86.2–107.3) mg/dL vs 86 (79–100) mg/dL, p=0.041], carotid intima-media thickness (0.69±0.12 mm vs 0.63±0.12 mm, p=0.031), and atherosclerotic carotid plaque (25% vs 5.4%, p=0.032) were higher compared with those in the control group. Multivariate logistic regression analysis showed that patients with IBD presented a 6.45-fold higher risk of carotid atherosclerotic plaque (odds ratio: 6.45; 95% confidence interval: 1.035–40.216; p<0.046).ConclusionPatients with IBD are at an increased risk of atherosclerosis and, consequently, an increased risk for cardiovascular diseases.

Increased fractalkine and vascular dysfunction in obesity and in type 2 diabetes. Effects of oral antidiabetic treatment

Activation of fractalkine and other chemokines plays an important role in atherogenesis and, in conjunction with endothelial dysfunction, promotes premature vascular damage in obesity and diabetes. We hypothesized that increased circulating fractalkine coexists with impaired vasomotor function in metabolically healthy or unhealthy obesity, and that treatment with antidiabetic drugs may impact these abnormalities in type 2 diabetes. Compared to lean subjects, in both obese groups the vasodilator responses to acetylcholine and sodium nitroprusside were impaired (both P < .001); ETA-receptor blockade resulted in greater vasodilation (both P < .001); and plasma levels of fractalkine, E-selectin and monocyte chemoattractant protein (MCP)-1 were increased (all P < .05). In diabetic patients, oral antidiabetic drugs (glyburide, metformin or pioglitazone) reduced circulating levels fractalkine and E-selectin (both P < .05), without affecting vascular responses (all P > .05). Our findings indicate that insulin resistant states are associated with elevated atherogenic chemokines and impaired vascular reactivity. Antidiabetic treatment results in lower circulating fractalkine, which may provide cardiovascular benefits.

Coronary Atherosclerosis Imaging.

Identifying patients at increased risk of coronary artery disease, before the atherosclerotic complications become clinically evident, is the aim of cardiovascular prevention. Imaging techniques provide direct assessment of coronary atherosclerotic burden and pathological characteristics of atherosclerotic lesions which may predict the progression of disease. Atherosclerosis imaging has been traditionally based on the evaluation of coronary luminal narrowing and stenosis. However, the degree of arterial obstruction is a poor predictor of subsequent acute events. More recent techniques focus on the high-resolution visualization of the arterial wall and the coronary plaques. Most acute coronary events are triggered by plaque rupture or erosion. Hence, atherosclerotic plaque imaging has generally focused on the detection of vulnerable plaque prone to rupture. However, atherosclerosis is a dynamic process and the plaque morphology and composition may change over time. Most vulnerable plaques undergo progressive transformation from high-risk to more stable and heavily calcified lesions, while others undergo subclinical rupture and healing. Although extensive plaque calcification is often associated with stable atherosclerosis, the extent of coronary artery calcification strongly correlates with the degree of atherosclerosis and with the rate of future cardiac events. Inflammation has a central role in atherogenesis, from plaque formation to rupture, hence in the development of acute coronary events. Morphologic plaque assessment, both invasive and non-invasive, gives limited information as to the current activity of the atherosclerotic disease. The addition of nuclear imaging, based on radioactive tracers targeted to the inflammatory components of the plaques, provides a highly sensitive assessment of coronary disease activity, thus distinguishing those patients who have stable disease from those with active plaque inflammation.

Supervised exercise training and increased physical activity to reduce cardiovascular disease risk in women with polycystic ovary syndrome: study protocol for a randomized controlled feasibility trial

BackgroundPolycystic ovary syndrome (PCOS) affects up to 20% of women and is characterised by higher amounts of visceral fat, obesity, insulin resistance, dyslipidemia and reproductive and cardiometabolic complications. Increased oxidised low-density lipoprotein (LDL) concentrations have been associated with an increased risk of cardiovascular disease (CVD)-related events. Oxidised LDL is rarely used as a marker for CVD risk in PCOS-related studies despite its widely accepted role in atherogenesis and the increased risk factors associated with PCOS. Additionally, prolonged periods of sedentary behaviour can negatively affect metabolic health. No studies have specifically examined the effects of reducing sedentary behaviour on CVD risk in PCOS with a lifestyle physical activity intervention. The aim of the current study is to measure the feasibility of a randomised controlled trial (RCT) examining the effects of supervised exercise and reducing sedentary behaviour in women with PCOS on CVD risk.Methods/designA feasibility, exploratory RCT will be conducted. Fifty-one pre-menopausal females will be randomly allocated between an exercise group (EG), a lifestyle physical activity group (LPAG) and a control group. Participants in the EG will undertake a 12-week supervised aerobic exercise programme. The LPAG will aim to increase daily physical activity and reduce sedentary behaviour for 12 weeks. The control group will not take part in any intervention. Primary outcomes are feasibility and acceptability of the intervention and procedures. Secondary outcomes are oxidised LDL, aerobic fitness, blood lipid profile, fasting glucose and insulin, testosterone and inflammatory markers.DiscussionPCOS is associated with various increased risk factors for CVD, including hypertension, dyslipidemia, abdominal obesity, insulin resistance, and inflammation. Whether oxidised LDL has a role in this increased risk is not yet known. The present study aims to measure the feasibility of implementing structured exercise training and/or increased lifestyle physical activity in women with PCOS, so that a subsequent adequately powered RCT can be designed. The results from the study will be used to refine the interventions and determine the acceptability of the study design. A limitation is that some self-monitoring in the lifestyle physical activity group may not be reliable or replicable, for example inputting information about time spent cleaning/gardening.Trial registrationClinicalTrials.gov, NCT03678714. Registered 20 September 2018.

The relationship between galectin-3 and SYNTAX Score I in patients with non-ST-segment elevation myocardial infarction.

The expression of galectin-3 has been found to be increased in human atherosclerotic lesions, suggesting a role in atherogenesis. However, there is a lack of data regarding an association between galectin-3 and the extent, severity, and complexity of coronary artery disease (CAD). The aim of this study was to investigate the relationship between galectin-3 and SYNTAX Score I in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study included a total of 95 consecutive patients who were diagnosed with NSTEMI and underwent coronary angiography. The baseline galectin-3 level of each patient was measured. The SYNTAX Score I of each patient was calculated using the online calculator (www.syntaxscore.com). The study population was divided into 2 groups: SYNTAX Score I ≤22 group (n=55) and SYNTAX Score I >22 group (n=40). The galectin-3 level was significantly higher in the SYNTAX Score I >22 group than in the SYNTAX Score I ≤22 group (22.1±8.3 ng/mL vs. 13.5±7.7 ng/mL; p<0.001). Forward stepwise logistic regression analysis demonstrated that galectin-3 (odds ratio [OR]: 1.195, 95% confidence interval [CI]: 1.097-1.302; p<0.001), left ventricular ejection fraction (OR: 0.941, 95% CI: 0.888-0.997; p=0.040), and platelet count (OR: 1.013, 95% CI: 1.003-1.024; p=0.014) were independently associated with intermediate and high SYNTAX scores. ROC analysis provided a cut-off value of 14.0 ng/mL for galectin-3 to predict an intermediate or high SYNTAX Score I with 75.0% sensitivity and 51.0% specificity (p<0.001). In patients with NSTEMI, galectin-3 was associated with the extent, severity, and complexity of CAD as assessed by the SYNTAX Score I.

NLRP3 inflammasome via IL-1β regulates PCSK9 secretion.

Background: Both PCSK9 and NLRP3 inflammasome play important roles in atherogenesis. This study was designed to test the hypothesis that NLRP3 inflammasome via IL-1β induces PCSK9 secretion. The inter-twined relationship between NLRP3 inflammasome, IL-1β and PCSK9 may be relevant in atherogenesis.Methods: We studied NLRP3 inflammasome-mediated PCSK9 secretion in mouse peritoneal macrophages and in a variety of tissues, such as liver, kidney and small intestine. Macrophages were derived from wild-type (WT) and a variety of gene deletion mice to define the mechanistic basis of NLRP3 inflammasome -mediated PCSK9 secretion. Additional studies were performed in high-fat diet fed mice.Results: We observed that NLRP3 and its downstream signals ASC, Caspase-1, IL-18, and IL-1β all participate in PCSK9 secretion. IL-1β seems to be more important than IL-18 in the induction of PCSK9 secretion. Further, there appears to be significant involvement of MAPKs in this process. Lastly, we observed that mice fed high fat diet have high expression of NLRP3 and a greater secretion of PCSK9 than mice fed a standard diet, and this increased secretion of PCSK9 in high fat diet-fed mice was attenuated in IL-1β-/- mice.Conclusions: This study based on extensive in vitro and in vivo data provides evidence that NLRP3 inflammasome via IL-1β plays an important role in determining PCSK9 secretion, particularly in the presence of high-fat diet.

Fasting and postprandial lipid parameters: A comparative evaluation of cardiovascular risk assessment in prediabetes and diabetes.

Context:Dyslipidemia plays a crucial role in atherogenesis, in both prediabetes and diabetes. There persists a lacuna in the evaluation of postprandial lipid parameters in prediabetes.Aims:To comparatively evaluate fasting and postprandial blood lipid parameters and atherogenic lipid ratios for cardiovascular risk assessment, in prediabetes and diabetes.Materials and Methods:Fifty-one patients diagnosed with diabetes mellitus and thirty-two with prediabetes were selected for the study. Lipid profile and blood glucose were analyzed in fasting and postprandial blood samples.Statistical Analysis Used:Kolmogorov–Smirnov test, Shapiro–Wilk test, one-way ANOVA, and Pearson's regression analysis were applied.Results:Postprandially, triglycerides (TG) was increased significantly in diabetes compared to controls (P < 0.01) and prediabetics (P < 0.05). Among the lipid ratios, triglyceride/high density lipoprotein (TG/HDLc) was significantly increased postprandially in diabetes compared to controls (P < 0.05). A comparative analysis of fasting and postprandial parameters within each group showed a significant increase in postprandial TG/HDLc compared to the fasting state in prediabetes (P < 0.001) and diabetes (P < 0.001). Postprandial TG (P < 0.01) and TG/HDLc (P < 0.01) showed a stronger correlation with HbA1c compared to fasting TG (P < 0.05) and TG/HDLc (P > 0.05). The prevalence of dyslipidemia and insulin resistance was higher in postprandial state than the fasting state in prediabetes and diabetes.Conclusions:Postprandial TG and the TG/HDLc reflect lipid abnormalities than the corresponding fasting variables in diabetes and prediabetes. Postprandial TG and TG/HDLc are better reflectors of cardiovascular status in prediabetes and diabetes.

In-silico and in-vitro analysis of endocan interaction with statins

Endocan known as a cardiovascular inflammatory biomarker, found to be elevated in atherosclerosis. However, the 3D structure and the stimulatory effect of endocan on macrophages are unknown. Hence, we predicted the three-dimensional structure of human endocan and calculated the binding efficiency of statins towards endocan and determined their inhibition potential. Molecular docking studies of simvastatin (−9.64 kcal/mol) showed that binding is stabilized by the hydrogen bonds with Cys60, Cys54 residues, and several hydrophobic interactions. Moreover, MD simulations and pull-down assay results confirmed that simvastatin binding is stable with human endocan. In-silico results obtained in the present study were validated under in-vitro condition by analysing the effect of endocan under simvastatin treatment. Western blot results have shown that simvastatin could reduce endocan expression in LPS-treated endothelial cells. Further, endocan treatment in RAW 264.7 macrophages stimulates NO, ROS production and increases iNOS, CRP expression. However, endocan and simvastatin combination treatment could suppress NO, ROS production and iNOS, CRP activation. The present study results suggest that endocan could induce vascular inflammation in macrophages. In addition, the results showed that simvastatin could interact with endocan and thereby suppress the stimuli-induced effect. Thus, endocan may play a role in atherogenesis by activating macrophages.