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Vascular Dysfunction (vascular + dysfunction)
Selected AbstractsUPREGULATED ENDOTHELIN SYSTEM IN DIABETIC VASCULAR DYSFUNCTION AND EARLY RETINOPATHY IS REVERSED BY CPU0213 AND TOTAL TRITERPENE ACIDS FROM FRUCTUS CORNICLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2007Wei Su SUMMARY 1The aims of the present study were to examine whether: (i) upregulation of the endothelin (ET) pathway is involved in impairment of vascular relaxation and early retinopathy in diabetic rats; and (ii) vascular and retinal abnormalities respond to the total triterpene acid (TTA) isolated from Fructus Corni compared with responses to the novel endothelin receptor antagonist CPU0213 and aminoguanidine (AMG), a special antagonist for advanced glycation end-products (AGE) and inducible nitric oxide synthase (iNOS). 2Male Sprague-Dawley rats were randomized into five groups, namely a normal control and four diabetic groups, which included an untreated diabetic group and groups treated with AMG (100 mg/kg, i.g.), CPU0213 (30 mg/kg, s.c.) or TTA (50 mg/kg, i.g.). Diabetes was induced by single injection of streptozotocin (60 mg/kg, i.p.) on the 1st day. The mRNA expression of prepro-endothelin-1 (ppET-1), endothelin-converting enzyme (ECE) and iNOS in the thoracic aorta and mRNA for ETA receptors and iNOS in the retina were detected by reverse transcription,polymerase chain reaction. Vasorelaxation to acetylcholine (ACh) and functional assessment of nitric oxide (NO) bioavailability was determined in the thoracic aorta. 3We observed upregulated mRNA expression of iNOS, ppET-1 and ECE in the thoracic aorta and upregulated mRNA for the ETA receptor and iNOS in the retina in the untreated diabetic group. Vasodilatation mediated by ACh and NO bioavailability were markedly reduced in the thoracic aorta compared with the normal control group. These abnormalities were essentially reversed by TTA, CPU0213 or AMG, with the exception with that AMG did not modify vasodilatation to ACh. 4These data suggest that upregulation of gene transcription of the ET system mediates depressed vasorelaxation, NO bioavailability and changes in iNOS and ETA receptors that reflect early retinopathy in diabetic rats. Total triterpene acid, in terms of pharmacological properties resembling the endothelin receptor antagonist CPU0213, is effective in normalizing expression of the ET system and iNOS in early diabetic retinopathy and vasculaopathy. [source] Higher carotid-radial pulse wave velocity in healthy offspring of patients with Type 2 diabetesDIABETIC MEDICINE, Issue 3 2004O. D. McEleavy Abstract Aims, To determine whether carotid-radial pulse wave velocity (crPWV), a simple non-invasive measurement of muscular artery structure and function, is increased in offspring of patients with Type 2 diabetes compared with well-matched controls with no family history of diabetes. Serum levels of intercellular adhesion molecule-1 (sICAM-1) were also examined. Methods, Offspring (n = 19, M = 8) were recruited via contact with patients attending clinics. Controls (n = 19, M = 8) were recruited by advertisement. crPWV was measured using COMPLIOR. Blood pressure and heart rate were determined and fasting blood taken for measurement of metabolic and endothelial parameters. Results, Offspring and controls were well matched [mean (sd)] for age [33.1 (9.6) vs. 32.8 (9.5) years], body mass index [24.8 (4.9) vs. 24.3 (3.4) kg/m2], waist circumference [78.3 (2.3) vs. 76.3 (2.5) cm], and systolic blood pressure [120 (9.3) vs. 119 (14.2) mmHg]. crPWV was 10% higher in the offspring [9.94 (1.3) m/s] compared with controls [9.01 (1.2) m/s, P = 0.02] despite similar pulse pressure [52 (10.5) vs. 53.5 (9.3) mmHg] and resting heart rate [71 (8.7) vs. 69 (14.0) beats/min]. They also showed a trend toward higher sICAM-1 [217 (55) vs. 188 (40) ng/ml, P = 0.07] concentrations which were also strongly correlated to crPWV in offspring (r = 0.63, P = 0.004). Conclusions, Vascular dysfunction in the form of increased muscular artery stiffness is present from an early stage in subjects at higher risk of developing diabetes. This may be secondary to impaired activation of endothelial signalling pathways in the context of inherited insulin resistance. [source] Endothelial dysfunction in rat adjuvant-induced arthritis: Vascular superoxide production by NAD(P)H oxidase and uncoupled endothelial nitric oxide synthaseARTHRITIS & RHEUMATISM, Issue 6 2006Yoshisuke Haruna Objective To investigate endothelial function and levels of vascular oxidative stress in rat adjuvant-induced arthritis (AIA), in view of mounting evidence for an association between rheumatoid arthritis (RA) and accelerated vascular disease. Methods Thoracic aortic rings were prepared from AIA and control rats. After preconstriction by norepinephrine, the vasodilatory response to acetylcholine was determined. The amounts of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine in AIA rat aortas were measured by Western blotting. Homogenates of the aortas were incubated with various substrates for superoxide-producing enzymes, and superoxide production was assessed by fluorogenic oxidation of dihydroethidium to ethidium. Expression of endothelial nitric oxide synthase (eNOS) in aortas was examined by real-time reverse transcriptase,polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin (BH4), a critical eNOS cofactor, were determined by high-performance liquid chromatography. Results Endothelium-dependent relaxation of the aortic ring was significantly depressed in AIA rats compared with control rats. The amounts of HNE and nitrotyrosine were increased in AIA rat aortas, indicating overproduction of reactive oxygen species. Incubation of AIA rat aorta homogenates with NADH or L -arginine, a substrate of eNOS, resulted in a significant increase in superoxide production. Endothelial NOS was highly expressed in AIA rat aortas. Serum levels of BH4 were significantly lower in AIA. Treatment of AIA with BH4 reversed the endothelial dysfunction, suggesting that its deficiency may contribute to the uncoupling of eNOS. Conclusion Vascular dysfunction in RA can be partially modeled in animals. NAD(P)H oxidase and uncoupled eNOS are responsible for the increase in vascular oxidative stress, which is likely to be involved in the endothelial dysfunction in AIA. [source] Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular diseaseACTA PHYSIOLOGICA, Issue 1 2010D. Lominadze Abstract Fibrinogen (Fg) is a high molecular weight plasma adhesion protein and a biomarker of inflammation. Many cardiovascular and cerebrovascular disorders are accompanied by increased blood content of Fg. Increased levels of Fg result in changes in blood rheological properties such as increases in plasma viscosity, erythrocyte aggregation, platelet thrombogenesis, alterations in vascular reactivity and compromises in endothelial layer integrity. These alterations exacerbate the complications in peripheral blood circulation during cardiovascular diseases such as hypertension, diabetes and stroke. In addition to affecting blood viscosity by altering plasma viscosity and erythrocyte aggregation, growing experimental evidence suggests that Fg alters vascular reactivity and impairs endothelial cell layer integrity by binding to its endothelial cell membrane receptors and activating signalling mechanisms. The purpose of this review is to discuss experimental data, which demonstrate the effects of Fg causing vascular dysfunction and to offer possible mechanisms for these effects, which could exacerbate microcirculatory complications during cardiovascular diseases accompanied by increased Fg content. [source] The effects of lipid-lowering drug therapy on cardiovascular responsiveness in type 2 diabetic patientsDIABETES OBESITY & METABOLISM, Issue 1 2006Laurence Guy HowesArticle first published online: 18 MAR 200 Type 2 diabetes is associated with a high prevalence of dyslipidaemia and a high incidence of cardiovascular disease. Lipid lowering therapy with HMG Co-A reductase inhibitors (statins) reduce the risk of cardiovascular events in type 2 diabetic and non-diabetic patients, effects which are believed to be partly due to improvements in vascular function. The aetiology of abnormal vascular function in type 2 diabetics is likely to be multifactorial and the pattern of vascular dysfunction in type 2 diabetes may differ from that which occurs in non-diabetic patients with dyslipidaemia. Abnormalities in endothelium derived hyperpolarising factor (EDHF) mediated vasodilation in resistance vessels may be more prominent in both type 1 and type 2 diabetes than in non-diabetic patients with endothelial dysfunction. The effects of lipid lowering therapy on vascular responsiveness may differ in type 2 diabetic patients from those found in non-diabetic patients. Statin therapy does not appear to improve responses to endothelial dependent vasodilators in type 2 diabetics, but may alter the ratio between nitric oxide (NO) and EDHF mediated responses. Fibrate therapy improves flow mediated dilation of brachial arteries in type 2 diabetic patients, but only appears to improve endothelium dependant vasodilator responses in resistance vessels when given in conjunction with co-enzyme Q. [source] Diabetic neuropathy and oxidative stressDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2006Rodica Pop-Busui Abstract This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-related neural dysfunction. Oxidative stress occurs when the balance between the production of reactive oxygen species (ROS) and the ability of cells or tissues to detoxify the free radicals produced during metabolic activity is tilted in the favor of the former. Although hyperglycemia plays a key role in inducing oxidative stress in the diabetic nerve, the contribution of other factors, such as endoneurial hypoxia, transition metal imbalances, and hyperlipidemia have been also suggested. The possible sources for the overproduction of ROS in diabetes are widespread and include enzymatic pathways, auto-oxidation of glucose, and mitochondrial superoxide production. Increase in oxidative stress has clearly been shown to contribute to the pathology of neural and vascular dysfunction in diabetes. Potential therapies for preventing increased oxidative stress in diabetic nerve dysfunction will be discussed. Copyright © 2006 John Wiley & Sons, Ltd. [source] Paradox of simultaneous intestinal ischaemia and hyperaemia in inflammatory bowel diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2005O. A. Hatoum Abstract This review has focused on evidence regarding intestinal perfusion of inflammatory bowel disease (IBD). Basic investigation has defined an altered microvascular anatomy in the affected IBD bowel, which corresponds with diminished mucosal perfusion in the setting of chronic, long-standing inflammation. Diminished perfusion is linked to impaired wound healing, and may contribute to the continued refractory mucosal damage, which characterizes IBD. Alterations in vascular anatomy and physiology in IBD suggests additional possible mechanisms by which micro-vessels may contribute to the initiation and perpetuation of IBD. This begs the following questions: will angiogenesis within the gut lead to sustained inflammation, does the growing vasculature generate factors that transform the surrounding tissue and does angiogenesis generate vascular anastomosis within the gut, with shunting of blood away from the mucosal surface, impairment of metabolism and potentiation of gut damage? Further studies are required to define the mechanisms that underlie the vascular dysfunction and its role in pathophysiology of IBD. [source] Free fatty acids exert a greater effect on ocular and skin blood flow than triglycerides in healthy subjectsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2004M. Bayerle-Eder Abstract Background, Free fatty acids (FFAs) and triglycerides (TGs) can cause vascular dysfunction and arteriosclerosis. Acute elevation of plasma FFA and TG concentration strongly increase ocular and skin blood flow. This study was designed to discriminate whether FFA or TG independently induce hyperperfusion by measuring regional and systemic haemodynamics. Methods, In a balanced, randomized, placebo-controlled, double-blind, three-way, crossover study nine healthy subjects received either Intralipid® (Pharmacia and Upjohn, Vienna, Austria) with heparin, Intralipid® alone or placebo control. Pulsatile choroidal blood flow was measured with laser interferometry, retinal blood flow and retinal red blood cell velocity with laser Doppler velocimetry, and skin blood flow with laser Doppler flowmetry during an euglycaemic insulin clamp. Results, A sevenfold increase of FFA during Intralipid®/heparin infusion was paralleled by enhanced choriodal, retinal, and skin blood flow by 17 ± 4%, 26 ± 5% (P < 0·001), and 47 ± 19% (P = 0·03) from baseline, respectively. In contrast, a mere threefold increase of FFA by infusion of Intralipid® alone did not affect outcome parameters, despite the presence of plasma TG levels of 250,700 mg dL,1; similar to those obtained during combined Intralipid®/heparin infusion. Systemic haemodynamics were not affected by drug infusion. Conclusions, Present findings demonstrate a concentration-dependent increase in ocular and skin blood flow by FFA independently of elevated TG plasma concentrations. As vasodilation of resistance vessels occur rapidly, FFA may play a role in the development of continued regional hyperperfusion and deteriorate microvascular function. [source] Red blood cells in the metabolism of nitric oxide-derived peroxynitriteIUBMB LIFE, Issue 10 2006Natalia Romero Abstract In this review we have analyzed the reactions of nitric oxide (·NO) with superoxide radical (O2·-) at the vascular compartment which results in limitation of the bioavailability of ·NO and the formation of peroxynitrite (ONOO-), a strong oxidant species. The intravascular formation of peroxynitrite can result in oxidative modifications of plasma and vessel wall proteins including the formation of protein-3-nitrotyrosine. The role of red blood cells (RBC) and oxyhemoglobin in the metabolism of intravascular peroxynitrite will be discussed. While RBC constitute an important 'sink' of both ·NO and peroxynitrite, redox reactions of these species with oxyhemoglobin may in part contribute to erythrocyte aging. The intravascular formation, reactions and detoxification of peroxynitrite are revealed as important factors controlling vascular dysfunction and degeneration in a variety of pathophysiologically-relevant conditions. iubmb Life, 58: 572-580, 2006 [source] Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathyJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Mohanraj Rajesh Abstract In this study, we investigated the effect of the xanthine oxidase (XO) inhibitor, allopurinol (ALP), on cardiac dysfunction, oxidative-nitrosative stress, apoptosis, poly(ADP-ribose) polymerase (PARP) activity and fibrosis associated with diabetic cardiomyopathy in mice. Diabetes was induced in C57/BL6 mice by injection of streptozotocin. Control and diabetic animals were treated with ALP or placebo. Left ventricular systolic and diastolic functions were measured by pressure,volume system 10 weeks after established diabetes. Myocardial XO, p22phox, p40phox, p47phox, gp91phox, iNOS, eNOS mRNA and/or protein levels, ROS and nitrotyrosine (NT) formation, caspase3/7 and PARP activity, chromatin fragmentation and various markers of fibrosis (collagen-1, TGF-,, CTGF, fibronectin) were measured using molecular biology and biochemistry methods or immunohistochemistry. Diabetes was characterized by increased myocardial, liver and serum XO activity (but not expression), increased myocardial ROS generation, p22phox, p40phox, p47phox, p91phox mRNA expression, iNOS (but not eNOS) expression, NT generation, caspase 3/7 and PARP activity/expression, chromatin fragmentation and fibrosis (enhanced accumulation of collagen, TGF-,, CTGF and fibronectin), and declined systolic and diastolic myocardial performance. ALP attenuated the diabetes-induced increased myocardial, liver and serum XO activity, myocardial ROS, NT generation, iNOS expression, apoptosis, PARP activity and fibrosis, which were accompanied by improved systolic (measured by the evaluation of both load-dependent and independent indices of myocardial contractility) and diastolic performance of the hearts of treated diabetic animals. Thus, XO inhibition with ALP improves type 1 diabetes-induced cardiac dysfunction by decreasing oxidative/nitrosative stress and fibrosis, which may have important clinical implications for the treatment and prevention of diabetic cardiomyopathy and vascular dysfunction. [source] Mitochondrial mechanism of oxidative stress and systemic hypertension in hyperhomocysteinemiaJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2005Neetu Tyagi Abstract Formation of homocysteine (Hcy) is the constitutive process of gene methylation. Hcy is primarily synthesized by de-methylation of methionine, in which s-adenosyl-methionine (SAM) is converted to s-adenosyl-homocysteine (SAH) by methyltransferase (MT). SAH is then hydrolyzed to Hcy and adenosine by SAH-hydrolase (SAHH). The accumulation of Hcy leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased. In this process, Ca2+ -dependent mitochondrial nitric oxide synthase (mtNOS) and calpain are induced which lead to cytoskeletal de-arrangement and cellular remodeling. This process generates peroxinitrite and nitrotyrosine in contractile proteins which causes vascular dysfunction. Chronic exposure to Hcy instigates endothelial and vascular dysfunction and increases vascular resistance causing systemic hypertension. To compensate, the heart increases its load which creates adverse cardiac remodeling in which the elastin/collagen ratio is reduced, causing cardiac stiffness and diastolic heart failure in hyperhomocysteinemia. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Vascular Function Measured by Fingertip Thermal Reactivity Is Impaired in Patients With Metabolic Syndrome and Diabetes MellitusJOURNAL OF CLINICAL HYPERTENSION, Issue 11 2009Naser Ahmadi MD Digital thermal monitoring (DTM) of vascular function has already been shown to correlate well with coronary artery calcium (CAC) score and coronary artery disease. To determine its utility in the metabolic syndrome (MS) and diabetes mellitus (DM), 233 asymptomatic patients with DM/MS but without coronary artery disease underwent DTM during and after 5 minutes of supra-systolic arm cuff inflation, as well as CAC. Post-cuff deflation adjusted temperature rebound (aTR) was lower in MS and DM compared with the normal group. The odds ratio of lowest vs upper 2 tertiles of aTR was 2.3 for MS and 3.5 for DM compared with the normal group, independent of age, sex, and risk factors. The area under the receiver operating characteristic curve to predict CAC ,100 was 0.69 for metabolic status (DM/MS), 0.79 for aTR, and 0.87 for both. This study demonstrates that vascular dysfunction measured by DTM is associated with DM/MS and could potentially be used to detect asymptomatic individuals with increased subclinical atherosclerosis. [source] Women with a recent history of early-onset pre-eclampsia have a worse periodontal conditionJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 3 2007Alina Kunnen Abstract Objective: Pre-eclampsia is a complication of pregnancy characterized by systemic vascular dysfunction and pathological changes in placental arteries. Growing evidence of chronic infection as an aetiological factor in vascular diseases prompted us to study maternal periodontal disease in subjects with early-onset pre-eclampsia (<34 weeks). Methods: A case,control study was carried out on 17 early-onset pre-eclamptic women and 35 controls with uncomplicated pregnancies in a period of 3,28 months postpartum. All were Caucasians. Full-mouth periodontal examinations were performed to determine the periodontal condition. Subgingival-plaque samples were analysed by anaerobic culture techniques for the presence of seven bacterial periodontal pathogens. Potential confounders as age, smoking, educational level and body mass index were determined. Results: Severe periodontal disease was found in 82% of the pre-eclamptic and in 37% of the control group (p=0.009). After adjusting for age, smoking and educational level, the odds ratio was 7.9 (95% CI: 1.9,32.8). The periodontopathic microorganism Micromonas micros was more prevalent in the case group (p=0.040) while Campylobacter rectus was more prevalent in the control group (p=0.047). Conclusion: These results indicate that Caucasian women with a recent history of early-onset pre-eclampsia have a worse periodontal condition, as compared with women with uncomplicated deliveries. [source] Aldose Reductase and AGE,RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging ratsAGING CELL, Issue 5 2010Kellie McCormick Hallam Summary Aging is inevitably accompanied by gradual and irreversible innate endothelial dysfunction. In this study, we tested the hypothesis that accentuation of glucose metabolism via the aldose reductase (AR) pathway contributes to age-related vascular dysfunction. AR protein and activity levels were significantly increased in aged vs. young aortic homogenates from Fischer 344 rats. Immunostaining revealed that the principal site of increased AR protein was the aortic endothelium as well as smooth muscle cells. Studies revealed that endothelial-dependent relaxation (EDR) in response to acetylcholine was impaired in aged rats compared to young rats and that treatment with the AR inhibitor (ARI) zopolrestat significantly improved EDR in aged rats. Methylglyoxal (MG), a key precursor of advanced glycation endproducts (AGEs), was significantly increased in the aortas of aged rats vs. young rats. Consistent with central roles for AR in generation of MG in aging, ARI treatment significantly reduced MG levels in aged rat aorta to those in young rats. Treatment of aged rats with soluble(s) RAGE, a soluble form of the chief signal transduction receptor for AGEs, RAGE, significantly improved EDR in aged rats, thus establishing the contribution of age-related increases in AGEs to endothelial dysfunction. These findings reveal that significant increases in AR expression and activity in aged rat vasculature linked to endothelial dysfunction may be mitigated, at least in part, via ARI and that aging-linked increased flux via AR generates AGEs; species which transduce endothelial injury consequent to their interaction with RAGE. These data demonstrate for the first time that AR mediates aging-related vascular dysfunction, at least in part, via RAGE. [source] Melatonin prevents lipopolysaccharide-induced hyporeactivity in ratJOURNAL OF PINEAL RESEARCH, Issue 3 2004Roberta D'Emmanuele Di Villa Bianca Abstract:, Melatonin (MT) is the principal secretory product of the pineal gland and its role as an immumo-modulator is well established. Recent evidence shows that MT exerts protective effects in septic shock, hemorrhagic shock and inflammation. Lipopolysaccharide (LPS), from Escherichia coli, administered to animals directly stimulates a number of cells and systems to produce various inflammatory mediators. LPS-induced septic shock is characterized by hypotension and vascular hyporeactivity to contracting agents. In particular, the reactive oxygen species such as superoxide and nitric oxide (NO) contribute to the pathophysiology of septic shock. In this study, we demonstrate that MT pretreatment prevents the hyporeactivity to phenylephrine in vivo and in aorta rings collected from rats treated with the endotoxin. The beneficial effect of MT seems related to its antioxidant properties and with inhibition of inducible nitric oxide synthase (iNOS) protein expression, reduction of NO production and nitrotyrosine formation, in aorta, preventing vascular, and endothelial injury. Additionally, we first demonstrate, that MT inhibited nuclear enzyme poly (ADP-ribose) synthetase activation in vascular tissue. The current study underlined the protective effect of MT on the vascular dysfunction associated with septic shock, data that could support the clinical use of MT in human endotoxemia. [source] CD146-based immunomagnetic enrichment followed by multiparameter flow cytometry: a new approach to counting circulating endothelial cellsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2008A. WIDEMANN Summary.,Background: Circulating endothelial cells (CECs) have emerged as non-invasive biomarkers of vascular dysfunction. The most widely used method for their detection is CD146-based immunomagnetic separation (IMS). Although this approach has provided consensus values in both normal and pathologic situations, it remains tedious and requires a trained operator. Objectives: Our objective was to evaluate a new hybrid assay for CEC measurement using a combination of pre-enrichment of CD146+ circulating cells and multiparametric flow cytometry measurement (FCM). Patients and methods: CECs were determined in peripheral blood from 20 healthy volunteers, 12 patients undergoing coronary angioplasty, and 30 renal transplant recipients, and blood spiked with cultured endothelial cells. CD146+ cells were isolated using CD146-coated magnetic nanoparticles and labeled using CD45,fluorescein isothiocyanate and CD146,PE or isotype control antibody and propidium iodide before FCM. The same samples were also processed using CD146-based immunomagnetic separation as the reference method. Results: The hybrid assay detected CECs, identified as CD45dim/CD146bright/propidium iodide+, with high size-related scatter characteristics, and clearly discriminated these from CD45bright/CD146dim activated T lymphocytes. The method demonstrated both high recovery efficiency and good reproducibility. Both IMS and the hybrid assay similarly identified increased CEC levels in patients undergoing coronary angioplasty and renal transplantation, when compared to healthy controls. In patients, CEC values from these two methods were of the same order of magnitude and highly correlated. Bland,Altman analysis revealed poor statistical agreement between methods, flerrofluid,FCM providing higher values than IMS. Conclusion: This new hybrid FCM assay constitutes an accurate alternative to visual counting of CECs following CD146-based IMS. [source] Impact of Chronic Anticholesterol Therapy on Development of Microvascular Rarefaction in the Metabolic SyndromeMICROCIRCULATION, Issue 8 2009Adam G. Goodwill ABSTRACT Objective: The obese Zucker rat (OZR) model of the metabolic syndrome is partly characterized by moderate hypercholesterolemia, in addition to other contributing comorbidities. Previous results suggest that vascular dysfunction in OZR is associated with chronic reduction in vascular nitric-oxide (NO) bioavailability and chronic inflammation, both frequently associated with hypercholesterolemia. As such, we evaluated the impact of chronic cholesterol-reducing therapy on the development of impaired skeletal muscle arteriolar reactivity and microvessel density in OZR and its impact on chronic inflammation and NO bioavailability. Materials and Methods: Beginning at seven weeks of age, male OZR were treated with gemfibrozil, probucol, atorvastatin, or simvastatin (in chow) for 10 weeks. Subsequently, plasma and vascular samples were collected for biochemical/molecular analyses, while arteriolar reactivity and microvessel network structure were assessed by using established methodologies after 3, 6, and 10 weeks of drug therapy. Results: All interventions were equally effective at reducing total cholesterol, although only the statins also blunted the progressive reductions to vascular NO bioavailability, evidenced by greater maintenance of acetylcholine-induced dilator responses, an attenuation of adrenergic constrictor reactivity, and an improvement in agonist-induced NO production. Comparably, while minimal improvements to arteriolar wall mechanics were identified with any of the interventions, chronic statin treatment reduced the rate of microvessel rarefaction in OZR. Associated with these improvements was a striking statin-induced reduction in inflammation in OZR, such that numerous markers of inflammation were correlated with improved microvascular reactivity and density. However, using multivariate discriminant analyses, plasma RANTES (regulated on activation, normal T-cell expressed and secreted), interleukin-10, monocyte chemoattractant protein-1, and tumor necrosis factor alpha were determined to be the strongest contributors to differences between groups, although their relative importance varied with time. Conclusions: While the positive impact of chronic statin treatment on vascular outcomes in the metabolic syndrome are independent of changes to total cholesterol, and are more strongly associated with improvements to vascular NO bioavailability and attenuated inflammation, these results provide both a spatial and temporal framework for targeted investigation into mechanistic determinants of vasculopathy in the metabolic syndrome. [source] Inflammatory and Hemodynamic Changes in the Cerebral Microcirculation of Aged Rats after Global Cerebral Ischemia and ReperfusionMICROCIRCULATION, Issue 4 2008Leslie Ritter ABSTRACT Effects of aging on inflammation and blood flow in the brain are unclear. Young (three to six months) and aged (19,22 months) male Brown Norway Fisher rats were used to compare (i) leukocyte function in nonischemic conditions and (ii) leukocyte function and hemodynamic changes after ischemia-reperfusion (I-R). In nonischemic studies, polymorphonuclear (PMN) CD11b expression and reactive oxygen species (ROS) production were measured with flow cytometry and PMN chemotaxis was measured with a Boyden chamber (+/-fMLP). In I-R studies, ischemia was induced by bilateral carotid artery occlusion and hypotension (20 minutes). During early reperfusion (30 minutes), leukocyte adhesion and rolling and blood-shear rates were measured using fluorescence microscopy. During late reperfusion (48 hours), mortality, neurological function, and leukocyte infiltration were measured. Stimulated PMN chemotaxis was increased in nonischemic aged rats (p < 0.05). In early reperfusion, there was a significant increase in leukocyte rolling and adhesion in the cerebral microcirculation and a significant decrease in shear rate in aged rats, compared to the young (p < 0.05). During late reperfusion, neurologic function was worse in aged vs. young rats (p < 0.05). These findings suggest that increased intravascular PMN adhesion and vascular dysfunction may contribute to poor neurologic outcome after cerebral I-R in the aged brain. [source] ORIGINAL ARTICLE: Role of Inflammatory Cytokines and eNOS Gene Polymorphism in Pathophysiology of Pre-EclampsiaAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2010Archana Singh Citation Singh A, Sharma D, Raghunandan C, Bhattacharjee J. Role of inflammatory cytokines and eNOS gene polymorphism in pathophysiology of pre-eclampsia. Am J Reprod Immunol 2010; 63: 244,251 Problem, Pre-eclampsia involves endothelial vascular dysfunction. The aim of this study was to test the hypothesis that (i) endothelial nitric oxide (NO) synthase Glu298Asp gene polymorphism limits constitutive NO production causing endothelial dysfunction and (ii) inflammatory cytokines impairs endothelium dependent relaxation in pre-eclampsia. Method of study, This cross-sectional study included 50 women with pre-eclampsia and 50 healthy pregnant women. Their blood samples were analyzed for NO, inflammatory cytokines and endothelial NO synthase (eNOS) gene polymorphism. Result, Decreased NO levels whereas increased tumor necrosis factor-,, interleukin (IL)-6 and interleukin-2 were found in pre-eclampsia (P < 0.001). No significant differences were found in genotype/allele distribution between two groups. Significant negative correlation was observed between NO and IL-6 in pre-eclamptic group (P = 0.001). Conclusion, An IL-6-mediated endothelium dependent NO-cyclic guanine monophosphate-mediated relaxation pathway may be inhibited in systemic vessels in pre-eclampsia. As observed in this study Glu298Asp eNOS gene polymorphism did not showed significant association with pre-eclampsia. [source] Sustained improvement of spinal muscular atrophy mice treated with trichostatin a plus nutritionANNALS OF NEUROLOGY, Issue 4 2008Heather L. Narver VMD Early treatment with the histone deacetylase inhibitor, trichostatin A, plus nutritional support extended median survival of spinal muscular atrophy mice by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after trichostatin A was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe spinal muscular atrophy. Early spinal muscular atrophy disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of histone deacetylase inhibitor treatment in human patients. Ann Neurol 2008; 64:465,470 [source] Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: Implications for vascular dysfunction and progression of diseaseARTHRITIS & RHEUMATISM, Issue 7 2003Sanjay Rajagopalan Objective To compare microvascular and macrovascular functions in a cohort of patients with primary and secondary Raynaud's phenomenon (RP) who were matched for demographic, risk factor, and severity profiles. Methods Forty patients with primary or secondary RP matched for vascular risk factors and severity scores underwent testing of endothelial function and cold pressor responsiveness of the brachial artery. Microvascular perfusion of the digital vasculature was assessed using laser Doppler fluxmetry in response to reactive hyperemia. Plasma was assayed for endothelin 1 (ET-1), asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1). Results Patients with RP had abnormal vasoconstrictor responses to cold pressor tests (CPT) that were similar in primary and secondary RP. There were no differences in median flow-mediated and nitroglycerin-mediated dilation or CPT of the brachial artery in the 2 populations. Patients with secondary RP were characterized by abnormalities in microvascular responses to reactive hyperemia, with a reduction in area under the curve adjusted for baseline perfusion, but not in time to peak response or peak perfusion ratio. Plasma ET-1, ADMA, VCAM-1, and MCP-1 levels were significantly elevated in secondary RP compared with primary RP. There was a significant negative correlation between ET-1 and ADMA values and measures of microvascular perfusion but not macrovascular endothelial function. Conclusion Secondary RP is characterized by elevations in plasma ET-1 and ADMA levels that may contribute to alterations in cutaneous microvascular function. [source] Screening for atherosclerosis in patients with rheumatoid arthritis: Comparison of two in vivo tests of vascular functionARTHRITIS & RHEUMATISM, Issue 1 2003S. Van Doornum Objective Inflammation appears to play a central role in atherosclerosis, and endothelial damage mediated by systemic inflammation may contribute to the increased cardiovascular mortality in rheumatoid arthritis (RA). Brachial artery flow-mediated dilatation (FMD) and pulse wave analysis (PWA) are measures of vascular function. The aim of this study was to determine if FMD and PWA are abnormal in patients with RA. Methods Twenty-five RA patients and 25 matched healthy controls were studied. All were free of traditional cardiovascular risk factors. FMD was measured in all subjects. PWA was performed in 18 RA patients and 18 controls, with results expressed as large and small artery compliance (C1 and C2). Modified Sharp scores were calculated in 13 RA patients. Results Results (mean ± SD) in RA patients and controls, respectively, were as follows: FMD 107.6 ± 4.6% versus 108.5 ± 4.1% (P = 0.49), C1 14.8 ± 2.8 ml/mm Hg × 10 versus 17.9 ± 3.1 ml/mm Hg × 10 (P = 0.0033), C2 4.5 ± 2.3 ml/mm Hg × 100 versus 7.7 ± 3.7 ml/mm Hg × 100 (P = 0.0039). There was an inverse correlation between C2 and modified Sharp scores in the RA patients (Spearman's rho ,0.69, P = 0.0085). Conclusion FMD was normal in these RA patients, whereas arterial compliance was markedly reduced. PWA appears to be a more sensitive measure of vascular dysfunction than FMD in RA and may be the preferred surrogate marker of vascular dysfunction in longitudinal studies of RA patients. The inverse correlation between C2 and the modified Sharp score, a measure that reflects disease activity over time, supports the notion that chronic inflammation plays a role in RA-associated atherosclerosis. [source] The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsiveness of rat carotid arteryAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2005M. H. M. Yousif Summary 1 G-protein-coupled receptor signalling, including transactivation of receptor tyrosine kinases (RTKs), has been implicated in vascular pathology. However, the role of specific RTKs in the development of diabetes-induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of genistein, a broad-spectrum inhibitor of tyrosine kinases (TKs), AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) TK activity, and AG825, a specific inhibitor of Erb2, to modulate the altered vasoreactivity of isolated carotid artery ring segments to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. 3 In diabetic carotid artery, the vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas vasodilator responses to carbachol and histamine were significantly reduced. Inhibition of TKs, EGFR or Erb2 pathway did not affect the body weight or agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. However, inhibition of TKs by genistein, EGFR TK by AG1478 or Erb2 by AG825 treatment produced a significant normalization of the altered agonist-induced vasoconstrictor responses without affecting blood glucose levels. Treatment with diadzein, an inactive analogue of genistein, did not affect the vasoconstrictor and vasodilator responses in the diabetic animals. 4 Treatment with genistein, AG1478 or AG825 resulted in a significant improvement in diabetes-induced impairment in endothelium-dependent relaxation to carbachol and histamine. 5 These data suggest that activation of TK-mediated pathways, including EGFR TK signalling and Erb2 pathway, are involved in the development of diabetic vascular dysfunction in the carotid artery. [source] Inhibition of calcium/calmodulin-dependent protein kinase II normalizes diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bedAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2003M. H. M. Yousif Summary 1 Calcium/calmodulin-dependent protein kinase II (CaMKII) has an important function in mediating insulin release but its role in the development of diabetes-induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of KN-93 (5 mg kg,1alt diem for 4 weeks), an inhibitor of CaMKII, to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. 3 The vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas, vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of the STZ-diabetic rats as compared with non-diabetic controls. 4 Inhibition of CaMKII by KN-93 treatment did not affect blood glucose levels but produced a significant normalization of the altered agonist-induced vasoconstrictor and vasodilator responses. KN-93 did not affect agonist-induced responses in control animals. In addition, KN-93 significantly reduced weight loss in diabetic rats. 5 The present data suggest that CaMKII is an essential mediator in the development of diabetic vascular dysfunction and may also play an important role in signalling pathways leading to weight loss during diabetes. [source] Can coenzyme Q10 improve vascular function and blood pressure?BIOFACTORS, Issue 1-4 2003Potential for effective therapeutic reduction in vascular oxidative stress Abstract Coenzyme Q10 (CoQ) is an endogenously synthesised compound that acts as an electron carrier in the mitochondrial electron transport chain. The presence of adequate tissue concentrations of CoQ may be important in limiting oxidative and nitrosative damage in vivo. Oxidative and nitrosative stress are likely to be elevated in conditions such as diabetes and hypertension. In these conditions elevated oxidative and nitrosative stress within the arterial wall may contribute to increased blood pressure and vascular dysfunction. The major focus of this review is the potential of CoQ to improve vascular function and lower blood pressure. Although there is substantial indirect support for the putative mechanism of effect of CoQ on the vascular system, to date there is little direct support for an effect of CoQ on in vivo markers of oxidative or nitrosative stress. The limited data available from studies in animal models and from human intervention studies are generally consistent with a benefit of CoQ on vascular function and blood pressure. The observed effects of CoQ on these endpoints are potentially important therapeutically. However, before any firm clinical recommendations can be made about CoQ supplementation, further intervention studies in humans are needed to investigate the effects of CoQ on vascular function, blood pressure and cardiovascular outcomes. The particularly relevant groups of patients for these studies are those with insulin resistance, type 2 diabetes, hypertension and the metabolic syndrome. [source] Improvement of radiation-induced healing delay by etanercept treatment in rat arteriesCANCER SCIENCE, Issue 8 2009Kenji Sugiyama Surgical treatment often causes difficulty in the irradiated field because of delayed wound healing, which is mainly due to vascular dysfunction. To overcome this difficulty, we attempted to accelerate the recovery from clamp injury in irradiated superficial epigastric arteries of rats as a model. Etanercept, a soluble receptor of tumor necrosis factor-,, was administered four times to rats with irradiated arteries before and after clamp injury. Loss of endothelial cells and necrosis of the media in the irradiated arteries continued for more than 1 week after the injury; however, in the rats treated with etanercept, the endothelial cells recovered in the intima, and ,-smooth muscle actin-positive smooth muscle cells recovered in the injured and irradiated arteries. After clamp injury of common carotid arteries that had previously been irradiated, the blood flow in these arteries was visualized by magnetic resonance (MR) angiography. The time-of-flight signal was weakened in the injured and irradiated arteries. This time-of-flight signal was recovered by the etanercept treatment. These findings suggest that etanercept improves the radiation-impaired healing of arteries in rats. (Cancer Sci 2009) [source] Age-related macular degeneration: hemodynamic changesACTA OPHTHALMOLOGICA, Issue 2009CJ POURNARAS Purpose Metabolic changes of the RPE associated to the dysfunction of choriocapillaries(CC)/RPE complex may induces the AMD-related changes. Additional vascular changes in the choroid potentially have deleterious effects on the RPE. Methods Quantification of CC number and lumen diameters in cross sections and alkaline phosphatase (APase) flat-embedding technique, expressing high constitutive APase activity in choriocapillaris and choroidal veins on human RPE/Bruch's Membrane/CC complex, significantly contributed to the analysis of the choroidal vasculature. Laser Doppler flowmetry (LDF) data provided additional information on the assessment of hemodynamic changes in AMD. Results Choroidal vascular density reduction and significant vasoconstriction of the choriocapillaries, occurs during the evolution of AMD. In eyes with geographic atrophy, the RPE degenerates first while CC loss is secondary to RPE degeneration. In eyes with exudative AMD, degeneration of the CC layer occurs while RPE is still functional. LDF data indicated choroidal blood flow decrease according to age and the degree of severity of AMD; the decrease in flow preceding the formation of choroidal CNV, strongly suggest that these changes may have a role in the development of CNV. As a result of vascular dysfunction, the choroidal blood flow is dysregulated in patients with neovascular AMD. The choroidal watershed zone (WZ) courses through the fovea more often in patients suffering from AMD than in age-matched controls, particularly in the presence of CNV. Choroidal neovascularisation usually arises within these WZ. Conclusion The role of choroidal ischemia in the pathophysiology of AMD is supported by the observed choroidal microcirculation anatomical and fucntional abnormalities. [source] Caspase-1/interleukin-1beta signaling in diabetic retinopathyACTA OPHTHALMOLOGICA, Issue 2008S MOHR Purpose The pro-inflammatory cytokine, interleukin-1, (IL-1,), is known to induce vascular dysfunction and cell death. Previously, we have shown that caspase-1 activity is increased in retinas of diabetic and galactosemic mice, and diabetic patients. Therefore, we investigated the role of IL-1, and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Methods First, we determined the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1, production and retinal capillary degeneration in diabetic and galactose-fed mice. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5mg/kg). Second, we examined the effect of genetic deletion of the IL-1, receptor on diabetes-induced caspase activities and retinal capillary degeneration using IL-1 receptor knock-out mice. Results At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1, production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro, but not in vivo. Mice deficient in the IL-1, receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. Conclusion These results indicate that the caspase-1/IL-1, signaling pathway plays an important role in diabetes-induced retinal pathology and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy. [source] Roles of Vitamins E and C on Neurodegenerative Diseases and Cognitive PerformanceNUTRITION REVIEWS, Issue 10 2002Antonio Martin Demographic changes, together with improvements in nutrition, general health, and life expectancy, will greatly change the social and economic structures of most industrialized and developing countries in the next 50 years. Extended life expectancy has increased the number of chronic illnesses and disabilities, including cognitive impairments. Inflammatory processes and vascular dysfunctions appear to play important roles in the pathogenesis of age-associated pathologies including Alzheimer's and Parkinson's disease. A large body of evidence shows that both vitamins E and C are important for the central nervous system and that a decrease in their concentrations causes structural and functional damage to the cells. Several studies reveal a link between diets rich in fruits and vegetables containing generous amounts of vitamins E and C and lower incidence of certain chronic diseases. [source] Oxidative stress: The special case of diabetesBIOFACTORS, Issue 1-2 2003N. F. Wiernsperger Abstract The implication of oxidative stress (OS) in diabetes is a major concern for the development of therapeutics aimed at improving the metabolic and/or vascular dysfunctions of this burdening disease. Ample evidence is available suggesting that OS is present in essentially all tissues and can even be observed in prediabetic states. This raises the question of the origin of OS and suggests that, although hyperglycemia is largely linked with free radical production, its role may mainly be the aggravation of a preexisting state. Indeed other factors are also causally linked to OS, such as hormones and lipids. The main debate is about the pertinence of antioxidant therapy since the large scale clinical trials performed recently have essentially failed to show any significant improvement in metabolic or vascular disturbances of diabetic patients. However this conclusion must be tempered by the fact that they have mainly been using vitamin E +/-C; indeed many arguments suggest that either the choice or the application modalities of these substances may have been inadequate. Potential reasons for the actual failure of antioxidant therapy in diabetes are discussed; the indisputable involvement of OS in this disease still leaves hope for alternative therapeutic approaches. [source] | ||||||||||||||||||||||||||||