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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

ABSTRACT: The endothelial function plays key roles in both promoting and protecting against atherosclerotic disease. Several methods, including peripheral arterial tonometry (PAT), have been reported to be useful for investigating endothelial dysfunction. Furthermore, the level of thrombomodulin (TM) is assumed to reflect the endothelial dysfunction. In the present study, we investigated endothelial dysfunction in patients with peripheral arterial disease (PAD) by measuring their TM levels, and evaluated the correlation between TM and various parameters.We measured the TM levels and performed PAT in 17 patients with PAD. We also recorded the patients' demographic information, including comorbidities, and investigated their hemodynamic status by measuring the ankle brachial pressure index (ABI). The PAT results were used to calculate the reactive hyperemia index (RHI), which reflected the patients' level of endothelial dysfunction.The RHI and ABI values and the serum level of creatinine were found to be significantly correlated with the TM level (P = 0.040, 0.041 and 0.005, respectively). After setting an RHI value of 1.67 as the cut-off, the patients with RHI values of <1.67 were found to have significantly higher TM levels (median, 20.3 U/mL) than the patients with RHI values of ?1.67 (median, 13.7 U/mL) (P = 0.023).The degree of endothelial dysfunction, as calculated by the TM level, might influence the prognostic value of the RHI, which is determined by PAT. The measurement of the TM level and PAT might both be useful methods of measuring endothelial dysfunction in patients with PAD.

SUBMITTER: Igari K

PROVIDER: S-EPMC5115826 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

Igari Kimihiro K Kudo Toshifumi T Toyofuku Takahiro T Inoue Yoshinori Y

PloS one 20161118 11

<h4>Introduction</h4>The endothelial function plays key roles in both promoting and protecting against atherosclerotic disease. Several methods, including peripheral arterial tonometry (PAT), have been reported to be useful for investigating endothelial dysfunction. Furthermore, the level of thrombomodulin (TM) is assumed to reflect the endothelial dysfunction. In the present study, we investigated endothelial dysfunction in patients with peripheral arterial disease (PAD) by measuring their TM l ...[more]

PMID: 27861629

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Project description:BackgroundPeripheral arterial atheroprogression is increasingly prevalent, and is a risk factor for major limb amputations in individuals with risk factors such as diabetes. We previously demonstrated that bioactive lipids are significantly altered in arterial tissue of individuals with diabetes and advanced peripheral arterial disease.MethodsHere we evaluated whether sphingolipid ceramide 18:1/16:0 (C16) is a cellular regulator in endothelial cells and peripheral tibial arterial tissue in individuals with diabetes.ResultsWe observed that C16 is the single most elevated ceramide in peripheral arterial tissue from below the knee in individuals with diabetes (11% increase, P < .05). C16 content in tibial arterial tissue positively correlates with sphingomyelin (SPM) content in patients with and without diabetes (r2 = 0.5, P < .005; r2 = 0.17, P < .05; respectively). Tibial arteries of individuals with diabetes demonstrated no difference in CERS6 expression (encoding ceramide synthase 6; the predominate ceramide synthesis enzyme), but higher SMPD expression (encoding sphingomyelin phosphodiesterase that catalyzes ceramide synthesis from sphingomyelins; P < .05). SMPD4, but not SMPD2, was particularly elevated in maximally diseased (Max) tibial arterial segments (P < .05). In vitro, exogenous C16 caused endothelial cells (HUVECs) to have decreased proliferation (P < .03), increased apoptosis (P < .003), and decreased autophagy (P < .008). Selective knockdown of SMPD2 and SMPD4 decreased native production of C16 (P < .01 and P < .001, respectively), but only knockdown of SMPD4 rescued cellular proliferation (P < .005) following exogenous supplementation with C16.ConclusionsOur findings suggest that C16 is a tissue biomarker for peripheral arterial disease severity in the setting of diabetes, and can impact endothelial cell viability and function.Clinical relevancePeripheral arterial disease and its end-stage manifestation known as chronic limb-threatening ischemia (CLTI) represent ongoing prevalent and intricate medical challenges. Individuals with diabetes have a heightened risk of developing CLTI and experiencing its complications, including wounds, ulcers, and major amputations. In the present study, we conducted a comprehensive examination of the molecular lipid composition within arterial segments from individuals with CLTI, and with and without diabetes. Our investigations unveiled a striking revelation: the sphingolipid ceramide 18:1/16:0 emerged as the predominant ceramide species that was significantly elevated in the peripheral arterial intima below the knee in patients with diabetes. Moreover, this heightened ceramide presence is associated with a marked impairment of endothelial cell function and viability. Additionally, our study revealed a concurrent elevation in the expression of sphingomyelin phosphodiesterases, enzymes responsible for catalyzing ceramide synthesis from sphingomyelins, within maximally diseased arterial segments. These findings underscore the pivotal role of ceramides and their biosynthesis enzymes in the context of CLTI, offering new insights into potential therapeutic avenues for managing this challenging disease process.

Project description:ObjectiveWe have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD.MethodsThis was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants.ResultsNinety-seven patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle-brachial index was 0.73 ± 0.14 and mean flow-mediated vasodilation was 7.0% ± 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m(2); β, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor α, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF (P = .033).ConclusionsIn patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process.

Project description:BACKGROUND:Peripheral arterial disease (PAD) involves arterial blockages in the body, except those serving the heart and brain. We explore the relationship of functional limitation and PAD symptoms obtained from a quality-of-life questionnaire about the severity of the disease. We used a supervised artificial intelligence-based method of data analyses known as machine learning (ML) to demonstrate a nonlinear relationship between symptoms and functional limitation amongst patients with and without PAD. OBJECTIVES:This paper will demonstrate the use of machine learning to explore the relationship between functional limitation and symptom severity to PAD severity. METHODS:We performed supervised machine learning and graphical analysis, analyzing 703 patients from an administrative database with data comprising the toe-brachial index (TBI), baseline demographics and symptom score(s) derived from a modified vascular quality-of-life questionnaire, calf circumference in centimeters and a six-minute walk (distance in meters). RESULTS:Graphical analysis upon categorizing patients into critical limb ischemia (CLI), severe PAD, moderate PAD and no PAD demonstrated a decrease in walking distance as symptoms worsened and the relationship appeared nonlinear. A supervised ML ensemble (random forest, neural network, generalized linear model) found symptom score, calf circumference (cm), age in years, and six-minute walk (distance in meters) to be important variables to predict PAD. Graphical analysis of a six-minute walk distance against each of the other variables categorized by PAD status showed nonlinear relationships. For low symptom scores, a six-minute walk test (6MWT) demonstrated high specificity for PAD. CONCLUSIONS:PAD patients with the greatest functional limitation may sometimes be asymptomatic. Patients without PAD show no relationship between functional limitation and symptoms. Machine learning allows exploration of nonlinear relationships. A simple linear model alone would have overlooked or considered such a nonlinear relationship unimportant.

Project description:BackgroundMitochondria play a central role in the regulation of energy metabolism, and the biogenesis of mitochondria is enhanced by the action of nitric oxide (NO), which is the key signaling molecule in the regulation of vascular homeostasis. A disturbance in the regulation of energy metabolism can be a key reason for the formation of insulin resistance and type 2 diabetes mellitus. Moreover, mitochondrial dysfunction leads to oxidative stress, which increases the production of proinflammatory cytokines. In this regard, the aim of this study was to identify the relationship of the copy number of mtDNA in adipose tissue from different locations (subcutaneous adipose tissue (SAT), mesentery (Mes), greater omentum (GO)), liver biopsy samples and mononuclear blood cells (MNCs) with endothelial dysfunction markers (eNOS, ET-1, iCAM-1, vCAM-1, VEGF) and inflammatory mediators (TNF-α, IL-6, IL-8, CRP, leptin) in obese patients (body mass index (BMI) > 35 kg/m2) with and without type 2 diabetes.MethodsThe study included 88 obese patients (BMI > 35 kg/m2) treated at the Kaliningrad Region Hospital. The control group consisted of 20 healthy donors. To measure mtDNA copy number we used droplet digital PCR. The concentrations of molecules (TNF-α, IL-6, IL-8, VEGF, eNOS, ET-1, iCAM-1, vCAM-1, VEGF) were measured in plasma using the following sandwich enzyme-linked immunosorbent assays (ELISAs). Quantitative determination of leptin was evaluated by flow-fluorimetry on a «Bio-Plex Protein Assay System». Statistical analysis and graphs were obtained in R Statistical Software (version 3.3.1).ResultsThe systemic character of chronic subclinical inflammation in obesity is established, and an increase in the level of endothelial dysfunction molecules was observed in the blood plasma. The levels of TNF-a, IL-6, and IL-8 were positively correlated with increases in BMI, serum glucose and cholesterol levels.ConclusionsThe copy number of mtDNA in various fat stores was higher in obese patients with type 2 diabetes than in obese patients without diabetes or in the control subjects and was related to the levels of leptin and proinflammatory cytokines.

Project description:AimsElevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology.Methods and resultsTo test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment.ConclusionVascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.

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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

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