Pathogenesis Of Endothelial Dysfunction Research Articles

Exploring trimethylamine n-oxide's role in coronary microvascular dysfunction and prognostic outcomes in ST-elevation myocardial infarction patients

Abstract Background Coronary microvascular dysfunction (CMD) subsequent to ST-elevation myocardial infarction (STEMI) is increasingly recognized as a determinant of adverse clinical prognoses. Despite its significance, CMD diagnosis is rare in clinical settings, mainly due to its complexity and technical challenges. Considering these challenges, this study endeavors to explore the diagnostic potential of Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbiota. TMAO has been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis, suggesting its utility as a novel biomarker for CMD and determining prognosis. Purpose To investigate the association between TMAO levels and CMD in STEMI patients, evaluating TMAO's utility as a biomarker for CMD and prognosis predictor. Methods In this prospective, observational study, 210 STEMI patients were enrolled. At the 3-month follow-up, these patients were subjected to comprehensive coronary physiology assessments, including measurements of coronary flow reserve (CFR), fractional flow reserve (FFR), and the index of microcirculatory resistance (IMR) via utilization of pressure-temperature sensor-tipped wires. CMD was diagnosed in patients presenting with an IMR ≥ 25 or a CFR < 2.0, alongside an FFR > 0.80. Levels of TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP), along with other traditional biomarkers were measured at baseline, 3 and 12-month follow-up. Using the Delong test and Youden index to find optimal TMAO cutoffs for CMD detection, due to no predefined TMAO threshold. The primary endpoint was the incidence of CMD at 3 months, with the secondary endpoint being major adverse cardiovascular and cerebrovascular events (MACCE) at 12 months. Results Among enrolled patients, 85 (40.5%) were female, with a median age of 65 (IQR: 58-76). TMAO's baseline receiver operating characteristic (ROC) curve area was 0.55 (95% CI: 0.46-0.64; p=0.426), improving to 0.80 (95% CI: 0.73-0.87; P<0.001) at 3-month follow-up. An optimal TMAO cutoff of 3.91 μM achieved 75% sensitivity (95% CI: 0.63-0.86) and 82% specificity (95% CI: 0.76-0.88), outperforming BNP and CRP with ROC areas of 0.62 and 0.67, respectively. Patients were divided into low (n=140) and high (n=70) TMAO groups at the 3.91 μM threshold. A higher percentage of females was noted in the high TMAO group (55.7% vs. 32.9%; p<0.001). Clinical characteristics and risk factors like stroke and CAD history showed no significant differences across TMAO groups. Multivariable logistic regression revealed TMAO levels at 3 months as an independent predictor for CMD. A cubic spline curve indicated a marked increase in CMD odds with TMAO between 3 and 6 μM.The Incidence of MACCE was significantly higher in patients with a TMAO≥3.91 (41.4% vs 10.7%; p < 0.001). Conclusion Elevated TMAO levels 3 months post-STEMI are significantly associated with increased CMD risk, and significantly predict MACCE.TMAO as a Biomarker for CMD and MACCETMAO Cubic Spline Analysis for CMD Odds

Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component.

Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.

Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus.

Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.

Neopterin in patients with COPD, asthma, and ACO: association with endothelial and lung functions

Background and objectiveEndothelial dysfunction has been widely recognized in chronic airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma; however, it remains unclear in asthma-COPD overlap (ACO). Neopterin (NP), a metabolite of guanosine triphosphate, is a novel biomarker for identifying the increased risk of adverse cardiovascular events. This study aims to investigate the association of NP with endothelial dysfunction and impaired lung function in COPD, asthma, and ACO patients.MethodsA total of 77 subjects were prospectively recruited. All the participants underwent lung function test, endothelial function evaluation, including pulse wave velocity (PWV) and flow-mediated dilation (FMD), and blood sample detection. Moreover, the effect of NP on endothelial cells (ECs) in anoxic environments was assessed in vitro.ResultsEndothelial function was significantly decreased in the COPD and ACO patients compared with that in the healthy controls (P < 0.05). Forced expiratory volume in 1 s (FEV1) was negatively correlated with PWV and positively correlated with FMD (P < 0.05). NP was significantly increased in patients with chronic respiratory diseases compared with that in the control group, with COPD being the highest, followed by asthma, and ACO as the last (P < 0.05). The plasma level of NP exhibited negative correlations with FEV1 and positive correlations with PWV (P < 0.05). In vitro, a high level of NP increased the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential (ΔΨm) of ECs dose-dependently in a hypoxic environment (P < 0.05).ConclusionNP was related to disease severity of chronic airway diseases and involved in the pathogenesis of endothelial dysfunction. A high NP level may contribute to endothelial dysfunction by increasing the oxidative stress of ECs dose-dependently in a hypoxic environment. Our findings may provide a novel evaluation and therapeutic target for endothelial dysfunction related to chronic airway diseases.

Xanthine Oxidoreductase in the Pathogenesis of Endothelial Dysfunction: An Update.

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in the formation of uric acid (UA) and is involved in the generation of reactive oxygen species (ROS). Overproduction of ROS has been linked to the pathogenesis of hypertension, atherosclerosis, and cardiovascular disease, with multiple studies over the last 30 years demonstrating that XOR inhibition is beneficial. The involvement of XOR and its constituents in the advancement of chronic inflammation and ROS, which are responsible for endothelial dysfunction, is the focus of this evidence-based review. An overabundance of XOR products and ROS appears to drive the inflammatory response, resulting in significant endothelium damage. It has also been demonstrated that XOR activity and ED are connected. Diabetes, hypertension, and cardiovascular disease are all associated with endothelial dysfunction. ROS mainly modifies the activity of vascular cells and can be important in normal vascular physiology as well as the development of vascular disease. Suppressing XOR activity appears to decrease endothelial dysfunction, probably because it lessens the generation of reactive oxygen species and the oxidative stress brought on by XOR. Although there has long been a link between higher vascular XOR activity and worse clinical outcomes, new research suggests a different picture in which positive results are mediated by XOR enzymatic activity. Here in this study, we aimed to review the association between XOR and vascular endothelial dysfunction. The prevention and treatment approaches against vascular endothelial dysfunction in atherosclerotic disease.

EGFR activation differentially affects the inflammatory profiles of female human aortic and coronary artery endothelial cells

Endothelial cells (EC) are key players in vascular function, homeostasis and inflammation. EC show substantial heterogeneity due to inter-individual variability (e.g. sex-differences) and intra-individual differences as they originate from different organs or vessels. This variability may lead to different responsiveness to external stimuli. Here we compared the responsiveness of female human primary EC from the aorta (HAoEC) and coronary arteries (HCAEC) to Epidermal Growth Factor Receptor (EGFR) activation. EGFR is an important signal integration hub for vascular active substances with physiological and pathophysiological relevance. Our transcriptomic analysis suggested that EGFR activation differentially affects the inflammatory profiles of HAoEC and HCAEC, particularly by inducing a HCAEC-driven leukocyte attraction but a downregulation of adhesion molecule and chemoattractant expression in HAoEC. Experimental assessments of selected inflammation markers were performed to validate these predictions and the results confirmed a dual role of EGFR in these cells: its activation initiated an anti-inflammatory response in HAoEC but a pro-inflammatory one in HCAEC. Our study highlights that, although they are both arterial EC, female HAoEC and HCAEC are distinguishable with regard to the role of EGFR and its involvement in inflammation regulation, what may be relevant for vascular maintenance but also the pathogenesis of endothelial dysfunction.

Interleukin-17, C-reactive protein, Neutrophil-to-Lymphocyte ratio, Lymphocyte-to-Monocyte ratio, and lipid profiles in healthy menopausal women with or without hot flashes: A cross-sectional study.

The reciprocation between systemic inflammatory markers (SIMs), dyslipidemia, and hot flashes (HFs) can play a part in the pathogenesis of endothelial dysfunction through menopause. This study intended to determine the association between some SIMs, lipids, and HFs in healthy menopausal women. We designed a cross-sectional study in which 160 healthy menopausal women aged 40-60 were enrolled. Concerning their HFs status, they were stratified into two groups by consecutive sampling: without HFs (n = 40) and with HFs (n = 120). In addition to clinical variables and HFs experience, we measured the fasting serum levels of SIMs and lipid profiles (LPs), including Interleukin-17 (IL-17), high- sensitivity C-Reactive Protein (hs-CRP), Total Cholesterol (TC), Triglycerides (TG), Low-Density Lipoprotein Cholesterol (LDL-C), and High-Density Lipoprotein Cholesterol (HDL-C) in each group. Then, we calculated TC/HDL-C concerning the related variables and determined Neutrophil-to-Lymphocyte Ratio (NLR), and Lymphocyte-to-Monocyte Ratio (LMR), according to Complete Blood Count (CBC) quantitative parameters in each group. Furthermore, we used logistic regression analysis to assess the association between SIMs, LPs, and HFs. We performed this study in a governmental teaching hospital, Guilan/Rasht, Iran, from April to September 2021. The two groups of menopausal women without and with HFs were not significantly different regarding the median of IL-17, hs-CRP, NLR, LMR, TG, HDL-C, and TC/HDL-C, and the mean of TC and LDL-C. Based on multiple logistic regression, TG levels appeared to be associated with the incidence of HFs (B = 0.004, P = 0.040, Odds Ratio:1.004, 95%CI:1.000-1.009). NLR seemed to have an increasing impact on the HFs severity, according to ordinal logistic regression (B = 0.779, P = 0.005, Odds Ratio = 2.180, 95%CI:1.270-3.744). Furthermore, hs-CRP negatively correlated with TG (r = -0.189, P = 0.039) and TC/HDL-C (r = -0.268, P = 0.003) in menopausal women with HFs. This study indicated an association between SIMs, lipids, and HFs. These connections may suggest HFs as links between SIMs/LPs alterations and their outcomes.

The Role of Perivascular Adipose Tissue in the Pathogenesis of Endothelial Dysfunction in Cardiovascular Diseases and Type 2 Diabetes Mellitus.

Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs) representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review, we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.

Mitochondrial dysfunction in the pathogenesis of endothelial dysfunction.

Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction.

Association between Serum α-Klotho Levels and Behçet Disease.

Endothelial dysfunction (ED) has a well-known role in promoting vascular inflammation in Behçet disease (BD). α-klotho is involved in regulation of endothelial function, and its reduction has been reported to be associated with ED. To assess serum α-klotho in patients with BD, compared with healthy control individuals. In a cross-sectional study, 55 patients with BD and 30 age- and sex-matched healthy controls were enrolled, and their serum levels of α-klotho were measured. Common clinical symptoms in patients with BD were oral aphthous ulcers, uveitis, and genital ulcers. Median (IQR) serum α-klotho levels in the BD and control groups were 0.30 (0.20-0.70) and 1.00 (0.70-2.52) ng/mL, respectively. The difference was statistically significant (P = .005). No significant correlation was observed between serum α-klotho and age (r = 0.194; P = .14). Serum α-klotho levels in patients with uveitis were significantly lower. α-klotho may have a role in the pathogenesis of ED and is a potential biomarker for uveitis in BD.

Abstract 9610: Endothelial Function and Coronary Arterial Imaging in Youth-Onset Type 2 Diabetes: Evidence for Early Vascular Aging Compared to Age-Matched Peers

Introduction: Youth-onset type 2 diabetes (Y-T2D) may be associated with accelerated vascular aging, but the tempo and mechanisms are unknown. Non-invasive cardiac MRI coupled with ex-vivo experiments to assess endothelial function are ideal for assessing risk in young adults. Plasma exosomes are pro-inflammatory extra-cellular vesicles that may modulate endothelial dysfunction. Methods: We hypothesized that Y-T2D would have endothelial dysfunction compared to healthy age-matched peers measured by right coronary wall thickness (CWT) and coronary and brachial artery dilation during isometric handgrip exercise using a 3.0 Tesla cardiac MRI. In a subset of 4 Y-T2D, we isolated, characterized, and incubated plasma-derived exosomes in human coronary artery epithelial cells (HCAECs) compared to control cells. Results: Y-T2D (n=14, 40% female, age 19.4±1.3y, BMI 38±9kg/m 2 , mean±SD) compared to peers (n=16, 40% female, age 22.9±2.6 y, BMI 23±3 kg/m 2 ) had higher HbA1c (6.5 ± 1.2 vs 5.0 ± 0.5%), C-reactive protein (6.5±8.3 vs. 3.1±2.0 mg/L), systolic blood pressure (130±14 vs. 114±11 mmHg, all P &lt;0.05) but similar LDL-cholesterol and triglycerides. Y-T2D had greater CWT (1.34±0.13 vs. 1.22±0.13 mm, P =0.02) and impaired arterial dilation (Figure 1A). HCAECs incubated with Y-T2D exosomes induced phenotypic changes of endothelial dysfunction: reduced expression of phosphorylated endothelial nitric oxide synthase (peNOS), increased expression of endothelial membrane ICAM-1 and phosphorylation of pERK(1/2) (Figure 1B). Conclusion: Accelerated vascular aging in Y-T2D was associated with paradoxical exercise-induced coronary artery vasoconstriction and peripheral endothelial dysfunction despite young age and the absence of traditional risk factors such as severe hyperglycemia, frank hypertension, or dyslipidemia. Plasma exosomes should be explored in the pathogenesis of endothelial dysfunction and early vascular aging in Y-T2D.

Abstract 13610: Imbalance Between GCN5L1 Mediated CypD Acetylation and Sirt3 Deacetylase Promotes Mitochondrial Oxidative Stress, Endothelial Dysfunction and Hypertension

Nearly half of adult population has hypertension which is a main risk factor for cardiovascular disease. Mitochondrial dysfunction contributes to hypertension and targeting mitochondria can potentially improve treatment of hypertension. We found hyperacetylation of mitochondrial Cyclophilin D (CypD) in essential hypertension and proposed that CypD acetylation can promote endothelial dysfunction and hypertension. CypD acetylation is mediated by general control of amino acid synthesis 5 like 1 (GCN5L1) protein which is counteracted by deacetylase Sirt3. We tested potential role GCN5L1 and Sirt3 in endothelial dysfunction and hypertension. Western blot of aortic mitochondria showed an increased GCN5L1 level in hypertensive mice coupled with the reduction of Sirt3 deacetylase resulting in 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. We reported pathogenic role of lipid oxidation products isolevuglandins (isoLGs) and scavenging isoLGs by mitochondria-targeted mito2HOBA reduces mitochondrial acetylation. We tested if mitochondrial isoLGs contributes to acetylase/deacetylase imbalance driving CypD acetylation. Treatment with mito2HOBA improves Sirt3 expression and reduces GCN5L1 level resulting in normalization of GCN5L1/Sirt3 ratio and reduced CypD acetylation. To define the pathophysiological role of GCN5L1 in endothelial cells we tested if GCN5L1 depletion prevents cytokine-induced of mitochondrial oxidative stress. Indeed, treatment of human aortic endothelial cells with AngII+TNFα induces mitochondrial O 2 . -, however, GCN5L1 depletion using siRNA completely abrogated the cytokine-induced mitochondrial oxidative stress. To define the role GNC5L1 in pathogenesis of endothelial dysfunction we developed new tamoxifen-inducible endothelial specific GNC5L1 knockout mice (Ec GNC5L1KO ). Depletion of endothelial GCN5L1 reduces vascular mitochondrial O 2 . -, prevents inactivation of endothelial nitric oxide and preserves endothelial dependent relaxation in angiotensin II-infused Ec GNC5L1KO mice compared with wild-type littermates. These data support the pathogenic role of GNC5L1 in CypD acetylation and endothelial dysfunction and targeting GNC5L1 can be beneficial in cardiovascular disease.

Endothelial cell autophagy in the context of disease development.

Endothelial cells (EC) are the anatomical boundaries between the intravascular and extravascular space. Damage to ECs is catastrophic and induces endothelial cell dysfunction. The pathogenesis is multifactorial and involves dysregulation in the signaling pathways, membrane lipids ratio disturbance, cell-cell adhesion disturbance, unfolded protein response, lysosomal and mitochondrial stress, autophagy dysregulation, and oxidative stress. Autophagy is a lysosomal-dependent turnover of intracellular components. Autophagy was recognized early in the pathogenesis of endothelial dysfunction. Autophagy is a remarkable patho (physiological) process in the cell homeostasis regulation including EC. Regulation of autophagy rate is disease-dependent and impaired with aging. Up-regulation of autophagy induces endothelial cell regeneration/differentiation and improves the function of impaired ones. The paper scrutinizes the molecular mechanisms and triggers of EC dysregulation and current perspectives for future therapeutic strategies by autophagy targeting.

The Role of Adrenoreceptors and Calcium Ions in the Pathogenesis of Endocardium Endothelium Damage of Rats Under Stress Action on the Background of Hypercholesterolemia

Abstract. Topicality. Endothelial dysfunction is a key link in the pathogenesis, formation and progression of clinical manifestations of a significant number of cardiovascular system diseases. Some pathogenetic links and structures associated with morphofunctional disorders of cardiac endothelial cells under the stress conditions and its combination with hypercholesterolemia need further examination.&#x0D; The aim of the study was to investigate the role of adrenoreceptors and calcium ions (by using of adrenoreceptors and Ca2+-channels blockers) in the pathogenesis of endocardium endothelium damage (by the content of free fatty acids in it and the number of exfoliated cells) as a result of emotional and pain stress action and its influence on the background of hypercholesterolemia.&#x0D; Materials and methods of research. An electro-pulse model was used for stress reproduction. The alimentary hypercholesterolemia was simulated by keeping animals on an atherogenic diet during 2 months. To establish the role of the above-mentioned cellular structures in the mechanisms of endothelial cell damage, the following pharmacological drugs were administered to animals: β-adrenoblocker, α-adrenoblocker and Ca2+-channel blocker. The endocardium endothelium state was studied by using light microscopy, by analyzing the smears-imprints from macropreparations of ventricles by counting the number of endothelial cells in them. The content of free fatty acids was determined by radiochemical method.&#x0D; Research results. It has been shown that β-adrenoblocker and Ca2+-channel blocker significantly limit the damage of endocardium endothelium of left ventricle under the action of emotional and pain stress, and to a much lesser extent, the same effect has α-adrenoblocker. The protective effect of mentioned preparations under the action of stressor factor against the background of alimentary hypercholesterolemia significantly decreases.&#x0D; Conclusions. The obtained data, their analysis and comparison with the results of other experimental and clinical studies allow to make certain conclusions about the pathogenesis of endothelial dysfunction under emotional stress, as well as under conditions of its combination with hypercholesterolemia. In particular, an important link in the development of structural and some biochemical changes of endocardial endothelial cells is the toxic effect of catecholamines, which affect the organism’s functional systems mainly by β-adrenoreceptors (involving Ca2+ ions), to a lesser extent – by α-adrenoreceptors.&#x0D; Key words: endocardium, stress, hypercholesterolemia, adrenoreceptors, calcium.

Abstract P237: Mitochondrial GCN5L1 Promotes CypD Acetylation, Oxidative Stress, Endothelial Dysfunction And Hypertension

Nearly half of adult population has hypertension which is a main risk factor for cardiovascular disease. Mitochondrial dysfunction contributes to hypertension and targeting mitochondria can potentially improve treatment of hypertension. We found hyperacetylation of mitochondrial Cyclophilin D (CypD) in essential hypertension and proposed that CypD acetylation can promote endothelial dysfunction and hypertension. CypD acetylation can be regulated by general control of amino acid synthesis 5 like 1 (GCN5L1) protein, therefore, we GCN5L1 can potentially promote endothelial dysfunction and hypertension. Western blot of aortic mitochondria showed an increased GCN5L1 level in hypertensive mice which was coupled with the reduction of Sirt3 deacetylase level resulting in 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. We reported pathogenic role of mitochondrial lipid oxidation products isolevuglandins (isoLGs) and scavenging of isoLGs with mitochondria-targeted mito2HOBA reduces mitochondrial acetylation. We tested if mitochondrial isoLGs contributes to acetylase/deacetylase imbalance driving CypD acetylation. It was found that mito2HOBA supplementation improves Sirt3 expression and reduces GCN5L1 level leading to normalization of GCN5L1/Sirt3 ratio and reduced CypD acetylation. To define the pathophysiological role of GCN5L1 in endothelial cells we tested if GCN5L1 depletion prevents cytokine-induced of mitochondrial oxidative stress. Indeed, treatment of human aortic endothelial cells with AngII+TNFα induces mitochondrial O 2 . -, however, GCN5L1 depletion using siRNA completely abrogated the cytokine-induced mitochondrial oxidative stress. To define the role GNC5L1 in pathogenesis of endothelial dysfunction we have developed new tamoxifen-inducible endothelial specific GNC5L1 knockout mice (Ec GNC5L1KO ). It was found that depletion of endothelial GCN5L1 reduces vascular production of mitochondrial O 2 . -, prevents inactivation of endothelial nitric oxide and preserves endothelial dependent relaxation in angiotensin II-infused Ec GNC5L1KO mice compared with wild-type littermates. These data support the pathogenic role of GNC5L1 in CypD acetylation and development of endothelial dysfunction.

Perfluorooctane Sulfonate Induces Dysfunction of Human Umbilical Vein Endothelial Cells via Ferroptosis Pathway.

(1) Background: Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant, and it is receiving increasing attention regarding its human health risks due to its extensive use. Endothelial dysfunction is a mark of cardiovascular disease, but the basic mechanism of PFOS-induced endothelial dysfunction is still not fully understood. Ferroptosis is a newly defined regulatory cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although ferroptosis has been shown to be involved in the pathogenesis of cardiovascular diseases, the involvement of ferroptosis in the pathogenesis of endothelial dysfunction caused by PFOS remains unclear. (2) Purpose: To explore the role of ferroptosis in the dysfunction of endothelial cells and underlying mechanisms. (3) Methods: Human umbilical vein endothelial cells (HUVECs) were exposed to PFOS or PFOS and Fer-1. The viability, morphology change under electronic microscope, lipid-reactive oxygen species (lipid-ROS), and production of nitric oxide (NO) were determined. The expression of glutathione peroxidase 4(GPX4), ferritin heavy chain protein 1 (FTH1), heme oxygenase 1 (HO-1) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) were analyzed via Western blot analysis. (4) Results: PFOS was shown to cause a decrease in viability and morphological changes of mitochondria, and well as an increase in lipid droplets. The expression of GPX4, FTH1 and HO-1 was decreased, and that of ACSL4 was increased after exposure to PFOS. In addition to the above-mentioned ferroptosis-related manifestations, there was also a reduction in NO content. (5) Conclusions: PFOS induces ferroptosis by regulating the GPX4 and ACSL4 pathways, which leads to HUVEC dysfunction.

Sensitivity, specificity of biochemical markers for early prediction of endothelial dysfunction in atherosclerotic obese subjects.

The obesity increased incidence of diabetes, hypertension and atherosclerosis and rate of morbidity and mortality. The main cause of atherosclerosis is endothelial dysfunction and formation of foam cells and macrophage that lead to unfavorable complications. This study evaluated specific biomarkers for endothelial dysfunction as sensitive indices for early predication of atherosclerosis in obese subjects. One hundred fifty male age and sex matching were included in the current study divided into three groups according to body mass index (BMI): Control (BMI ≤ 22), obese (BMI> 28) and obese with atherosclerosis (BMI> 28). Fasting serum was subjected for determination of adhesion molecules, sICAM-1, sVCAM-1, E-selectin, oxo-LDL and 8-iso-PGF2α by ELISA technique. Data obtained showed that, a significant elevation of serum inflammatory markers CRP, IL-6 and TNF-α and adhesion molecules sICAM-1 (p<0.001) with sensitivity 96%, sVCAM-1 (p <0.01) with sensitivity 92%, E-selectin (p<0.001) with sensitivity 94%, oxo-LDL (p <0.05) and 8-iso-PGF2α (p < 0.001) with sensitivity 97% in obese with atherosclerosis compared with obese and control. The levels of serum adhesion molecules contributed in the pathogenesis of endothelial dysfunction can be used as sensitive biomarkers for early prediction of atherosclerosis in obese subjects.

Effect of vasodilator and immunosuppressive therapy on the endothelial dysfunction in patients with systemic sclerosis.

A comparative analysis of flow-mediated vasodilation (FMD), vasoactive angiogenic, and fibrogenic mediators between treatment-naive and treated systemic sclerosis (SSc) patients is an unmet need. (1)To assess the FMD and different pathogenic mediators in SSc patients about endothelial dysfunction. (2) To assess the proportion of circulating endothelial cells (CECs) in treatment-naïve patients. SSc patients were grouped into treatment-naïve (Group-I, n = 24) on vasodilator (Group-II, n = 10), on vasodilator + immunosuppressive (Group-III, n = 22)]. Age-sex matched healthy controls (n = 20) were included. Endothelial dysfunction (ED) was measured radiologically using FMD. Serum levels of NO, ET1, NO/ET1, sVCAM, sICAM, TGF, IL-6, and VEGF, as well as gene expressions of eNOS, iNOS, ET-1, and TGF, were measured to assess the status of ED in various study groups. CEC was measured in Group-I and HC. CEC was used as a marker to identify a key regulator of ED in SSc. FMD was significantly decreased in all SSc patients through receiving treatment. Upregulation of serum NO and ET concentrations was noted post-treatment with an unaltered NO/ET1 ratio. NO was positively correlated with FMD (r = 0.6) and negatively with TGFβ (r = - 0.5). ET-1 showed a negative correlation with TGFβ (r = - 0.5) but no significant correlation with FMD. Circulating endothelial cell (CEC) was significantly higher in Group-I (3.2%) than HC (0.8%) (p = 0.002), and it showed a good correlation with NO (r = - 0.7, p = 0.0001) and NO/ET1 (r = - 0.6, p = 0.007). Persistent ED was observed in all SSc patients irrespective of treatment. Dysbalance in NO/ET1 ratio might be the considering factor for the underlying progression of ED. Based on our findings, it may be hypothesized that reduced NO may be a contributing factor in the pathogenesis of endothelial dysfunction in SSc.

Upregulation of FOXO1 contributes to lipopolysaccharide-induced pulmonary endothelial injury by induction of autophagy.

BackgroundAutophagy is activated during the pathogenesis of endothelial dysfunction and sepsis-associated acute lung injury (ALI). This study aimed to investigate whether autophagy affected endothelial barrier dysfunction and lung injury in a murine model of lipopolysaccharide (LPS)-induced ALI, and then further clarify whether forkhead box O1 (FOXO1), an autophagy-related transcriptional factor, contributed to autophagy activation and ALI induced by LPS.MethodsMale C57BL/6 mice were treated with LPS (30 mg/kg), and then were allocated to a control group and an LPS group with or without FOXO1 inhibitor (AS1842856) treatment, respectively. Primary cultured mouse lung vascular endothelial cells (MLVECs) were treated with LPS, autophagy inhibitor 3-methyladenine (3-MA), AS1842856, and small interfering RNA (siRNA) targeting autophagy-related gene 5 (ATG5) or FOXO1. Endothelial autophagic flux was assessed by transfection of MLVECs with red fluorescent protein (RFP)-green fluorescent protein (GFP) tandem fluorescent-tagged LC3 (RFP-GFP-LC3) adenovirus. Endothelial permeability was analyzed by the diffusion of fluorescein isothiocyanate-carboxymethyl (FITC)-dextran through the endothelial monolayer. Evans blue albumin tracer was used to measure the pulmonary transvascular permeability, and hematoxylin and eosin (H&E) staining was used to observe pathological changes in the lung tissues. Immunofluorescence staining was also used to detect the expression of zonula occludens-1 (ZO-1) and FOXO1.ResultsThis study found autophagy induction in lung tissues of endotoxemic mice and LPS-treated MLVECs, as evidenced by elevated expression of light chain 3 II (LC3-II) and Unc-51-like kinase (ULK1) and autophagic flux. LPS treatment decreased vascular endothelial (VE)-cadherin and ZO-1 expression and increased endothelial permeability in MLVECs, which were significantly alleviated by autophagy inhibitor 3-MA and ATG5 siRNA. It was found that both phosphorylated FOXO1 and FOXO1 were upregulated in the lung tissues of endotoxemic mice and LPS-treated MLVECs. Both FOXO1 inhibitor AS1842856 and FOXO1 siRNA suppressed LPS-induced autophagy and endothelial cell injury in MLVECs. Moreover, FOXO1 inhibition profoundly alleviated autophagy, lung endothelial hyperpermeability, and ALI in endotoxemic mice.ConclusionsThis work demonstrated that FOXO1 upregulation is an important contributor to LPS-induced autophagy in pulmonary VE cells. The detrimental effects of FOXO1 in endotoxemia-associated endothelial dysfunction and ALI are partly due to its potent pro-autophagic property. Inhibition of FOXO1 may be a potential therapeutic option for the treatment of ALI.

The pathogenesis of endothelial dysfunction

<p indent=0mm>Endothelial dysfunction is the most common pathological feature of diabetes, hypertension and atherosclerosis. Endothelial dysfunction can occur not only in large conduit arteries such as aorta and renal artery, but also in microvascular circulation in the retina and kidney. Decreased production and secretion of endothelium-derived vasodilator factors (mainly nitric oxide) or increased synthesis and release of vasoconstrictor factors (such as angiotensin II, endothelin-1, reactive oxygen species and cyclooxygenase metabolites) are the main causes of endothelial dysfunction, which is closely associated with pathogenesis of hypertension, diabetes, atherosclerosis, myocardial ischemia, and heart failure. This review briefly summarizes the mechanisms underlying endothelial dysfunction in relation to activation of the renin angiotensin system, cyclooxygenase 2, and bone morphogenetic protein 4, as well as increased oxidative stress and inflammatory response in blood vessels, hoping to identify the key molecular mediators of endothelial dysfunction, thereby providing new clues for both basic and translational research in cardio-metabolic biology and medicine.