3-nitrotyrosine and Hyperemia

Endothelial dysfunction is a fundamental step in the atherosclerotic disease process. Activation or injury of the endothelium leads to a variety of inflammatory disorders, including the release of microparticles. Endothelial progenitor cells may contribute to the maintenance of the endothelium by replacing injured mature endothelial cells.. We studied the influence of dietary fat on the release of endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) in elderly subjects.. Twenty healthy, elderly subjects (10 men and 10 women) consumed 3 diets following a randomized crossover design, each for 4 wk: a saturated fatty acid diet; a low-fat, high-carbohydrate diet; and a Mediterranean diet (MedDiet) enriched in monounsaturated fatty acids. We investigated total microparticles, EMPs from activated endothelial cells (activated EMPs), EMPs from apoptotic endothelial cells (apoptotic EMPs), EPCs, oxidative stress variables, and ischemic reactive hyperemia (IRH).. The MedDiet led to lower total microparticle, activated EMP, and apoptotic EMP concentrations and higher EPC numbers than did the other diets (P < 0.001). We detected lower superoxide dismutase activity (P < 0.001), a higher plasma β-carotene concentration (P < 0.001), and lower urinary isoprostane and plasma nitrotyrosine concentrations after consumption of the MedDiet than after consumption of the other 2 diets (P < 0.05). Furthermore, the occurrence of IRH was higher after consumption of the MedDiet than after consumption of the other 2 diets (P < 0.05).. Consumption of the MedDiet induces a reduction in endothelial damage and dysfunction, which is associated with an improvement in the regenerative capacity of the endothelium, in comparison with 2 other diets.

Topics: Aged; Apoptosis; Atherosclerosis; beta Carotene; Cell Count; Cross-Over Studies; Diet, Mediterranean; Dietary Fats; Endothelial Cells; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Humans; Hyperemia; Isoprostanes; Male; Oxidative Stress; Regeneration; Stem Cells; Superoxide Dismutase; Tyrosine

Obstructive sleep apnea (OSA) in children is associated with cardiovascular morbidity such as systemic and pulmonary hypertension. However, it remains unclear whether endothelial dysfunction occurs in pediatric OSA and whether it is reversible on effective treatment of OSA.. Consecutive nonobese children (aged 6 to 11 years) who were diagnosed with OSA after overnight polysomnography and control children matched on the basis of age, gender, ethnicity, and body mass index underwent blood draw the next morning for soluble CD40 ligand, asymmetric dimethylarginine (ADMA), and nitrotyrosine levels, as well as 2 iterations of 60-second cuff-occlusion tests for assessment of endothelial function. These tests were repeated 4 to 6 months after adenotonsillectomy. OSA children showed blunted reperfusion kinetics after release of occlusion, which completely normalized in 20 of 26 patients after adenotonsillectomy. All 6 children in whom no improvements occurred had a strong family history of cardiovascular disease (versus 2 of the remaining 20 patients; P<0.04). Plasma nitrotyrosine and ADMA levels were similar in OSA and control children; however, soluble CD40 ligand levels were higher in OSA children and were reduced after treatment, particularly in those with normalized hyperemic responses.. Postocclusive hyperemia is consistently blunted in children with OSA, and such altered endothelial function is reversible 4 to 6 months after treatment, particularly if a family history of cardiovascular disease is not present. Although no evidence for either nitric oxide-dependent oxidative/nitrosative stress or for the increased presence of the circulating nitric oxide synthase inhibitor ADMA was found in children with OSA, soluble CD40 ligand levels were increased in OSA and reflected the changes in endothelial function after treatment.

Topics: Adenoidectomy; Arginine; Body Weight; CD40 Ligand; Child; Endothelium, Vascular; Female; Humans; Hyperemia; Hypoxia; Male; Nitric Oxide; Polysomnography; Sleep Apnea, Obstructive; Tonsillectomy; Tyrosine; Vasculitis

Dysregulation of cerebral vascular function and, ultimately, cerebral blood flow (CBF) may contribute to complications such as stroke and cognitive decline in diabetes. We hypothesized that 1) diabetes-mediated neurovascular and myogenic dysfunction impairs CBF and 2) under hypoxic conditions, cerebral vessels from diabetic rats lose myogenic properties because of peroxynitrite (ONOO(-))-mediated nitration of vascular smooth muscle (VSM) actin. Functional hyperemia, the ability of blood vessels to dilate upon neuronal stimulation, and myogenic tone of isolated middle cerebral arteries (MCAs) were assessed as indices of neurovascular and myogenic function, respectively, in 10- to 12-week control and type 2 diabetic Goto-Kakizaki rats. In addition, myogenic behavior of MCAs, nitrotyrosine (NY) levels, and VSM actin content were measured under normoxic and hypoxic [oxygen glucose deprivation (OGD)] conditions with and without the ONOO(-) decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl) prophyrinato iron (III), chloride (FeTPPs). The percentage of myogenic tone was higher in diabetes, and forced dilation occurred at higher pressures. Functional hyperemia was impaired. Consistent with these findings, baseline CBF was lower in diabetes. OGD reduced the percentage of myogenic tone in both groups, and FeTPPs restored it only in diabetes. OGD increased VSM NY in both groups, and although FeTPPs restored basal levels, it did not correct the reduced filamentous/globular (F/G) actin ratio. Acute alterations in VSM ONOO(-) levels may contribute to hypoxic myogenic dysfunction, but this cannot be solely explained by the decreased F/G actin ratio due to actin nitration, and mechanisms may differ between control and diabetic animals. Our findings also demonstrate that diabetes alters the ability of cerebral vessels to regulate CBF under basal and hypoxic conditions.

Topics: Actins; Animals; Cell Hypoxia; Cerebrovascular Circulation; Diabetes Mellitus, Type 2; Disease Models, Animal; Hyperemia; Male; Metalloporphyrins; Middle Cerebral Artery; Muscle, Smooth, Vascular; Peroxynitrous Acid; Rats; Rats, Wistar; Tyrosine

We investigated the role of vascular oxidative stress in the mechanisms of the impairment in cerebrovascular regulation produced by the amyloid-beta peptide (Abeta). In particular, we sought to provide evidence of vascular oxidative stress in mice overexpressing the amyloid precursor protein (APP) and to determine whether the Abeta-induced attenuation in functional hyperemia is mediated by free radical overproduction. Oxidative/nitrosative stress was assessed by 3-nitrotyrosine immunoreactivity, while free radical production was determined in cerebral microvessels by hydroethidine microfluorography. To study functional hyperemia the somatosensory cortex was activated by whisker stimulation while local blood flow was monitored by laser-Doppler flowmetry. It was found that APP mice show signs of oxidative/nitrosative stress in pial and intracerebral blood vessels well before they develop oxidative stress in neurons and glia or amyloid plaques. Treatment of cerebral microvessels isolated from wild-type mice with Abeta (1 microM) increased free radical production as assessed by the hydroethidine technique. The Abeta-induced attenuation of the increase in somatosensory cortex blood flow produced by whisker stimulation was prevented by treatment with the free radical scavengers MnTBAP or tiron. These data provide evidence that in APP mice vascular oxidative stress precedes the development of parenchymal oxidative stress, and that Abeta-produced vascular reactive oxygen species are involved in the attendant attenuation in functional hyperemia. Thus, vascular oxidative stress is an early event in the course of the brain dysfunction produced by APP overexpression and Abeta, and, as such, could be the target of early therapeutic interventions based on antioxidants.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebrovascular Circulation; Free Radical Scavengers; Free Radicals; Humans; Hyperemia; Mice; Oxidative Stress; Peptide Fragments; Physical Stimulation; Reactive Oxygen Species; Regional Blood Flow; Somatosensory Cortex; Tyrosine