Diabetes Coronary Artery Disease Research Articles

Intermedin attenuates macrophage phagocytosis via regulation of the long noncoding RNA Dnm3os/miR-27b-3p/SLAMF7 axis in a mouse model of atherosclerosis in diabetes

Atherosclerosis in diabetes is a leading cause of cardiovascular complications. Intermedin (IMD) is a calcitonin peptide that is known to inhibit macrophage phagocytosis in atherosclerosis, but the exact mechanism is unclear. We investigate genes that are differentially expressed in response to IMD in hyperglycemic conditions and determine whether they delay the progression of atherosclerosis. An atherosclerotic and diabetic-murine model was generated in 8-week-old male ApoE−/− mice receiving streptozotocin and a high-fat diet. The mouse model was treated with IMD and the expression levels of NF-κB, Dnm3os, miR-27b-3p, and SLAMF7 were detected in plaque tissue and macrophages cultured with high glucose concentrations. Phagocytosis was determined by oxidized-low-density lipoprotein (Ox-LDL) uptake and the interactions among Dnm3os, SLAMF7 and miR-27b-3p were assessed by dual-luciferase reporter assays. The expression of NF-κB, Dnm3os, and SLAMF7 was enhanced in atherosclerotic plaques but decreased by IMD. The suppression of Dnm3os reduced plaque formation in IMD-treated mice even further whereas increased by miR-27b-3p. Dnm3os and SLAMF7 were competitively bind to miR-27b-3p in vivo. In vitro, ox-LDL uptake is elevated in macrophages cultured in hyperglycemic conditions but reduced by IMD. Dual-luciferase assays indicate that Dnm3os positively regulates SLAMF7 through miR-27b-3p expression. In conclusion, Dnm3os is involved in macrophage phagocytosis through the competitive binding of SLAMF7 with miR-27b-3p. IMD induces the suppression of Dnm3os to inhibit macrophage phagocytosis and alleviate atherosclerosis in diabetes.

Disturbed Lipid Metabolism in Diabetic Patients with Manifest Coronary Artery Disease Is Associated with Enhanced Inflammation.

Background: Diabetic vasculopathy plays an important role in the pathophysiology of coronary artery disease (CAD) with oxidative stress as a strong mediator. This study aims to elucidate the underlying pathomechanisms of diabetic cardiac vasculopathy leading to coronary disease with an emphasis on the role of oxidative stress. Therefore, novel insights into antioxidant pathways might contribute to new strategies in the treatment and prevention of diabetic CAD. Methods: In 20 patients with insulin-dependent or non-insulin dependent diabetes mellitus (IDDM/NIDDM) and 39 non-diabetic (CTR) patients, myocardial markers of oxidative stress, vasoactive proteins, endothelial nitric oxide synthase (eNOS), activated phosphorylated eNOS (p-eNOS), and antioxidant enzymes, e.g., tetrahydrobiopterin generating dihydrofolate reductase (DHFR), heme oxygenase (HO-1), as well as serum markers of inflammation, e.g., E-selectin, interleukin-6 (IL-6), and lipid metabolism, e.g., high- and low-density lipoptrotein (HDL- and LDL-cholesterol) were determined in specimens of right atrial tissue and in blood samples from type 2 diabetic and non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery. Results: IDDM/NIDDM increased markers of inflammation (e.g., E-selectin, p = 0.005 and IL-6, p = 0.051), decreased the phosphorylated myocardial p-eNOS (p = 0.032), upregulated the myocardial stress response protein HO-1 (p = 0.018), and enhanced the serum LDL-/HDL-cholesterol ratio (p = 0.019). However, the oxidative stress markers in the myocardium and the expression of vasoactive proteins (eNOS, DHFR) showed only marginal adverse changes in patients with IDDM/NIDDM. Conclusion: Dyslipidemia and myocardial inflammation seem to be the major determinants of diabetic CAD complications. Dysregulation in pro-oxidative enzymes might be attributable to the severity of CAD and oxidative stress levels in all included patients undergoing CABG.

Lean or obese, the epicardial fat thickness is increased in diabetics of south India – is it a south Indian paradox?

Abstract Type 2 Diabetes Mellitus (T2DM) is considered a Coronary Artery Disease (CAD) risk equivalent (1) Increased epicardial fat (EFT) thickness is one hypothesis contributing to the disproportionate CV morbidity and mortality in T2DM (2). Studies have shown, EFT was higher in patients T2DM and high BMI compared to the non diabetic group. (3). The aim of our study was to determine if T2DM patients had an increased EFT thickness even when their BMI was normal or low and whether there was a relation between the T2DM duration and the EFT thickness. Study cohort consisted of 260 patients, who underwent coronary angiography (CAG) for suspected CAD. All patients underwent detailed history, examination, routine biochemistry, HBA1c, Anthropometric measurements such as weight, height, waist circumference and BMI. Transthoracic ECHO assessment of EFT was done one day prior to CAG using the ECHO unit with a 3.6MHz transducer. The EFT thickness was measured as the echo-free space between the myocardium and visceral pericardium on the right ventricular free wall in end-systole in the parasternal long and short-axis views for 3 cardiac cycles. CAG was performed in the fasting state, using the Judkins' technique, by the femoral or radial artery approach. The severity of CAD was assessed by modified Gensini scoring system. The collected data were analysed with IBM.SPSS statistics software. Of the 260 patients 90 (73.1%) were males and 70 (26.9%) were females. In this study, the average value for normal EFT was 5.2mm in the control group (HBA1c <7) and anything more than 6 was taken as abnormal. Patients were divided into 4 groups based on their HbA1c levels viz Group A (HbA1c <7), Group B (HbA1c 7–9), Group C (HbA1c 9.1–12) and Group D (HbA1c >12). The EFT increased with increasing HbA1c levels and the correlation was statistically significant P value 0.0005. There was no gender differences in EFT in our study. EFT was higher when the T2DM duration was >5 yrs which was statistically significant. p value 0.0005 (Table 1). There have been no reports of the correlation between the duration of DM and EFT in literature to the best of our knowledge.There was a strong correlation between HbA1c and EFT and the severity of the coronary lesions which was statistically significant. There was no correlation between the BMI and EFT or CAD (Figure 1) and the EFT was increased even in non obese diabetics. This may be due to the fact that EFT is a part of visceral obesity whereas BMI is a measure of generalised obesity. Our study showed a linear correlation between EFT thickness, HBA1c, duration of T2DM irrespective of BMI values confirming the recent thinking that regional fat depots such as EFT are of greater importance as a CAD risk factor than overall adiposity as was previously considered. ECHO measured EFT can be used to raise the clinical suspicion of CAD in asymptomatic diabetics and being non invasive can also be used for followup. Funding Acknowledgement Type of funding sources: None. Table 1. Relation of T2DM duration with EFTFigure 1. Relation of BMI to EFT

The association between diabetes and mortality in young adults presenting with myocardial infarction

Abstract Background The incidence of diabetes mellitus and coronary artery disease continue to rise and collectively comprise two of the most prevalent and costly diseases worldwide. The goal of this study is to report the prognosis of young patients with diabetes presented with acute myocardial infarction (AMI). Methods This is a retrospective observational cohort study that included consecutive patients aged 18–45 years who underwent cardiac catheterization for AMI between 2006 and 2016 in an integrated healthcare system in Southern California. The prognosis of patients with diabetes were compared to those without diabetes. Results A total of 1,560 patients (average age 40.2±5.3 years, 25.6% female) presenting with AMI were included. Of these 272 (17.4%) had diabetes. Diabetics were older (41.1±4.4 vs 40.0±5.4 years), more likely to be female (32.4% vs 24.1%, p=0.006), Hispanic (51.5% vs 40.5%, p<0.001), have a higher body mass index (BMI) (33.6±7.1 vs 31.2±6.8kg/m2, p<0.001), have hypertension (HTN) (67.6% vs 23.8%, p<0.001), hyperlipidemia (HLD) (78.3% vs 24.1%, p<0.001), peripheral vascular disease (9.9% vs 1.9%, p<0.001), chronic kidney disease (CKD) (23.2% vs 2.7%, p<0.001), hypothyroidism (7% vs 4%, p=0.034), and prior strokes (4.4% vs 2.2%, p=0.034). On multivariate analysis accounting for other cardiovascular risk factors, the association remained significant (OR 1.82, 95% CI 1.04–3.19, p=0.036). At a median follow-up of 5.8 years (interquartile range 3.7–8.7 years), diabetes was independently associated with increased all-cause mortality (Hazard ratio [HR] 3.10, 95% CI 1.68–5.69, p<0.001) when adjusting for age, sex, race, BMI, HTN, HLD, CKD, hypothyroidism, prior stroke, and ACS etiology. In a propensity score matched cohort, diabetes remained significantly associated with all-cause mortality (HR 5.29, 95% CI 2.34–12.02, p<0.001). Conclusion Diabetes is an independent predictor of increased mortality in young adults <45 years old presenting with AMI. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): KAISER PERMANENTE LOS ANGELES MEDICAL CENTER

Quantification of epicardial fat with cardiac CT and association with cardiovascular risk factors and obstructive coronary disease

Abstract Introduction Recent studies advocate epicardial fat (EF) as a biologically active organ that influence coronary atherosclerosis development through endocrine and paracrine pathways. We aim to study the relations between EF, thoracic adipose tissue (TAT), cardiovascular risk factors (CRF) and obstructive coronary disease (OCD). Methods Retrospective analysis of patients (pts) referred to 64-multislice cardiac computed tomography (CT) in one center. The authors underwent a standardized protocol for quantification of EAT, TAT (subcutaneous and visceral), abdominal visceral fat, coronary calcium score and angiography. Results Total of 178 pts: male 99 (56%), mean age 65.9±12.9 years. Indications for performing CT were coronary disease (76%), valvular heart disease (15%), atrial fibrillation (6%) and congenital heart disease (2%). Regarding CRF, EF was only significant higher in patients with diabetes (115±60 vs 95±47, p=0.018), in male gender (114±60 vs 91±42, p=0.04) and was linear correlated with age (p=0.004). The authors also found that EF volume is significant higher in patients with typical angina (p=0.02) and with coronary atherosclerosis: non-obstructive (p=0.0049) and OCD (p=0.001) – Graphic 1. ROC analysis of EF (AUC 0.659, p=0.0039) and EF/TAT relation (AUC 0.704, p=0.003) allowed to estimate that EF>100 ml and EF/TAT >0.06 had a sensibility to predict OCD of 53% and 58%, respectively, and specificity of 66% and 60%. We did not find a correlation between EF, EF/TAT or TAT and coronary calcium score. Conclusion EF is higher in patients with diabetes and coronary atherosclerosis. EF and EF/TAT relation had moderate sensibility and specificity to predict OCD, irrespective of calcium score. EF and EF/TAT are promising atherosclerotic markers that could be routinely use in the near future. Funding Acknowledgement Type of funding sources: None.

Diet and nutritional behaviors in patients with psoriasis: A cross-sectional study

To the Editor: Connections between diet and skin disease have long piqued the interest of patients and physicians.1,2 While traditionally, acne has been the focus, there has been a recent turn toward psoriasis,3 connected to multiple comorbidities, including diabetes mellitus, atherosclerosis, and obesity.2,4 As a result, patients with psoriasis may express interest in dietary interventions to improve their skin and associated diseases.3,5 This study aimed to assess which dietary interventions and supplements are popular among patients with psoriasis and may lead to improved psoriasis.

HMOX1 upregulation promotes ferroptosis in diabetic atherosclerosis

ObjectiveAtherosclerotic vascular disease remains the principal cause of death and disability among patients with type 2 diabetes. Unfortunately, the problem is not adequately resolved by therapeutic strategies with currently available drugs or approaches that solely focus on optimal glycemic control. To identify the key contributors and better understand the mechanism of diabetic atherosclerotic vascular disease, we aimed to elucidate the key genetic characteristics and pathological pathways in atherosclerotic vascular disease through nonbiased bioinformatics analysis and subsequent experimental demonstration and exploration in diabetic atherosclerotic vascular disease. Methods and resultsSixty-eight upregulated and 23 downregulated genes were identified from the analysis of gene expression profiles (GSE30169 and GSE6584). A comprehensive bioinformatic assay further identified that ferroptosis, a new type of programmed cell death and HMOX1 (a gene that encodes heme oxygenase), were vital factors in atherosclerotic vascular disease. We further demonstrated that diabetes significantly increased ferroptosis and HMOX1 levels compared to normal controls. Importantly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated diabetic atherosclerosis, suggesting the causative role of ferroptosis in diabetic atherosclerosis development. At the cellular level, Fer-1 ameliorated high glucose high lipid-induced lipid peroxidation and downregulated ROS production. More importantly, HMOX1 knockdown attenuated Fe2+ overload, reduced iron content and ROS, and alleviated lipid peroxidation, which led to a reduction in ferroptosis in diabetic human endothelial cells. ConclusionsWe demonstrated that HMOX1 upregulation is responsible for the increased ferroptosis in diabetic atherosclerosis development, suggesting that HMOX1 may serve as a potential therapeutic or drug development target for diabetic atherosclerosis.

Abstract P346: Ferroptosis Is Critical In Diabetic Atherosclerosis Through Heme Oxygenase 1 Regulated Lipid Peroxidation Pathway

Introduction: The patients with diabetes dramatically accelerates atherosclerosis. Although improved diabetes treatment strategy has prevented the pathogenesis, diabetic atherosclerosis is still the main cause of morbidity and mortality. It is urgent to clarify its in-depth mechanism and identify new therapeutic targets for preventing diabetic atherosclerosis. Hypothesis: We assessed the hypothesis that ferroptosis and HMOX1 may be implicated in diabetes atherosclerosis through comprehensive in-depth bioinformatics analysis. Methods and Results: Analysis of Gene expression profiles (GSE30169 and GSE6584) provided a total of 91 differentially expressed genes (DEGs) including 68 up-regulated and 23 down-regulated genes (A). Ferroptosis, a type of programmed cell death dependent on iron, and HMOX1, a gene that encodes heme oxygenase, were identified as key factors in diabetes atherosclerosis (B). To explore the potential mechanism, we measured iron content and reactive oxygen species (ROS) generation and conducted a lipid peroxidation assay. Compared with animals on a normal diet (ND), ferroptosis and HMOX1 expression in ApoE -/- mice on high-fat diet (HFD) were significantly increased (C, n = 3). Ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated the diabetic atherosclerosis area in HFD animals (D, n = 5, P < 0.01 vs HFD). In addition, Fer-1 restored the ferroptosis-related protein (GPX4 and SLC7A11) with high glucose high lipid (HGHL) treatment in Mouse arterial endothelial cells (MAECs) (E, n=6). More importantly, HMOX1 deficiency rebalanced Fe 2+ overload, decreased iron content, reduced ROS, and alleviated the lipid peroxidation, which led to the reduction of ferroptosis in diabetic endothelial cells (F). Conclusions: We demonstrate that ferroptosis is critical in diabetic AS progression and HMOX1 is an implicated factor responsible for ferroptosis in diabetic AS development, suggesting HMOX1 may serve as a potential therapeutic or drug development target.

Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus.

Gycyrrhizic acid (GA), an inhibitor of high mobility group box 1 (HMGB1), inhibits inflammatory responses and is involved in the occurrence and development of several inflammation-related diseases. However, the role of GA in the atherosclerotic lesions caused by diabetes mellitus (DM) remains unknown. In the present study, Sprague Dawley rats were selected to desi=gn a diabetic atherosclerosis (AS) model. Rats from the DM-AS group were subsequently divided into DM-AS, DM-AS + GA (50 mg/kg) and DM-AS + GA (150 mg/kg) groups. Biochemical analyzers were used to measure levels of blood glucose, fasting insulin, total cholesterol, total triglyceride, low-density lipoprotein and high-density lipoprotein. The number of plaques was recorded after collection of thoracic aortas from the rats. The intimal thickness of arterial tissue was detected by hematoxylin and eosin staining. The expression levels of CD68 and α-smooth muscle actin (α-SMA) were detected by immunohistochemistry. The expression of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β in the serum of the rats was detected by ELISA. The expression of fatty acid synthetase, sterol regulatory element binding protein 1C, HMGB1 and receptor for advanced glycation end products (RAGE) was detected by western blotting. Reverse transcription quantitative PCR was used to detect the mRNA expression of HMGB1 and RAGE. The results demonstrated that GA treatment could decrease the body weight, blood glucose level and biochemical parameters of AS DM rats in a dose-dependent manner. In addition, GA decreased the intimal thickness of carotid artery and the formation of plaque in rats with diabetic AS. Furthermore, GA inhibited macrophage activation and decreased α-SMA expression in vascular smooth muscle cells, and decreased the expression of proteins (FAS and SREBP-1c) and inflammatory factors. Taken together, the findings from the present study demonstrated that GA may have a therapeutic effect on DM-associated AS. This study provides a theoretical basis for the treatment of diabetic AS.

Перспективи використання ресвератролу для лікування цукрового діабету та його ускладнень

Ресвератрол характеризується широким спектром фармакологічних ефектів і має множинну біологічну активність щодо хронічних захворювань, як протизапальний, протипухлинний, антидіабетичний, нейро- і кардіопротекторний засіб. Ресвератрол здійснює позитивний ефект при цукровому діабеті (ЦД) та діабетичних ускладненнях судин, що обумовлено його здатністю посилювати опосередковану оксидом азоту вазодилатацію. Продукти, багаті на ресвератрол, надають захисний ефект при таких вікових захворюваннях, як ЦД 2-го типу, атеросклероз, рак, артрит, катаракта, остеопороз, артеріальна гіпертензія і хвороба Альцгеймера. Ефекти ресвератролу свідчать про його перспективність як дієтичної добавки, що дозволяє поліпшити стан хворих на тяжкі хронічні захворювання, а також для профілактики цих захворювань у здорових людей і уповільнення процесів старіння.

Left Main Coronary Artery Disease in Diabetics: Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting?

The choice between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for myocardial revascularization in patients with left main disease (LMD) is controversial. There is general agreement that CABG is appropriate for all patients, and PCI is acceptable for those with low-to-intermediate anatomic complexity. However, there is uncertainty about the relative safety and efficacy of PCI in patients with more complex LMD and with comorbidities such as diabetes. No direct comparison trial has focused on revascularization in diabetic patients with LMD, and thus conclusions on the topic are subject to the limitations of subgroup analysis, as well as the heterogeneous exclusion criteria, and methodologies of individual trials. The available evidence suggests that among diabetics, CABG is superior in patients with LMD with SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and dardiac surgery) score greater than 33, distal bifurcation disease, or multivessel disease. PCI may be appropriate in those with less-extensive disease or those with limited life expectancy or high surgical risk.

Skin advanced glycation end products as a diagnostic and monitoring tool among psoriatic patients: how the therapy helps reduce cardiovascular disease risk.

Psoriasis is a disturbing and burdensome inflammatory skin disorder, with a global prevalence of 2-3%. An increased risk of cardiometabolic disease between psoriatic patients has been recently demonstrated. This is probably due to the psoriasis systemic inflammation and the increased levels of inflammatory cytokines, such as IL-17, IL-23, and TNF-α. Advanced glycation end products (AGEs) are the products of nonenzymatic glycation and oxidation of proteins and lipids which modify their structure and function. They have a significant role in the pathogenesis of diabetic nephropathy, atherosclerosis, and cardiovascular diseases of diabetic adults and children. The accumulation of AGEs can be measured by skin autofluorescence (SAF). Adalimumab (Humira ®) is a fully human monoclonal antibody, administered via subcutaneous injection, which binds the tumor necrosis factor (TNF) and is used to treat moderate-to-severe chronic plaque psoriasis. We performed an observational prospective study of 24 weeks to assess the reduction of AGEs through SAF measurement during treatment with adalimumab. SAF measurements in patients were performed at T0 and after 24 weeks of therapy. Adalimumab efficacy was assessed using Psoriasis Area and Severity Index (PASI), Visual Analogue Scale (VAS) for pain, and erythrocyte sedimentation rate (ESR). ESR, AGEs, PASI, and VAS for pain decreased throughout the study period. Adalimumab reduced AGEs in psoriatic patients. Biologic therapies may also prevent cardiovascular disease, suggesting a new approach of combined therapy for psoriasis and cardiovascular diseases.

Well-posedness of a mathematical model of diabetic atherosclerosis

Atherosclerosis is a leading cause of death in the United States and worldwide; it emerges as a result of multiple dynamical cell processes including hemodynamics, endothelial damage, innate immunity and sterol biochemistry. Making matters worse, nearly 21 million Americans have diabetes, a disease where patients' cells cannot efficiently take in dietary sugar, causing it to build up in the blood. In part because diabetes increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke. Past work has shown that hyperglycemia and insulin resistance alter function of multiple cell types, including endothelium, smooth muscle cells and platelets, indicating the extent of vascular disarray in this disease. Although the pathophysiology of diabetic vascular disease is generally understood, there is no mathematical model to date that includes the effect of diabetes on plaque growth. In this paper, we propose a mathematical model for diabetic atherosclerosis; the model is given by a system of partial differential equations with a free boundary. We establish local existence and uniqueness of solution to the model. The methodology is to use Hanzawa transformation to reduce the free boundary to a fixed boundary and reduce the system of partial differential equations to an abstract evolution equation in Banach spaces, and apply the theory of analytic semigroup.

Rosmarinic Acid Increases Macrophage Cholesterol Efflux through Regulation of ABCA1 and ABCG1 in Different Mechanisms.

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.

Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Placenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

Caspase-3-mediated GSDME induced Pyroptosis in breast cancer cells through the ROS/JNK signalling pathway.

Pyroptosis is a new form of programmed cell death generated by some inflammasomes, piloting the cleavage of gasdermin (GSDM) and stimulation of dormant cytokines like IL‐18 and IL‐1β; these reactions are narrowly linked to certain diseases like diabetic nephropathy and atherosclerosis. Doxorubicin, a typical anthracycline, and famous anticancer drug has emerged as a prominent medication in several cancer chemotherapies, although its application is accompanied with expending of dose‐dependent, increasing, irreversible and continuing cardiotoxic side effects. However, the exact path that links the induced pyroptosis to the mechanism by which Doxorubicin (DOX) acts against breast cancer cells is still puzzling. The present study seeks to elucidate the potential link between DOX‐induced cell death and pyroptosis in two human breast cancer cell lines (MDA‐MB‐231 and T47D). We proved that treatment with DOX reduced the cell viability in a dose‐dependent way and induced pyroptosis morphology in MDA‐MB‐231 and T47D cells. Also, protein expression analyses revealed GSDME as a key regulator in DOX‐induced pyroptosis and highlighted the related role of Caspase‐3 activation. Furthermore, DOX treatments induced intracellular accumulation of ROS, stimulated the phosphorylation of JNK, and Caspase‐3 activation, subsequently. In conclusion, the study suggests that GSDME triggered DOX‐induced pyroptosis in the caspase‐3 dependent reactions through the ROS/JNK signalling pathway. Additionally, it showed that the DOX‐induced cardiotoxicity and pyroptosis in breast cancer cells can be minimized by reducing the protein level of GSDME; thus, these outcomes provide a new research target and implications for the anticancer investigations and therapeutic applications.

Association between a family history of diabetes and carotid artery atherosclerosis in Korean adults.

OBJECTIVESDiabetes is a well-known risk factor for atherosclerosis, but the association between a family history of diabetes and atherosclerosis remains unknown. In this study, we assessed the association between a family history of diabetes and increased carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, in a middle-aged Korean population.METHODSThis cross-sectional study included 3,974 community-dwelling adults (1,404 male and 2,570 female) aged 30-64 years from the Cardiovascular and Metabolic Diseases Etiology Research Center cohort. The presence of a family history of diabetes was assessed through face-to-face interviews using a standardized questionnaire. Carotid IMT was assessed using B-mode ultrasonography, and increased IMT was defined as a value in the top quartile of the IMT values of all participants. Multivariate logistic regression was used to evaluate independent associations between a family history of diabetes and increased IMT.RESULTSA family history of diabetes was significantly associated with increased carotid IMT (odds ratio, 1.23; 95% confidence interval, 1.03 to 1.48) after adjusting for sex; age; body mass index; systolic blood pressure; total cholesterol, triglyceride, and hemoglobin A1c levels; smoking; alcohol consumption; exercise; use of antidiabetic, antihypertensive, and antilipidemic drugs; and a family history of hypertension. The positive association remained significant after excluding participants with diabetes (odds ratio, 1.21; 95% confidence interval, 1.00 to 1.47).CONCLUSIONSA family history of diabetes was positively associated with increased carotid IMT, even in participants without diabetes. Therefore, information on a family history of diabetes may help identify individuals at high risk of atherosclerotic cardiovascular disease.

Elevated levels of resistin are associated with prothrombotic state in coronary artery disease

Background and Aims: Resistin has been linked to obesity, type 2 diabetes mellitus, inflammation and atherosclerosis. The purpose of this study was to examine the relationship between resistin and prothrombotic factors in patients with coronary artery disease (CAD).

Myocardial Ischemia and Diabetes Mellitus. Approaches and Recommendation

The outlook epidemiological auguring an increase considerable the number of sub-jects with diabetes and cardiological problem during diabetes, and the recent prog-ress registered in the explorations and the treatment of coronary are necessary for to continue research. Since long been recognized as a factor of risk vascular age, the diabetes can be regarded as a genuine vascular disease in because of the frequency and in the severity. The share growing, observed and expected, of the population of diabetics, whose prognosis life is dominated by the complication’s coronary up the diabetes mellitus among the priorities of health public in France. The specifi c features of diabetic coronary artery disease, marked by the often-insidious nature of its development, place silent myocardial ischemia (IMS) and possible atheromatous involvement of the epicardial coronary artery trunks at the center of the diagnostic and therapeutic approach. The progress, drug and instrumentals, the treatment of the inadequacy coronary lead naturally to reconsider the treatment, and therefore the screening early to IMS in the aim of reducing the morbidity and the mortality heart of patients with diabetes.

Predictive Value of the Triglyceride to High-Density Lipoprotein Cholesterol Ratio for All-Cause Mortality and Cardiovascular Death in Diabetic Patients With Coronary Artery Disease Treated With Statins.

Background and Aims: Studies have highlighted the role of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio on subsequent cardiovascular events. However, the association of the TG/HDL-C ratio with survival outcomes in diabetic patients with coronary artery disease (CAD) treated with statins remains unknown. This study aimed to assess the predictive value of the TG/HDL-C ratio for all-cause mortality and cardiovascular death in diabetic patients with CAD treated with statins.Methods: The data of patients with type 2 diabetes and angiographically-confirmed CAD who were undergoing statin therapy and visited Tianjin Chest Hospital between January 2016 and September 2016 were retrospectively collected. The patients were categorized based on the baseline TG/HDL-C ratio tertile. Kaplan-Meier analysis and multivariate Cox proportional hazard regression were applied to assess the role of the TG/HDL-C ratio in predicting all-cause mortality and cardiovascular death.Results: A total of 2,080 patients were included. During the 4-year follow-up, 209 patients died, 136 of whom from cardiovascular death. The Kaplan-Meier analyses showed that an increased TG/HDL-C ratio was associated with an increased risk of all-cause mortality (P < 0.001) and cardiovascular death (P < 0.001). The multivariate cox hazard regression analysis revealed a similar effect of the TG/HDL-C ratio on the risk of all-cause mortality (P = 0.046) and cardiovascular death (P = 0.009). The role of the TG/HDL-C ratio in predicting all-cause mortality and cardiovascular death was similar among all subgroups (P > 0.050). For all-cause mortality, the TG/HDL-C ratio significantly improved the C-statistic from 0.799 to 0.812 (P = 0.018), and the net reclassification index (NRI) and integrated discrimination index (IDI) were 0.252 (95% CI: 0.112–0.392; P < 0.001) and 0.012 (95% CI: 0.003–0.022; P = 0.012), respectively. Similarly, for cardiovascular death, the TG/HDL-C ratio significantly improved the C-statistic from 0.771 to 0.804 (P < 0.001), and the NRI and IDI were 0.508 (95% CI: 0.335–0.680; P < 0.001) and 0.033 (95% CI: 0.015–0.050; P < 0.001).Conclusion: TG/HDL-C ratio might be useful for predicting all-cause mortality and cardiovascular death in diabetic patients with CAD treated with statins.