Impaired Endothelium-dependent Vasodilation Research Articles

Diffusion‐weighted MRI with intravoxel incoherent motion modeling for assessment of muscle perfusion in the thigh during post‐exercise hyperemia in younger and older adults

Aging is associated with impaired endothelium-dependent vasodilation that leads to muscle perfusion impairment and contributes to organ dysfunction. Impaired muscle perfusion may result in inadequate delivery of oxygen and nutrients during and after muscle contraction, leading to muscle damage. The ability to study the relationship between perfusion and muscle damage has been limited using traditional muscle perfusion measures, which are invasive and risky. To overcome this limitation, we optimized a diffusion-weighted MRI sequence and validated an intravoxel incoherent motion (IVIM) analysis based on Monte Carlo simulation to study muscle perfusion impairment with aging during post-exercise hyperemia. Simulation results demonstrated that the bias of IVIM-derived perfusion fraction (fp ) and diffusion of water molecules in extra-vascular tissue (D) ranged from -3.3% to 14% and from -16.5% to 0.002%, respectively, in the optimized experimental condition. The dispersion in fp and D ranged from 3.2% to 9.5% and from 0.9% to 1.1%, respectively. The mid-thigh of the left leg of four younger (21-30year old) and four older (60-90year old) healthy females was studied using the optimized protocol at baseline and at seven time increments occurring every 3.25min following in-magnet dynamic knee extension exercise performed using a MR-compatible ergometer with a workload of 0.4bar for 2.5min. After exercise, both fp and D significantly increased in the rectus femoris (active muscle during exercise) but not in adductor magnus (inactive muscle), reflecting the fact that the local increase in perfusion with both groups showed a maximum value in the second post-exercise time-point. A significantly greater increase in perfusion from the baseline (p<0.05) was observed in the younger group (37±12.05%) compared with the older group (17.57±15.92%) at the first post-exercise measurement. This work establishes a reliable non-invasive method that can be used to study the effects of aging on dynamic changes in muscle perfusion as they relate to important measures of physical function.

Изменения микроциркуляции в области пародонта крыс под воздействием золедроновой кислоты

There is a rather high prevalence of oncological complications in the world, in particular, the development of osteonecrosis while using bisphosphonate drugs. There are several reasons for their development. We had a task to evaluate microcirculation in the development of medication-related osteonecrosis in an experimental model of rats. We administered the Zoledronic acid for 3 weeks to rats, and studied the line rate of blood flow using laser and high-frequency Doppler ultrasound in the periodontal area of an extracted tooth in rats with application of vasoactive substance Acetylcholine 3% for 1 min. The changes in the bone structure were assessed using computer tomography of the head of the examined rats. The results revealed a quick decrease in microcirculation against the background of the use of Zoledronic acid for 3 weeks. A decrease in blood flow in the mucous membrane and bone tissue was detected. The obtained data correlated with different hypotheses of the effect of bisphosphonates on the blood flow. Zoledronic acid causes a statistically significant impairment of the periosteal blood flow, the mucous membrane due to a complex of disorders, which includes the cellular component (impaired endothelium-dependent vasodilation of the mucous membrane vessels) and the reduction of microcirculation in the mucous membrane and bone tissue.

Impact of weight reduction on insulin resistance, adhesive molecules and adipokines dysregulation among obese type 2 diabetic patients.

Type 2 diabetes mellitus is usually related to vascular problems and is associated with impairment in endothelial function characterized by impaired endothelial-dependent vasodilation and increased platelet adhesion. There is limitation in clinical studies that have addressed the beneficial effects of weight reduction in modulating biomarkers of endothelial dysfunction and adipokines dysregulation for obesity associated with type 2 diabetes mellitus. This study was designed to detect the effects of weight loss on insulin resistance, adhesive molecules and adipokines dysregulation in obese type 2 diabetic patients. Eighty obese patients with type 2 diabetes mellitus, their age ranged from 35-55 years and their body mass index ranged from 31-37 kg/m2 were equally assigned into 2 groups: the weight reduction group received aerobic exercises in addition to diet regimen, where the control group received medical treatment only for 12 weeks. There was a 24.04%, 19.33%, 22.78% ,12.28%, 9.35%, 22.53% & 10.12 % reduction in mean values of Homeostasis Model Assessment-Insulin Resistance Index (HOMA-IR), Leptin, Adiponectin, Resistin, intercellular cell adhesion molecule -1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin & body mass index (BMI) respectively in addition to 26.20% & 24.58% increase in the mean values of adiponectin & the quantitative insulin-sensitivity check index (QUICKI) respectively in group (A) at the end of the study. The mean values of leptin, resistin, insulin, HOMA-IR, ICAM-1, VCAM-1, E-selectin & BMI were significantly decreased in addition to significant increase in the mean values of adiponectin & QUICKI in group (A) those that received aerobic exercise training in addition to diet regimen. While the results of group (B) those that received no treatment intervention were not significant. In addition, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment (P<0.05). Within the limit of this study, 10% reduction in body mass index modulates insulin resistance, adhesive molecules and adipokines dysregulation among obese type 2 diabetic patients.

Placental nitric oxide formation and endothelium-dependent vasodilation underlie pravastatin effects against angiogenic imbalance, hypertension in pregnancy and intrauterine growth restriction.

Pre-eclampsia and hypertensive disorders of pregnancy are frequently associated with foeto-placental growth restriction, and that may be triggered by angiogenic imbalance and endothelial dysfunction. Impaired nitric oxide (NO) bioavailability seems to be involved in these pathophysiological changes observed in hypertensive pregnancy. Pravastatin has shown efficacy and to be safe during hypertension in pregnancy. However, NO involvement in pravastatin effects during maternal hypertension and foeto-placental development is unclear. Therefore, we aimed to examine pravastatin effects on placental NO formation, endothelium-dependent vasodilation, systolic blood pressure and foeto-placental development in hypertensive pregnant rats. Biochemical determinants of angiogenesis and oxidative stress were also assessed. Pregnant rats were distributed into four groups: normal pregnancy (Norm-Preg), pregnancy+pravastatin (Preg-Prava), hypertensive pregnancy (HTN-Preg) and hypertensive pregnancy+pravastatin (HTN-Preg+Prava). Our results showed that pravastatin treatment blunts hypertension and foeto-placental growth restriction. Also, increases in placental NO levels were found in the HTN-Preg+Prava group. Pravastatin prevents impaired endothelium-dependent acetylcholine-induced vasodilation, exacerbated contractile response to phenylephrine and increases in oxidative stress in the HTN-Preg+Prava group. Increased soluble fms-like tyrosine kinase-1-to-placental growth factor (sFlt-1/PlGF) ratio is reversed by pravastatin treatment in the HTN-Preg+Prava group. We conclude that NO formation and endothelium-dependent vasodilation underlie pleiotropic effects associated with pravastatin treatment against hypertension in pregnancy, intrauterine growth restriction, vascular dysfunction and angiogenic imbalance.

Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism

ObjectivePerivascular adipose tissue (PVAT) regulates vascular function in a paracrine manner and the vasodilatory effect of PVAT on vessels is completely abolished in obesity. In addition, autophagy is required for maintaining biological function of PVAT and has been shown to be inhibited in obesity. The aim of this study was to explore whether alogliptin improves endothelial function by promoting autophagy in PVAT in obese mice. MethodsC57BL/6 mice were maintained on high fat diet with or without alogliptin intervention for 3 months. Vasorelaxation function of thoracic aorta with or without PVAT was determined. Autophagy related protein level of p62 and LC3B, along with phosphorylated mTOR (p-mTOR) were evaluated. In addition, the effects of alogliptin on autophagy were also investigated in cultured adipocytes. ResultsThe presence of PVAT significantly impaired endothelium-dependent vasodilation in obese mice and alogliptin intervention corrected this defect. Autophagy in PVAT was decreased in obese mice and alogliptin intervention activated autophagy. Activating autophagy in PVAT improved endothelium-dependent vasodilation while blocking it in PVAT impaired vasodilation function. Further, addition of glucagon-like peptide-1 (GLP-1) but not alogliptin alone activated autophagy. Moreover, GLP-1 and alogliptin co-treatment did not show additive effect on activating autophagy. ConclusionsThese results revealed that promoting autophagy in PVAT improved endothelial function in response to alogliptin intervention. Additionally, the beneficial effect of alogliptin intervention on PVAT was GLP-1 dependent.

Abstract P266: Western Diet Impairs Small Vessel Relaxation and Initiates Kidney Endothelial Stiffening, Fibrosis and Tubulointerstitial Fibrosis Through the Endothelial Mineralocorticoidreceptor

Obesity enhances mineralocorticoid receptor (MR) activation, development of vascular stiffness and end organ injury. In this context, western diet (WD) activation of the endothelial mineralocorticoid receptor (ECMR) contributes to endothelial cell stiffening and promotes maladaptive inflammatory responses and fibrosis in cardiovascular tissue of female mice. However, the role of ECMR on kidney endothelial stiffening, inflammation and fibrosis remains unknown. We hypothesized that deletion of the ECMR would prevent WD-induced increases in endothelial cell stiffness, reductions in bioavailable nitric oxide (NO), increased perivascular and tubulointerstitial inflammation oxidant stress, and fibrosis in females. Four-week-old female ECMR knockout and wild-type mice were fed either a mouse chow or a WD high in saturated fat and refined carbohydrates for 16 weeks. Without blood pressure changes between groups, WD-feeding increased body weight and fat mass as well as indices of vascular stiffness (pulse wave velocity and kidney endothelial cell stiffness) and impaired endothelial-dependent vasodilatation. The WD-induced kidney endothelial cell stiffness was associated with attenuated endothelial NO synthase activation, increased oxidative stress, along with pro-inflammatory immune responses, alterations in extracellular matrix degradation pathways and tubulointerstitial fibrosis. ECMR deletion prevented these abnormalities through improvements in endothelial NO synthase and reductions in macrophage polarization, LARP6, TG2 and MMP2. Our data support that activation of ECMR contributes to endothelial dysfunction, increased permeability and stiffening in the kidney which, in turn, promotes macrophage infiltration, M1 polarization, inflammation and oxidative stress, resulting in alterations in matrix degradation that promote tubulointerstitial fibrosis in females consuming a WD.

Resveratrol Counteracts Insulin Resistance-Potential Role of the Circulation.

Pre-clinical data and human trials indicate that resveratrol supplementation may help to counteract diabetes. Several mechanisms of action have been proposed to explain its metabolic benefits, including activation of sirtuins and estrogen receptors (ER) to promote glucose transporter type-4 (GLUT4) translocation and increase glucose uptake. Resveratrol can also enhance vasodilator function, yet the possibility that this action might help to alleviate insulin resistance in type-2 diabetes mellitus has received little attention. In this brief review we propose that, by restoring impaired endothelium-dependent vasodilatation in insulin resistant individuals resveratrol increases blood perfusion of skeletal muscle, thereby facilitating glucose delivery and utilization with resultant improvement of insulin sensitivity. Thus, circulatory improvements by vasoactive nutrients such as resveratrol may play a role in preventing or alleviating insulin resistance.

FGF23 impairs peripheral microvascular function in renal failure.

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

Prolonged forearm ischemia attenuates endothelium-dependent vasodilatation and plasma nitric oxide metabolites in overweight middle-aged men

PurposeRepeated cycles of endothelial ischemia–reperfusion injury and the resulting respiratory burst contribute to the irreversible pathophysiology of vascular diseases, and yet, the effects of ischemia reperfusion on vascular function, oxidative stress, and nitric oxide (NO) bioavailability have not been assessed simultaneously. Therefore, this study sought to examine the effects of prolonged forearm occlusion and subsequent reperfusion on NO-dependent brachial artery endothelial function.MethodsFlow-mediated dilatation was measured at baseline and 15, 30, and 45 min after 20-min forearm occlusion in 14 healthy, but physically inactive middle-aged men (53.7 ± 1.2 years, BMI: 28.1 ± 0.1 kg m−2). Venous blood samples collected from the occluded arm were analyzed for NO metabolites and markers of oxidative stress.ResultsFMD was significantly depressed after the prolonged occlusion compared to baseline, with a significant reduction 15-min post-occlusion (6.6 ± 0.7 to 2.9 ± 0.4%, p < 0.001); FMD remained depressed after 30 min (4.1 ± 0.6%, p = 0.001), but was not significantly different to baseline after 45-min recovery (5.4 ± 0.7%, p = 0.079). Plasma nitrate (main time effect: p = 0.015) and nitrite (main time effect: p = 0.034) concentrations were significantly reduced after prolonged occlusion. Plasma catalase activity was significantly elevated at 4- (p = 0.016) and 45-min (p = 0.001) post-occlusion, but plasma peroxiredoxin 2 and protein carbonyl content did not change.ConclusionsProlonged forearm occlusion resulted in acute impairment of endothelium-dependent vasodilatation of the brachial artery for at least 30 min after reperfusion. We demonstrate that this vascular dysfunction is associated with oxidative stress and reduced NO bioavailability following reperfusion.

Arginase upregulation and eNOS uncoupling contribute to impaired endothelium-dependent vasodilation in a rat model of intrauterine growth restriction.

Individuals born after intrauterine growth restriction (IUGR) are at increased risk of developing cardiovascular diseases in adulthood, notably hypertension (HTN). Alterations in the vascular system, particularly impaired endothelium-dependent vasodilation, may play an important role in long-term effects of IUGR. Whether such vascular dysfunction precedes HTN has not been fully established in individuals born after IUGR. Moreover, the intimate mechanisms of altered endothelium-dependent vasodilation remain incompletely elucidated. We therefore investigated, using a rat model of IUGR, whether impaired endothelium-dependent relaxation precedes the development of HTN and whether key components of the l-arginine-nitric oxide (NO) pathway are involved in its pathogenesis. Pregnant rats were fed with a control (CTRL, 23% casein) or low-protein diet (LPD, 9% casein) to induce IUGR. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography in 5- and 8-wk-old male offspring. Aortic rings were isolated to investigate relaxation to acetylcholine, NO production, endothelial NO synthase (eNOS) protein content, arginase activity, and superoxide anion production. SBP was not different at 5 wk but significantly increased in 8-wk-old offspring of maternal LPD (LP) versus CTRL offspring. In 5-wk-old LP versus CTRL males, endothelium-dependent vasorelaxation was significantly impaired but restored by preincubation with l-arginine or the arginase inhibitor S-(2-boronoethyl)-l-cysteine; NO production was significantly reduced but restored by l-arginine pretreatment; total eNOS protein, dimer-to-monomer ratio, and arginase activity were significantly increased; superoxide anion production was significantly enhanced but normalized by pretreatment with the NO synthase inhibitor Nω-nitro-l-arginine. In this model, IUGR leads to early-impaired endothelium-dependent vasorelaxation, resulting from arginase upregulation and eNOS uncoupling, which precedes the development of HTN.

Arginase overexpression and NADPH oxidase stimulation underlie impaired vasodilation induced by advanced glycation end products

BackgroundAdvanced glycation endproducts (AGEs) play a major role in the development of many vascular complications that are mediated by endothelial dysfunction. The present work aimed to investigate the mechanism by which AGEs impair vasodilation. MethodsThe effect of AGEs on vasodilation induced by acetylcholine or D NONOate was examined by incubating isolated rat aortae with different AGEs concentrations. ACh-induced nitric oxide generation was assessed using the fluorescent probe diaminofluorecein (DAF-FM). The effect of AGEs on expression of mRNA for arginase 2, NADPH oxidase and endothelial nitric oxide synthase (eNOS) were determined by real-time PCR. ResultsOne-hour in vitro incubation of rat aortae with AGEs impaired endothelial-dependent vasodilation produced by ACh, while increasing D NONOate-induced vasodilation. Preincubation of aortae with l-ornithine, an arginase 2-inhibitor, prevented the impairment effect induced by AGEs on endothelial-dependent vasodilation. Superoxide scavenging by tempol or NADPH oxidase inhibition by apocynin also blocked the effect of AGEs. AGEs decreased ACh-induced NO production and this was inhibited by both l-ornithine and apocynin. Furthermore, AGEs exposure increased arginase mRNA expression but decreased mRNA expression for eNOS in isolated rat aortae. ConclusionThe present results indicate that AGEs impairs endothelial-dependent vasodilation, and this effect is mediated via arginase overexpression and NADPH oxidase stimulation.

Increased Hydrogen Peroxide After Traumatic Brain Injury Disrupts Phosphatidylinositol 4,5‐Bisphosphate Metabolism Causing Impaired Inward Rectifier Potassium Channel Function

Severe trauma, including traumatic brain injury (TBI), can result in several deleterious outcomes including coagulopathy, multi‐organ failure and death. We previously showed that TBI in rodents causes uncoupling of mesenteric artery (MA) nitric oxide production, resulting in excessive reactive oxygen species (ROS) generation and impaired endothelial‐dependent vasodilation. The inward‐rectifier potassium channel (KIR) is an essential component of agonist‐ and flow‐induced vasodilation and signal transduction in mesenteric arteries (MAs); however, its function following trauma has not been assessed. Phosphatidylinositol 4,5‐bisphosphate (PIP2) is a membrane phospholipid which is required for normal KIR channel function in MAs. We hypothesized that oxidative stress, specifically hydrogen peroxide (H2O2), was driving down PIP2 levels, causing KIR channelopathies. We studied male rats 24 hours after fluid percussion TBI, compared to controls. Plasma oxidative‐reduction potential (ORP), an indicator of oxidative stress, was significantly elevated in TBI rats compared to controls. In TBI but not control plasma, catalase application significantly reduced the ORP signal to control values, suggesting that H2O2 contributes to global oxidative stress following TBI. We then measured KIR currents in isolated endothelial cells (ECs) from MAs, using the whole‐cell patch‐clamp technique from control and TBI rats. KIR channel currents were significantly diminished in ECs from TBI rats compared to controls. KIR currents in ECs from TBI MAs were rescued with the addition of PIP2 to the pipette solution when compared to untreated TBI cells, and showed no difference from their control, treated counterparts, implying depletion of PIP2 following TBI is a contributing factor to KIR channel dysfunction. Next, diameter responses of arteries using pressure myography were measured. In control arteries, increasing concentrations of extracellular potassium from 6 to 10 mM K+ caused dilations; concentrations between 14 to 60 mM K+ caused constrictions. Dilations to 10 mM K+ were significantly reduced following TBI, consistent with an impaired KIR channel response. Next, basal KIR function was assessed using the KIR and KIR2.1 antagonists BaCl2 (100 μM) and ML 133 (20 μM). Following TBI, arteries constricted significantly less to both BaCl2 and ML 133. Furthermore, dilations to 10 mM K+ and constrictions to ML 133 were restored in TBI arteries in the presence of catalase. Lastly, To further quantify cellular pathology following TBI, the metabolomic phenotype was measured by liquid chromatography‐mass spectrometry (LC‐MS) in plasma obtained from control and TBI rats. Rats exhibited a profound metabolopathy following TBI; within the lipidome: arachidonate metabolism, glycerophospholipid synthesis, and fatty acid mobilization were significantly altered. These data suggest H2O2 production serves an antagonistic role on KIR channel function through changes in second messenger and lipid signaling pathways in the mesenteric circulation following TBI.Support or Funding InformationThis work was supported by the Totman Medical Research Trust and the National Institute of Health (K08‐GM‐098795 and UM1‐HL‐120877).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CD70 Modulates the Role of eNOS In Endothelial Cells

CD70 has traditionally been identified on antigen presenting cells and interacts with CD27 on T cells, promoting proliferation and memory cell formation. We have recently shown that CD70 is important in the formation of effector memory T cells in hypertension. However, the precise cell types that express CD70 and the role of CD70 on non‐immune cells has not been investigated. Here we describe a new role of CD70 in endothelial function. We found that human umbillical vein endothelial cells express CD70 mRNA and that this is increased by &gt; 30 fold by laminar (15 dynes/cm2) compared to oscillatory shear. Studies of mesenteric vascular reactivity showed that CD70−/− mice have markedly impaired endothelium‐dependent vasodilation to acetylcholine compared to WT mice (45± 5 vs 25 ± 4 %) at baseline. In contrast, there were no differences in relaxation responses to sodium nitroprusside. Pre‐incubating vessels with the endothelial nitric oxide synthase (eNOS) inhibitor L‐NAME blocked endothelium‐dependent vasodilatation to acetylcholine in WT mice nearly 75%; in contrast, L‐NAME had no effect on endothelial vessel relaxation in CD70−/− mice. This suggests that vessels of CD70−/− mice lack the capacity to produce nitric oxide (NO). Western blot for the endothelial nitric oxide synthase (eNOS) showed a marked reduction of this enzyme in the aortas of CD70−/− as compared to wild type mice. We found that CD70 and eNOS interact by co‐immunoprecipitation, however this association is abolished by siRNA against CD70. In additional experiments, aortas from CD70−/− did demonstrate expression of both neuronal NOS (nNOS) and inducible NOS (iNOS). In order to assess functional effects of this expression, nNOS NO production was blocked with LVNIO, resulting in further impairment in vasodilation of CD70−/− mesenteric vessels (−logEC50 of 5.4 after treatment, compared to 6.2 before treatment); however blockade of iNOS with 1400 W resulted in apparent recovery of acetylcholine‐induced vasodilation. These data indicate that loss of CD70−/− leads to destabilization of the eNOS protein in endothelial cells resulting in endothelial dysfunction. In the absence of eNOS in CD70−/− vessels, iNOS contributes to endothelial dysfunction, while nNOS has a compensatory role. These studies have identified a new role of the immune co‐stimulatory protein CD70 in modulating endothelial eNOS protein levels and vascular function.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission

The accumulation of uremic toxins in chronic kidney disease (CKD) induces inflammation, oxidative stress and endothelial dysfunction, which is a key step in atherosclerosis. Accumulating evidence indicates increased mitochondrial fission is a contributing mechanism for impaired endothelial function. Hippurate, a uremic toxin, has been reported to be involved in cardiovascular diseases. Here, we assessed the endothelial toxicity of hippurate and the contribution of altered mitochondrial dynamics to hippurate-induced endothelial dysfunction.Treatment of human aortic endothelial cells with hippurate reduced the expression of endothelial nitric oxide synthase (eNOS) and increased the expression of intercellular cell adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF). The mechanisms of hippurate-induced endothelial dysfunction in vitro depended on the activation of Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and overproduction of mitochondrial reactive oxygen species (mitoROS). In a rat model in which CKD was induced by 5/6 nephrectomy (CKD rat), we observed increased oxidative stress, impaired endothelium-dependent vasodilation, and elevated soluble biomarkers of endothelial dysfunction (ICAM-1 and vWF). Similarly, endothelial dysfunction was identified in healthy rats treated with disease-relevant concentrations of hippurate. In aortas of CKD rats and hippurate-treated rats, we observed an increase in Drp1 protein levels and mitochondrial fission. Inhibition of Drp1 improved endothelial function in both rat models.These results indicate that hippurate, by itself, can cause endothelial dysfunction. Increased mitochondrial fission plays an active role in hippurate-induced endothelial dysfunction via an increase in mitoROS.

ENDOTHELIAL PROTECTIVE EFFECT OF LIRAGLUTIDE IN TYPE 2 DIABETES MELLITUS

Background . Endothelial dysfunction underlies the development of chronic complications in type 2 diabetes mellitus. Glucose-lowering drugs with additional protective effects on endothelium are required. Objective . To study endothelial protective action of liraglutide in patients with type 2 diabetes mellitus and to detect its relation with glycemic control. Design and methods . The study was held in patients with type 2 diabetes mellitus with glycated hemoglobin 7,5–9,0 % who received metformin monotherapy. Metformin dose had been titrated for 3 months. Patients who reached glycated hemoglobin level less than 7,5 % were included in the group 1 — they had received metformin monotherapy for next 6 months. Patients with glycated hemoglobin over 7,5 % after 3 months formed the group 2, and they received liraglutide in addition to metformin for the following 6 months. At baseline, at 3, 6 and 9 months, endothelium-dependent vasodilation was evaluated by forearm microcirculation dopplerography with 0,3 % acetylcholine solution ionophoresis. Results. At baseline, patients of groups 1 and 2 showed impaired endothelium-dependent vasodilation (decrease of the reaction to acetylcholine, curve form change). There was no significant change in the linear blood flow parameters in the group 1 when euglycemia was reached by metformin monotherapy. Additional administration of liraglutide in the group 2 led to the increase in the amplitude and favourable change of the curve form. These changes were more prominent after 6 months of combined therapy. Endothelium-dependent vasodilation amplitude reached values observed in healthy subjects after 9 months from the study beginning. Conclusions. The improvement of glycemia control (euglycemia) does not have endothelial protective properties on its own. Liraglutide has its own endothelial protective action independent of glycemia control.

An Update on Hypertension in Children With Type 1 Diabetes.

The prevalence of hypertension in children with type 1 diabetes is reported to be between 6% and 16%. This potentially modifiable cardiovascular risk factor may go undiagnosed and undertreated, particularly in children with type 1 diabetes. Recent updated Canadian clinical practice guidelines recommend blood pressure screening every 2 years in children with type 1 diabetes as well as routine use of ambulatory blood pressure monitoring. Risk factors for hypertension in type 1 diabetes include poor glycemic control, overweight and obesity and genetic predisposition for hypertension. In terms of pathophysiology, sustained hyperglycemia, angiotensin I and II and inflammatory cytokines have been implicated. Endothelial and vascular dysfunction, with impaired endothelial-dependent vasodilation and increased carotid artery intima-media thickness, are evident in preclinical and clinical studies of children and not just in adults with type 1 diabetes. Early targeted therapy is critical to the control of hypertension and the development of related morbidity. As with hypertension in adults with type 1 diabetes, lifestyle modifications remain first-line therapy, including diet and glycemic control. Initial antihypertensive therapy should be an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker because of their associated effects of reducing microalbuminuria and improving renovascular outcomes. Pediatric hypertension in type 1 diabetes is an area of evolving study and opinion; identification and appropriate treatment is critical for the prevention of micro- and macrovascular complications in adulthood.

Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening

AimsMore than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities.Methods and resultsDM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure–volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained.ConclusionsThe combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.

Hronična niskostepena inflamacija u procesu starenja kao karika u lancu vaskularnih poremećaja koji su povezani sa gojaznošću

The pathogenesis of obesity-related vascular disorders has not been fully elucidated. The fundamental role of inflammation in aging process is now widely recognized, particularly for atherosclerotic disease which begins before birth. The number of obese individuals worldwide has reached two billion, leading to an explosion of obesity-related vascular disorders associated with increased morbidity and mortality. Obesity, as a chronic low grade inflammatory process, is important risk factor for metabolic and cardiovascular disease. Despite a well-known genetic component, this risk appears to originate from several abnormalities in adipose tissue function associated with a chronic inflammatory state. In particular, obesity as the most common nutritional disorder in industrialized countries, is closely related to impaired endothelial function, a well-known marker of preatherosclerotic disease. These conditions disrupt vascular homeostasis by causing an imbalance between the nitric oxide pathway and the endothelin-1 system, with impaired insulin-stimulated endothelium-dependent vasodilation. Having in mind the growing population of overweight and obese people worldwide, along with an increasingly aging population, understanding the pathophysiology of obesity on cardiovascular system is essential. The mechanisms linking obesity-related vascular disorders and low grade inflammation in aging process are the focus of this paper.

Comparative Study of Nitric Oxide Levels in Metabolic Syndrome and Diabetes Mellitus Patients

The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes (DM). A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Our aim is to evaluate the endothelial dysfunction in metabolic syndrome & Diabetes patients by estimation of nitric oxide levels. The study was conducted at SLIMS, Puducherry. The study included 200 diabetic patients, 200 metabolic syndrome patients and 200 Controls. When compared to controls, It was found a significant increase (p<0.001) in nitric oxide among metabolic syndrome and diabetes group and significant difference (p<0.001) between diabetes mellitus and metabolic syndrome groups being higher in metabolic syndrome group. Nitric oxide is reduced in the course of vascular disease in diabetes mellitus. Increased production of superioxide anion on oxidative stress to reduce plasma nitric oxide levels.

Arginine and aerobic training prevent endothelial and metabolic alterations in rats at high risk for the development of the metabolic syndrome - CORRIGENDUM.

Endothelial function is a key mechanism in the development of CVD. Arginine and exercise are important non-pharmacological strategies for mitigating the impact of metabolic changes in the metabolic syndrome, but the effect of their combined administration is unknown. Thus, the aim of this study was to investigate the isolated and combined effects of aerobic training and arginine supplementation on metabolic variables and vascular reactivity in rats at high risk for developing the metabolic syndrome. Wistar rats were divided into two groups: control and fructose (F - water with 10 % fructose). After 2 weeks, the F group was divided into four groups: F, fructose+arginine (FA, 880 mg/kg per d of l-arginine), fructose+training (FT) and fructose+arginine+training (FTA); treatments lasted for 8 weeks, and no difference was observed in body mass gain. Arginine did not improve the body protein content, and both the FA and FT groups show a reversal of the increase in adipose tissue. Insulin increase was prevented by training and arginine, without additive effect, and the increase in serum TAG was prevented only by training. The F group showed impaired endothelium-dependent vasodilation and hyperreactivity to phenylephrine, but arginine and training were capable of preventing these effects, even separately. Higher nitric oxide level was observed in the FA and FT groups, and no potentiating effect was detected. Thus, only training was able to prevent the increase in TAG and improve the protein mass, and training and arginine exert similar effects on fat content, insulin and endothelial function, but these effects are not additive.