Do T2DM and Hyperglycaemia Affect the Expression Levels of the Regulating Enzymes of Cellular O-GlcNAcylation in Human Saphenous Vein Smooth Muscle Cells?

Protein O-GlcNAcylation, a dynamic and reversible glucose-dependent post-translational modification of serine and threonine residues on target proteins, has been proposed to promote vascular smooth muscle cell proliferation and migration events implicated in vein graft failure (VGF). Therefore, targeting the enzymes (glutamine fructose-6P amidotransferase (GFAT), O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA)) that regulate cellular O-GlcNAcylation could offer therapeutic options to reduce neointimal hyperplasia and venous stenosis responsible for VGF. However, it is unclear how type 2 diabetes mellitus (T2DM) and hyperglycaemia affect the expression of these enzymes in human saphenous vein smooth muscle cells (HSVSMCs), a key cell type involved in the vascular dysfunction responsible for saphenous VGF. Therefore, our aim was to assess whether T2DM and hyperglycaemia affect GFAT, OGT, and OGA expression levels in HSVSMCs in vitro. Expression levels of GFAT, OGT, and OGA were determined in low-passage HSVSMCs from T2DM and non-T2DM patients, and in HSVSMCs treated for 48 h with hyperglycaemic (10 mM and 25 mM) glucose concentrations, by quantitative immunoblotting. Expression levels of OGT, OGA, and GFAT were not significantly different in HSVSMC lysates from T2DM patients versus non-T2DM controls. In addition, treatment with high glucose concentrations (10 mM and 25 mM) had no significant effect on the protein levels of these enzymes in HSVSMC lysates. From our findings, T2DM and hyperglycaemia do not significantly impact the expression levels of the O-GlcNAcylation-regulating enzymes OGT, OGA, and GFAT in HSVSMCs. This study provides a foundation for future studies to assess the role of O-GlcNAcylation on VGF in T2DM

The effect of atorvastatin (and subsequent metformin) on adipose tissue acylation-stimulatory-protein concentration and inflammatory biomarkers in overweight/obese women with polycystic ovary syndrome

Copyright © 2019 Sathyapalan, Hobkirk, Javed, Carroll, Coady, Pemberton, Smith, Cianflone and Atkin. Background: Atorvastatin has been shown to improve cardiovascular risk (CVR) indices in women with polycystic ovary syndrome (PCOS). Low-grade chronic inflammation of adipose tissue may link PCOS and adverse CVR. In pro-inflammatory states such as PCOS, spontaneous activation of the alternative pathway of complement results in increased generation of acylation stimulating protein (ASP) from adipocytes irrespective of body mass index. Methods: The objective of this study was to determine the effect of atorvastatin on markers of adipose tissue dysfunction and inflammation; acylation-stimulating-protein (ASP), interleukin-6 (IL-6), and monocyte-chemoattractant-protein-1 (MCP-1) in PCOS. This was a randomized, double-blind, placebo-controlled study where 40 medication-naive women with PCOS and biochemical hyperandrogenaemia were randomized to either atorvastatin 20 mg daily or placebo for 12 weeks. Following the 12 week randomization; both group of women with PCOS were subsequently started on metformin 1,500 mg daily for further 12 weeks to assess whether pre-treatment with atorvastatin potentiates the effects of metformin on markers of adipose tissue function We conducted a post-hoc review to detect plasma ASP and the pro-inflammatory cytokines IL6 and MCP-1 before and after 12 and 24 weeks of treatment. Results: There was significant reduction in ASP (156.7 ± 16.2 vs. 124.4 ± 14.8 ng/ml

The clinical and lifestyle determinants of serum HDL-c, apolipoprotein A-1, paraoxonase-1 activity and oxidised LDL in healthy, medication naive middle-aged adults.

Introduction: HDL cholesterol may underestimate the anti-oxidative potential of HDL. HDL anti-oxidative potential is mediated by PON-1, which metabolises lipid peroxides and impacts on oxidised LDL (ox-LDL) concentrations. We sought to investigate the determinants of HDL-c, apo A-I and PON-1 activity and to ascertain whether HDL-c, apo A-I, PON-1 activity could explain the variance of ox-LDL concentrations in a sub-group of high PON-1 activity (n=22) >230 or low (n=22) <63 nmol/min/ml participants. Methods: 221 (72% male) participants were assessed during health assessments at Nuffield Health Medical Centre in Manchester. Participants avoided vigorous physical activity and alcohol 24 hours prior to assessment. Lifestyle factors including smoking status, alcohol intake and physical activity and cardio-respiratory fitness were assesssed. Participants with CVD or T2D were excluded. Fasting blood was taken to measure HDL-c, PON-1 activity, apo AI and ox-LDL and other blood variables. Correlations and regression analysis assessed inter-relationships and determinants of HDL-c, apo A-1, PON-1 activity and ox-LDL. Regression models included age, sex, waist, TG, alcohol, physical activity, fitness, hs-CRP and QRISK. Results: The correlation between PON-1 activity and HDL-c (r=0.12), apo A-I (r=0.11) were non-significant. Waist circumference, TG, alcohol intake, sex and fitness were predictors of HDL-c, accounting for 40.3% of the variance. Waist circumference, TG and alcohol predicted apo A-I concentrations, accounting for 13.1% of the variance. None of the variables measured predicted PON-1 activity. Ox-LDL was not significantly correlated with HDL-c (r=0-.19) apo A-I (r=-0.20) or PON-1 activity (r=0.09) but was to TG (r=0.69, p<0.001). Furthermore, TG (52%), hs-CRP (7.4%) and age (6.6%) accounted for 66% of the variance in ox-LDL. Discussion: PON-1 activity did not correlate with any clinical or lifestyle variables. Concentrations of ox-LDL were strongly related to TG concentrations. Lifestyle factors that regulate TG metabolism are an important therapy to decrease highly atherogenic ox-LDL particles

Effects of reducing inspired oxygen concentration for one hour in patients with chronic heart failure: implications for air travel

AimsThe objective of this study was to establish the acute effects of hypoxia on clinical, spirometric, haemodynamic, and echocardiographic variables. Reducing inspired oxygen to 15%, as experienced during commercial air travel, decreases arterial oxygen saturation, increases respiratory rate and pulmonary artery pressure in healthy subjects. The effect on patients with chronic heart failure is unknown.Methods and resultsSeventy-two patients with chronic heart failure and an LVEF < 40%, in NYHA functional class II (74%) or III (26%), on stable treatment were studied and compared with 18 age-matched controls (65 ± 11 vs. 62 ± 12 years, respectively). Clinical, spirometric, haemodynamic, and echocardiographic measurements were performed in patients and controls before and after one hour inspiring 15% oxygen. Inspired 15% oxygen for 1 h was tolerated in all subjects and caused no worsening of symptoms. Arterial oxygen saturation decreased to a similar extent in patients (from 97 ± 2% to 86 ± 4%) and controls (from 97 ± 2% to 86 ± 3%). Mean arterial pressure increased from 81 ± 13 mmHg to 87 ± 12 mmHg in patients, but did not change in controls. There was no effect on heart rate, but systolic pulmonary artery pressure rose from 30.2 ± 14.0mmHg to 34.0 ± 15.2 mmHg in patients, and from 22.4 ± 5.5 mmHg to 24.1 ± 6.9 mmHg in controls.ConclusionsInspiring 15% oxygen was tolerated and caused no worsening of symptoms despite reductions in arterial oxygen saturation and increases in mean arterial pressure and systolic pulmonary artery pressure. All rights reserved. © 2013 The Author

The predictive ability of triglycerides and waist (hypertriglyceridemic waist) in assessing metabolic triad change in obese children and adolescents.

BACKGROUND: The metabolic triad [fasting insulin, apolipoprotein B, and low-density lipoporotein (LDL) peak particle density] is characteristic of increased intra-abdominal adipose tissue and insulin resistance and can be predicted by the simple and adoptable screening tool, the hypertriglyceridemic waist. The associations between hypertriglyceridemic waist components [fasting triglycerides (TG) and waist circumference cut-points derived from a child-specific metabolic syndrome definition] with the metabolic triad were examined in obese youth before and after weight loss. METHODS: A continuous metabolic triad score (MTS) was calculated as a cumulative and standardized residual score of fasting insulin, apolipoprotein B, and LDL peak particle density (z-scores of the metabolic triad variables regressed onto age and sex). The predictive ability of TG and waist in assessing metabolic triad change was undertaken in 75 clinically obese boys and girls, aged 8-18, body mass index (BMI) 34.2±6.4 kg/m(2) before and after weight loss. RESULTS: Fasting TG concentrations (r(2)=0.216, P<0.0001) and waist circumference (r(2)=0.049, P=0.019) were both significant independent predictors of the cumulative MTS, together accounting for 26.5% of its total variance. All cardiometabolic risk factors [except a reduction in high-density lipoprotein cholesterol (HDL-C)] were favorably modified following weight loss. Fasting TG change was the only significant predictor of the MTS change (r(2)=0.177, P<0.0001). Waist circumference was not a significant predictor of MTS change. CONCLUSION: The reduction in fasting TG concentration (but not waist circumference) was the only significant predictor of MTS change. Fasting TG may be the most important metabolic syndrome component to best characterize the metabolic heterogeneity in obese cohorts and the changes in metabolic risk in clinically obese youth

Prevalence of, associations with, and prognostic value of Tricuspid Annular Plane Systolic Excursion (TAPSE) among out-patients referred for the evaluation of heart failure

Background: Prevalence, predictors, and prognostic value of right ventricular (RV) function measured by the tricuspid annular plane systolic excursion (TAPSE) in patients with chronic heart failure (CHF) symptoms with a broad range of left ventricular ejection fraction (LVEF) are unknown. Methods and Results: Of 1,547 patients, mean (±SD) age was 71 ± 11 years, 48% were women, median (interquartile range [IQR]) TAPSE was 18.5 (14.0–22.7) mm, mean LVEF was 47 ± 16%, 47% had LVEF ≤45% and 67% were diagnosed with CHF, defined as systolic (S-HF) if LVEF was ≤45% and as heart failure with preserved ejection fraction (HFPEF) if LVEF was &gt;45% and treated with a loop diuretic. During a median (IQR) follow-up of 63 (41–75) months, mortality was 34%. In multivariable analysis, increasing age, N-terminal pro–B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, right atrial volume index, and transtricuspid pressure gradient; lower TAPSE, diastolic blood pressure, and hemoglobin; and atrial fibrillation (AF) or COPD were associated with an adverse prognosis. Receiver operating characteristic curve analysis identified a TAPSE of 15.9 mm as the best prognostic threshold (P = .0001); 47% of S-HF and 20% of HFPEF had a TAPSE of &lt;15.9 mm. The main associations with a TAPSE &lt;15.9 mm were higher NT-proBNP, presence of atrial fibrillation and presence of LV systolic dysfunction. Conclusions: In patients with CHF, low values for TAPSE are common, especially in those with reduced LVEF. TAPSE, unlike LVEF, was an independent predictor of outcome

Prevalence of, associations with, and prognostic value of tricuspid annular plane systolic excursion (TAPSE) among out-patients referred for the evaluation of heart failure

Background: Prevalence, predictors, and prognostic value of right ventricular (RV) function measured by the tricuspid annular plane systolic excursion (TAPSE) in patients with chronic heart failure (CHF) symptoms with a broad range of left ventricular ejection fraction (LVEF) are unknown. Methods and Results: Of 1,547 patients, mean (±SD) age was 71 ± 11 years, 48% were women, median (interquartile range [IQR]) TAPSE was 18.5 (14.0-22.7) mm, mean LVEF was 47 ± 16%, 47% had LVEF ≤45% and 67% were diagnosed with CHF, defined as systolic (S-HF) if LVEF was ≤45% and as heart failure with preserved ejection fraction (HFPEF) if LVEF was > 45% and treated with a loop diuretic. During a median (IQR) follow-up of 63 (41-75) months, mortality was 34%. In multivariable analysis, increasing age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, right atrial volume index, and transtricuspid pressure gradient; lower TAPSE, diastolic blood pressure, and hemoglobin; and atrial fibrillation (AF) or COPD were associated with an adverse prognosis. Receiver operating characteristic curve analysis identified a TAPSE of 15.9 mm as the best prognostic threshold (P =.0001); 47% of S-HF and 20% of HFPEF had a TAPSE of < 15.9 mm. The main associations with a TAPSE < 15.9 mm were higher NT-proBNP, presence of atrial fibrillation and presence of LV systolic dysfunction. Conclusions: In patients with CHF, low values for TAPSE are common, especially in those with reduced LVEF. TAPSE, unlike LVEF, was an independent predictor of outcome. © 2012 Elsevier Inc. All rights reserved