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1.
J Thromb Haemost ; 6(1): 20-31, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17944986

ABSTRACT

BACKGROUND: P-selectin is a cell adhesion molecule that is involved in atherogenesis, and soluble concentrations of this biomarker reflect cardiovascular risk. However, the clinical correlates and genetic characterization of soluble P-selectin have not been clearly elucidated. OBJECTIVE: To describe clinical and genetic correlates of circulating P-selectin in the community. METHODS: In Framingham Heart Study Offspring (European descent) and Omni (ethnic/racial minority) participants, we examined the association of cardiovascular risk factors with soluble P-selectin concentrations. In Offspring participants, we evaluated heritability, linkage and association of 29 SELP single-nucleotide polymorphisms (SNPs) with adjusted P-selectin concentrations. RESULTS: In multivariable analysis of 3,690 participants (54% women, mean age 60 +/- 10 years), higher log-transformed P-selectin concentrations were inversely associated with female sex and hormone replacement therapy, and positively associated with age, ethnic/racial minority status, cigarette smoking, waist circumference, systolic blood pressure, fasting glucose, and total/high-density lipoprotein cholesterol and triglyceride concentrations. Clinical factors explained 10.4% of the interindividual variability in P-selectin concentrations. In 571 extended pedigrees (n = 1,841) with >or= 2 phenotyped members per family, multivariable-adjusted heritability was 45.4 +/- 5.8%. Among the SELP SNPs examined, a non-synonymous SNP (rs6136) encoding a threonine-to-proline substitution at position 715 was highly significantly associated with decreased P-selectin concentrations (P = 5.2 x 10(-39)), explaining 9.7% of variation after adjustment for clinical factors. CONCLUSIONS: Multiple clinical factors and an SNP in the SELP gene were significantly associated with circulating P-selectin concentrations. One SNP in SELP explained significant variation in circulating P-selectin concentrations, even after accounting for known clinical correlates.


Subject(s)
Cardiovascular Diseases/etiology , P-Selectin/blood , Polymorphism, Single Nucleotide , Residence Characteristics , Aged , Cardiovascular Diseases/blood , Cardiovascular Diseases/genetics , Female , Genetic Linkage , Humans , Inheritance Patterns , Male , Middle Aged , Multivariate Analysis , Pedigree , Phenotype , Risk Factors
2.
Neurology ; 68(13): 1032-8, 2007 Mar 27.
Article in English | MEDLINE | ID: mdl-17389308

ABSTRACT

BACKGROUND: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). METHODS: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. RESULTS: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. CONCLUSIONS: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.


Subject(s)
Alzheimer Disease/drug therapy , Brain Ischemia/etiology , Brain/pathology , Inflammation Mediators/blood , Inflammation/complications , Inflammation/diagnosis , Adult , Age Distribution , Age Factors , Aged , Aged, 80 and over , Alzheimer Disease/blood , Alzheimer Disease/pathology , Biomarkers/analysis , Biomarkers/blood , Brain/physiopathology , Brain Ischemia/blood , Brain Ischemia/pathology , Cardiovascular Diseases/complications , Cross-Sectional Studies , Female , Humans , Inflammation/physiopathology , Inflammation Mediators/analysis , Interleukin-6/analysis , Interleukin-6/blood , Magnetic Resonance Imaging , Male , Middle Aged , Osteoprotegerin/analysis , Osteoprotegerin/blood , Sex Distribution , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/blood
3.
Aging Cell ; 5(4): 325-30, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16913878

ABSTRACT

Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging-related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40-89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = -0.41, P < 0.0001) and age-adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (r =-0.16, P = 0.007) and urinary 8-epi-PGF(2alpha) (r = -0.16, P = 0.005) - an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age-adjusted TRF length (hypertensives = 5.93 +/- 0.042 kb, normotensives = 6.07 +/- 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.


Subject(s)
Hypertension/blood , Insulin Resistance , Leukocytes/ultrastructure , Oxidative Stress , Telomere/ultrastructure , Adult , Aged , Cohort Studies , Humans , Leukocytes/physiology , Male , Middle Aged
4.
J Thromb Haemost ; 3(8): 1825-34, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16102049

ABSTRACT

Atherosclerosis and its resultant cardiovascular events represent a state of heightened oxidative stress that is commonly thought to contribute to atherogenesis. The aim of this review is to summarize the data linking oxidative events to the pathogenesis of atherosclerosis. Despite abundant data supporting the presence of lipid and protein oxidation in the vascular wall, the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis remain a fundamental problem for implicating oxidative stress as pathophysiologically important. Direct evidence that oxidative stress in general, and the oxidative modification of low-density lipoprotein in particular, is both necessary and sufficient for atherosclerosis has been difficult to find. There are many potential reasons for this difficulty, not the least of which is our lack of sufficient knowledge delineating the precise molecular events that beget oxidative stress in the vessel wall, and the precise mediators involved. Further investigation elucidating these oxidative events are required to provide us with the tools to limit oxidative stress at its source and ameliorate all of its secondary phenomena. Only then will we know what components of atherosclerosis are directly due to oxidative stress.


Subject(s)
Arteries/pathology , Endothelium, Vascular/pathology , Oxidative Stress , Animals , Arteries/metabolism , Atherosclerosis/pathology , Cardiovascular Diseases/metabolism , Cardiovascular System , Free Radicals , Humans , Inflammation , Lipid Metabolism , Lipoproteins, LDL/metabolism , Models, Biological , NADPH Oxidases/metabolism , Oxygen/metabolism
6.
Hypertension ; 38(6): 1349-54, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11751716

ABSTRACT

Black Americans have increased morbidity and mortality rates from cardiovascular disease, greater prevalence of hypertension, and altered responses to vasodilator medications compared with those of white Americans. Hypertension and black race have been linked to impaired vascular function in the microcirculation. To examine these effects and their interaction in the conduit vasculature, we examined vasomotor responses of the brachial artery by using high-resolution vascular ultrasound in 228 subjects (48% hypertensive, 54% black). Subjects had no history of diabetes mellitus and were matched for age and gender. Flow-mediated dilation (8.5+/-5.3% versus 11.7+/-6.3%, P<0.001) and nitroglycerin-mediated vasodilation (14.9+/-6.0 versus 18.5+/-7.8, P=0.003) were both impaired in hypertensive compared with normotensive individuals. Multivariate analysis identified higher systolic blood pressure (P=0.003) and larger baseline vessel (P<0.001) size as independent predictors of lower flow-mediated dilation. Race did not significantly influence flow-mediated dilation. In contrast, blacks had a greater vasodilator response to nitroglycerin compared with whites (17.7+/-7.5% versus 15.0+/-6.2%, respectively; P=0.02). By multivariate analysis, black race (P=0.004), smaller vessel size (P=0.001), lower serum glucose (P=0.02), lower systolic blood pressure (P=0.02), and lower serum total cholesterol (P=0.04) were independent predictors of higher nitroglycerin-mediated dilation. Thus, hypertension is associated with impaired NO-mediated vasodilation in the conduit brachial artery. Overall, race did not influence flow-mediated dilation, but black race was associated with an enhanced response to sublingual nitroglycerin. This later observation provides further evidence of racial differences in the responses to medical therapy that may be relevant to the treatment of patients with cardiovascular disease.


Subject(s)
Black People , Hypertension/drug therapy , Hypertension/physiopathology , Nitroglycerin/pharmacology , Vasodilation/drug effects , Adult , Black People/genetics , Brachial Artery/physiopathology , Female , Humans , Male , Middle Aged , Multivariate Analysis , Vasodilation/genetics , White People
7.
Free Radic Biol Med ; 31(10): 1245-53, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11705703

ABSTRACT

Oxidized low-density lipoproteins (LDL) are implicated in atherosclerosis. However, large-scale intervention studies designed to test whether antioxidants, such as vitamin E, can ameliorate cardiovascular disease have generated ambivalent results. This may relate to the fact that the mechanism whereby lipid oxidation is initiated in vivo is unknown and the lack of direct evidence for a deficiency of antioxidants in atherosclerotic lesions. Further, there is little evidence to suggest that vitamin E acts as an antioxidant for lipid peroxidation in vivo. Here we tested the antioxidant effect of dietary vitamin E (alpha-tocopherol) supplementation on intimal proliferation and lipid oxidation in balloon-injured, hypercholesterolemic rabbits. alpha-Tocopherol supplementation increased vascular content of alpha-tocopherol over 30-fold compared to nonsupplemented and alpha-tocopherol-deficient chows. Balloon injury resulted in oxidized lipid deposition in the aorta. Maximum levels of primary lipid oxidation products, measured as hydroperoxides of esterified lipid (LOOH) and oxidized linoleate (HODE), were 0.22 and 1.10 nmol/mg, representing 0.21 and 0.39% of the precursor molecule, respectively. Secondary lipid oxidation products, measured as oxysterols, were maximal at 5.60 nmol/mg or 1.48% of the precursor compound. Vascular HODE and oxysterols were significantly reduced by vitamin E supplementation. However, the intima/media ratio of aortic vessels increased with vitamin E supplementation, suggesting that the antioxidant promoted intimal proliferation. Thus, the study demonstrates a dissociation of aortic lipid oxidation and lesion development, and suggests that vitamin E does not prevent lesion development in this animal model.


Subject(s)
Antioxidants/pharmacology , Arteriosclerosis/prevention & control , Lipid Peroxidation/drug effects , Tunica Intima/drug effects , Vitamin E/pharmacology , Angioplasty, Balloon , Animals , Aorta/drug effects , Aorta/metabolism , Arteries/injuries , Arteries/pathology , Arteriosclerosis/pathology , Cell Division/drug effects , Cell Division/physiology , Cholesterol, Dietary/administration & dosage , Dietary Supplements , Hypercholesterolemia/metabolism , Male , Rabbits , Tunica Intima/metabolism , Tunica Intima/pathology , Vitamin E Deficiency/metabolism
9.
Am J Cardiol ; 88(2): 153-9, 2001 Jul 15.
Article in English | MEDLINE | ID: mdl-11448412

ABSTRACT

Prior studies suggest that acute elevations in plasma triglycerides alter vascular tone and impair endothelial function. To investigate the relation between acute hypertriglyceridemia and vascular function, we examined the effects of high- and low-fat meals on brachial artery reactivity in 14 healthy volunteers. Flow-mediated dilation declined from 14.7 +/- 8.3% to 10.6 +/- 6.2% after the high-fat meal only (p <0.001), and this decline was associated with a 6% increase in baseline brachial artery diameter (3.50 +/- 0.74 mm to 3.70 +/- 0.81 mm, p <0.001), but not a decrease in the arterial diameter during hyperemia. The high-fat meal increased serum triglycerides and insulin by 94% and 438%, respectively. To investigate the effects of triglyceride elevation in isolation from hyperinsulinemia, we examined vascular responses to an intravenous infusion of a triglyceride emulsion in 28 subjects. Triglyceride emulsion increased serum triglycerides 197% but had no effect on serum insulin. Brachial artery diameter increased 4%, from 3.68 +/- 0.51 mm to 3.81 +/- 0.56 mm (p <0.05), and forearm flow increased 36%, reflecting vasodilation of forearm resistance vessels. Flow-mediated dilation and nitroglycerin-mediated dilation were unaffected. The triglyceride emulsion had no direct dilator effect on rabbit aortic tissue in vitro. In conclusion, acute hypertriglyceridemia is associated with vasodilation of conduit and resistance vessels in the arm and does not impair endothelial vasodilator function per se. The dilator effect is not insulin-dependent and does not appear to be a direct effect of triglycerides on vascular tissue.


Subject(s)
Brachial Artery/physiology , Hypertriglyceridemia/physiopathology , Vasodilation/physiology , Adult , Animals , Dietary Fats/administration & dosage , Endothelium, Vascular/physiology , Fat Emulsions, Intravenous , Female , Forearm/blood supply , Humans , Hyperemia/physiopathology , In Vitro Techniques , Insulin/blood , Male , Rabbits , Regional Blood Flow/physiology , Triglycerides/administration & dosage
10.
Am J Physiol Cell Physiol ; 281(2): C719-25, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11443071

ABSTRACT

The bioactivity of endothelium-derived nitric oxide (NO) is an important component of vascular homeostasis that is sensitive to intracellular redox status. Because glutathione (GSH) is a major determinant of intracellular redox state, we sought to define its role in modulating endothelial NO bioactivity. In porcine aortic endothelial cells (PAECs), we depleted intracellular GSH (>70%) using 1) buthionine-(S,R)-sulfoximine (BSO), which inhibits GSH synthesis; 2) diamide, which oxidizes thiols; or 3) 1-chloro-2,4-dinitrobenzene (CDNB), which putatively depletes GSH through glutathione S-transferase activity. Cellular GSH depletion with BSO had no effect on endothelial NO bioactivity measured as A-23187-induced cGMP accumulation. In contrast, oxidation of intracellular thiols with diamide inhibited both A-23187-induced cGMP accumulation and the cGMP response to exogenous NO. Diamide treatment of either PAECs, PAEC membrane fractions, or purified endothelial nitric oxide synthase (eNOS) resulted in significant inhibition (approximately 75%) of eNOS catalytic activity measured as L-[(3)H]arginine-to-L-[(3)H]citrulline conversion. This effect appeared related to oxidation of eNOS thiols as it was completely reversed by dithiothreitol. Glutathione depletion with CDNB inhibited A-23187-stimulated cGMP accumulation but not the cGMP response to exogenous NO. Rather, CDNB treatment impaired eNOS catalytic activity in intact PAECs, and this effect was reversed by excess NADPH in isolated purified eNOS assays. Consistent with these results, we found spectral evidence that CDNB reacts with NADPH and renders it inactive as a cofactor for either eNOS or glutathione reductase. Thus thiol-modulating agents exert pleiotropic effects on endothelial NO bioactivity, and these data may help to resolve a number of conflicting previous studies linking GSH status with endothelial cell NO bioactivity.


Subject(s)
Buthionine Sulfoximine/pharmacology , Diamide/pharmacology , Dinitrochlorobenzene/pharmacology , Endothelium, Vascular/metabolism , Enzyme Inhibitors/pharmacology , Nitric Oxide/metabolism , Sulfhydryl Compounds/antagonists & inhibitors , Sulfhydryl Reagents/pharmacology , Animals , Cattle , Cells, Cultured , Dinitrochlorobenzene/antagonists & inhibitors , Endothelium, Vascular/cytology , Glutathione/antagonists & inhibitors , NADP/antagonists & inhibitors , NADP/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type III , Recombinant Proteins/antagonists & inhibitors , Swine
11.
Circulation ; 103(23): 2799-804, 2001 Jun 12.
Article in English | MEDLINE | ID: mdl-11401935

ABSTRACT

BACKGROUND: Some epidemiological studies have shown that increased iron stores are associated with increased cardiovascular events. Redox-active iron may contribute to lipid peroxidation, endothelial cell activation, and generation of reactive oxygen species (especially hydroxyl radical, via Fenton chemistry). Increased oxidative stress is associated with impaired action of endothelium-derived nitric oxide in patients with atherosclerosis. METHODS AND RESULTS: To test the hypothesis that reducing vascular iron stores would reverse endothelial dysfunction, we examined the effects of the iron chelator deferoxamine (500 mg intra-arterially over 1 hour) on vasomotor function in forearm resistance vessels of patients with coronary artery disease by venous occlusion plethysmography. Patients with coronary artery disease had impaired endothelium-dependent vasodilation in response to methacholine compared with healthy control subjects (P<0.001). Deferoxamine infusion decreased serum iron levels (P<0.001). Deferoxamine improved the blood flow response to methacholine in patients with coronary artery disease (P<0.01 by 2-way repeated-measures ANOVA) but had no effect on the response to sodium nitroprusside. In normal volunteers, deferoxamine had no effect on the response to methacholine. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine abolished augmentation of the methacholine response associated with deferoxamine. The hydroxyl radical scavenger mannitol had no effect on the methacholine response. CONCLUSIONS: Deferoxamine improved nitric oxide-mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.


Subject(s)
Coronary Disease/physiopathology , Deferoxamine/administration & dosage , Endothelium, Vascular/drug effects , Iron Chelating Agents/administration & dosage , Vasomotor System/drug effects , Adult , Blood Flow Velocity/drug effects , Coronary Disease/blood , Endothelium, Vascular/physiopathology , Enzyme Inhibitors/pharmacology , Female , Forearm/blood supply , Free Radical Scavengers/pharmacology , Humans , Infusions, Intra-Arterial , Iron/blood , Male , Methacholine Chloride , Middle Aged , Nitric Oxide Synthase/antagonists & inhibitors , Nitroprusside/pharmacology , Plethysmography , Vasodilation/drug effects , Vasomotor System/physiopathology , omega-N-Methylarginine/pharmacology
12.
Arterioscler Thromb Vasc Biol ; 21(6): 1084-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11397724

ABSTRACT

Epidemiological studies suggest that tea consumption is associated with a decreased risk of cardiovascular events, but the mechanisms of benefit remain undefined. Platelet aggregation is a precipitating event in cardiovascular disease, and tea contains antioxidant flavonoids that are known to decrease platelet aggregation in vitro. To test the effect of tea consumption on platelet aggregation, we randomized 49 patients with coronary artery disease to either 450 mL of black tea or water consumed initially, followed by 900 mL of tea or water daily for 4 weeks in a crossover design. Ex vivo platelet aggregation in platelet-rich plasma was assessed in response to ADP and thrombin receptor-activating peptide at baseline and 2 hours and 4 weeks after beverage consumption. We observed dose-dependent platelet aggregation in response to each agonist, and neither relation was altered by acute or chronic tea consumption. Plasma flavonoids increased with acute and chronic tea consumption, indicating adequate absorption of tea flavonoids. In conclusion, these results demonstrate that acute and chronic black tea consumption does not affect ex vivo platelet aggregation in patients with coronary artery disease. These findings suggest that an effect of tea flavonoids on platelet aggregation is unlikely to be the explanation for the reduction in risk of cardiovascular events noted in epidemiological studies.


Subject(s)
Coronary Disease/blood , Platelet Aggregation/drug effects , Tea , Adenosine Diphosphate/pharmacology , Coronary Artery Disease/blood , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Humans , Lipids/blood , Male , Middle Aged , Peptide Fragments/pharmacology
13.
Am J Obstet Gynecol ; 184(6): 1060-3, 2001 May.
Article in English | MEDLINE | ID: mdl-11349156

ABSTRACT

OBJECTIVE: We investigated the antioxidant effect of tamoxifen, esterified estradiol, and physiologic concentrations of 17beta-estradiol on endothelial cell-mediated oxidation of low-density lipoprotein. STUDY DESIGN: Human umbilical vein endothelial cells were preincubated with nanomolar concentrations of estradiol, estradiol stearate, and tamoxifen. Low-density lipoprotein was isolated and incubated with cells in serum-free medium. Oxidation of low-density lipoprotein was quantified after 8, 16, and 24 hours of incubation as the formation of thiobarbituric acid-reactive substances. RESULTS: Compared with control, preincubation of human umbilical vein endothelial cells with 1- or 10-nmol/L estradiol resulted in a 12% reduction in the formation of thiobarbituric acid-reactive substances at 24 hours. Preincubation of human umbilical vein endothelial cells with either 10-nmol/L estradiol 17-stearate or 10-nmol/L tamoxifen resulted in 26% and 20% decreases, respectively, in formation of thiobarbituric acid-reactive substances at 24 hours. The difference in the reduction in thiobarbituric acid-reactive substances between control and treatment wells became more pronounced over time. CONCLUSION: Under these experimental conditions, tamoxifen, esterified estradiol, and physiologic concentrations of exogenous estradiol inhibit oxidation of low-density lipoprotein by human umbilical vein endothelial cells.


Subject(s)
Endothelium, Vascular/metabolism , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Lipoproteins, LDL/metabolism , Tamoxifen/pharmacology , Cells, Cultured , Endothelium, Vascular/cytology , Esterification , Estradiol/metabolism , Humans , Osmolar Concentration , Oxidation-Reduction/drug effects
14.
J Biol Chem ; 276(19): 16045-50, 2001 May 11.
Article in English | MEDLINE | ID: mdl-11278982

ABSTRACT

The phenotypic properties of the endothelium are subject to modulation by oxidative stress, and the c-Jun N-terminal kinase (JNK) pathway is important in mediating cellular responses to stress, although activation of this pathway in endothelial cells has not been fully characterized. Therefore, we exposed endothelial cells to hydrogen peroxide (H(2)O(2)) and observed rapid activation of JNK within 15 min that involved phosphorylation of JNK and c-Jun and induction of AP-1 DNA binding activity. Inhibition of protein kinase C and phosphoinositide 3-kinase did not effect JNK activation. In contrast, the tyrosine kinase inhibitors, genistein, herbimycin A, and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated H(2)O(2)-induced JNK activation as did endothelial cell adenoviral transfection with a dominant-negative form of Src, implicating Src as an upstream activator of JNK. Activation of JNK by H(2)O(2) was also inhibited by AG1478 and antisense oligonucleotides directed against the epidermal growth factor receptor (EGFR), implicating the EGFR in this process. Consistent with this observation, H(2)O(2) stimulated EGFR tyrosine phosphorylation and complex formation with Shc-Grb2 that was abolished by PP2, implicating Src in H(2)O(2)-induced EGFR activation. Tyrosine phosphorylation of the EGFR by H(2)O(2) did not involve receptor autophosphorylation at Tyr(1173) as assessed by an autophosphorylation-specific antibody. These data indicate that H(2)O(2)-induced JNK activation in endothelial cells involves the EGFR through an Src-dependent pathway that is distinct from EGFR ligand activation. These data represent one potential pathway for mediating oxidative stress-induced phenotypic changes in the endothelium.


Subject(s)
Adaptor Proteins, Signal Transducing , Endothelium, Vascular/metabolism , ErbB Receptors/metabolism , Hydrogen Peroxide/pharmacology , Mitogen-Activated Protein Kinases/metabolism , Proteins/metabolism , Transcriptional Activation/physiology , Animals , Aorta , Benzoquinones , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Enzyme Activation , Enzyme Inhibitors/pharmacology , ErbB Receptors/drug effects , ErbB Receptors/genetics , GRB2 Adaptor Protein , Genistein/pharmacology , JNK Mitogen-Activated Protein Kinases , Lactams, Macrocyclic , Phosphorylation , Phosphotyrosine/metabolism , Protein-Tyrosine Kinases/metabolism , Proteins/drug effects , Proteins/genetics , Pyrimidines/pharmacology , Quinazolines , Quinones/pharmacology , Rifabutin/analogs & derivatives , Swine , Transcriptional Activation/drug effects , Tyrphostins/pharmacology
15.
Am J Physiol Heart Circ Physiol ; 280(2): H528-34, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11158948

ABSTRACT

Hypertension is associated with low plasma ascorbic acid levels and impaired endothelial function. Recent evidence suggests that increased vascular oxidative stress contributes to the pathophysiology of endothelial dysfunction and hypertension. We recently showed that chronic oral ascorbic acid therapy lowers blood pressure in hypertensive patients. We hypothesized that it would also improve endothelial vasomotor function. In a randomized, double-blind, placebo-controlled study, we examined the effect of acute (2 g po) and chronic (500 mg/day for 1 mo) ascorbic acid treatment on brachial artery flow-mediated dilation in 39 patients with hypertension. Compared with 82 age- and gender-matched normotensive controls, these patients had impaired endothelium-dependent, flow-mediated dilation of the brachial artery [8.9 +/- 6.1 vs. 11.2 +/- 5.7% (SD), P < 0.04]. After therapy, plasma ascorbic acid concentrations increased acutely from 50 +/- 12 to 149 +/- 51 micromol/l and were maintained at 99 +/- 33 micromol/l with chronic treatment (both P < 0.001). As previously reported, chronic ascorbic acid therapy reduced systolic and mean blood pressure in these patients. However, acute or chronic ascorbic acid treatment had no effect on brachial artery endothelium-dependent, flow-mediated dilation or on endothelium-independent, nitroglycerin-mediated dilation. These results demonstrate that conduit vessel endothelial dysfunction secondary to hypertension is not reversed by acute or chronic treatment with oral ascorbic acid. The effects of this treatment on resistance vessel vasomotor function warrant further investigation.


Subject(s)
Antioxidants/administration & dosage , Ascorbic Acid/administration & dosage , Endothelium, Vascular/physiopathology , Hypertension/drug therapy , Hypertension/physiopathology , Adult , Antioxidants/metabolism , Ascorbic Acid/blood , Brachial Artery/physiology , Cohort Studies , Cyclic GMP/blood , Eicosanoids/blood , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Female , Humans , Hypertension/metabolism , Male , Middle Aged , Nitric Oxide/metabolism , Regional Blood Flow/drug effects , Vasodilation/drug effects
16.
J Nutr ; 131(2): 374S-7S, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11160564

ABSTRACT

Vitamin E is the principal lipid-soluble antioxidant in human plasma, and some studies indicate that it may provide cardiovascular protection. To investigate putative mechanisms for vitamin E in this regard, the effect of vitamin E on vascular function and platelet aggregation was examined. In animal models of endothelial dysfunction, vitamin E improved the activity of endothelium-derived nitric oxide, and this effect was not dependent upon the antioxidant protection of LDL. In fact, vitamin E improved endothelial function in part due to the inhibition of protein kinase C (PKC) stimulation. This activity of vitamin E was examined in platelets, and vitamin E inhibited platelet aggregation in part through a mechanism that involves PKC. Moreover, the platelet inhibitory activity of vitamin E was independent of its antioxidant action because platelet inhibition was still observed with isoforms of vitamin E that were devoid of antioxidant activity.


Subject(s)
Blood Platelets/drug effects , Cardiovascular Diseases/prevention & control , Platelet Aggregation Inhibitors/therapeutic use , Protein Kinase C/antagonists & inhibitors , Vitamin E/therapeutic use , Antioxidants/pharmacology , Blood Platelets/physiology , Dose-Response Relationship, Drug , Humans , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacology , Thrombosis/prevention & control , Vitamin E/administration & dosage , Vitamin E/pharmacology
17.
Free Radic Biol Med ; 29(9): 814-24, 2000 Nov 01.
Article in English | MEDLINE | ID: mdl-11063907

ABSTRACT

Recent evidence suggests that lipoprotein oxidation is increased in diabetes, however, the mechanism(s) for such observations are not clear. We examined the effect of glucose on low-density lipoprotein (LDL) oxidation using metal ion-dependent and -independent oxidation systems. Pathophysiological concentrations of glucose (25 mM) enhanced copper-induced LDL oxidation as determined by conjugated diene formation or relative electrophoretic mobility (REM) on agarose gels. Similarly, iron-induced LDL oxidation was stimulated by glucose resulting in 4- to 6-fold greater REM than control incubations without glucose. In contrast, glucose had no effect on metal ion-independent LDL oxidation by aqueous peroxyl radicals. The effect of glucose on metal ion-dependent LDL oxidation was associated with enhanced reduction of metal ions, and in the case of iron-induced LDL oxidation, was completely inhibited by superoxide dismutase. The effect of glucose was mimicked by other reducing sugars, such as fructose and mannose, and the extent to which each sugar enhanced LDL oxidation was closely linked to its metal ion-reducing activity. Thus, promotion of LDL oxidation by glucose is specific for metal ion-dependent oxidation and involves increased metal ion reduction. These results provide one potential mechanism for enhanced LDL oxidation in diabetes.


Subject(s)
Glucose/metabolism , Lipoproteins, LDL/metabolism , Amidines/pharmacology , Carbohydrate Metabolism , Carbohydrates/pharmacology , Copper/metabolism , Copper/pharmacology , Coronary Disease/etiology , Diabetes Mellitus/metabolism , Diabetic Angiopathies/etiology , Free Radicals/metabolism , Glucose/pharmacology , Humans , In Vitro Techniques , Iron/metabolism , Iron/pharmacology , Lipoproteins, LDL/chemistry , Lipoproteins, LDL/drug effects , Male , Oxidants/pharmacology , Oxidation-Reduction , Peroxides/metabolism , Superoxide Dismutase/metabolism , Superoxide Dismutase/pharmacology
18.
Mol Aspects Med ; 21(4-5): 99-166, 2000.
Article in English | MEDLINE | ID: mdl-11044550

ABSTRACT

Atherosclerosis is an important source of morbidity and mortality in the developed world. Despite the fact that the association between LDL cholesterol and atherosclerosis has been evident for at least three decades, our understanding of exactly how LDL precipitates atherosclerosis is still in its infancy. At least three working hypotheses of atherosclerosis are now nearing the stage where their critical evaluation is possible through a combination of basic science investigation and murine models of atherosclerosis. As we move forward in our understanding of this disease, efforts will be increasingly focused on the molecular mechanisms of disease activation that precipitate the clinical manifestations of atherosclerosis such as heart attack and stroke. Two candidates for such investigation involve the events surrounding plaque activation and endothelial dysfunction. Further investigation in these fields should provide the necessary insight to develop the next generation of interventions that will reduce the clinical manifestations of this devastating disease. The purpose of this work is to review the major theories of atherogenesis, examine the aspects of atherosclerosis that lead to disease activation and discuss aspects of disease activation that are amenable to treatment.


Subject(s)
Arteriosclerosis/etiology , Animals , Antioxidants/pharmacology , Arteriosclerosis/drug therapy , Arteriosclerosis/pathology , Arteriosclerosis/physiopathology , Disease Models, Animal , Endothelium, Vascular/physiopathology , Humans , Lipoproteins, LDL/metabolism , Mice , Models, Cardiovascular , Nitric Oxide/metabolism , Oxidation-Reduction , Risk Factors
19.
Ann Thorac Surg ; 70(3): 883-8; discussion 888-9, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11016328

ABSTRACT

BACKGROUND: Diltiazem is widely used to prevent radial artery spasm after coronary bypass grafting (CABG). However, recent in vitro and in vivo studies have shown that nitroglycerin is a superior conduit vasodilator compared to diltiazem. A clinical comparison of these agents in patients undergoing CABG has not been previously performed. METHODS: One hundred sixty-one consecutive patients undergoing isolated CABG with the radial artery were prospectively randomized to 24-hour intravenous infusion of nitroglycerin or diltiazem followed by 6-month treatment with a daily dose of isosorbide mononitrate (n = 84) or diltiazem CD (n = 77). Analyses were performed on "intention-to-treat" basis. RESULTS: Crossovers because of low cardiac output, complete heart block, or sinus bradycardia occurred in 5 patients in the diltiazem group and none in the nitroglycerin group (p = 0.05). Operative mortality (nitroglycerin, 1.2% versus diltiazem, 1.3%), major morbidity (14% versus 16%), perioperative myocardial infarction (1.2% versus 0%), peak serum creatinine phosphokinase MB fraction levels (27 versus 21 U), intensive care unit stay (34+/-19 versus 38+/-30 hours) and total hospital length of stay (4.7+/-1.4 versus 4.7+/-1.3 days) were similar (p = not significant for all). Cardiac pacing was required more often in the diltiazem group (28% versus 13%, p = 0.01). Follow-up longer than 2 months was available in 145 patients (90%). Follow-up mortality (nitroglycerin, 1.2%; diltiazem, 1.3%), myocardial infarction (6%, versus 5%), and reintervention (8% versus 6%) rates and average angina class (1.3+/-0.7 versus 1.1+/-0.4) were similar (p = not significant for all). Thallium stress test obtained in 117 patients showed abnormal perfusion in the radial artery territory in only 4 patients (3%), 2 in each group (p = not significant). Treatment with diltiazem was more costly ($16,340 versus $1,096). CONCLUSIONS: Nitroglycerin is preferable to diltiazem for prevention of conduit spasm. Nitroglycerin is safe, effective, better tolerated, and less costly than diltiazem, and therefore, should be the agent of choice.


Subject(s)
Coronary Artery Bypass , Diltiazem/therapeutic use , Nitroglycerin/therapeutic use , Spasm/prevention & control , Vasodilator Agents/therapeutic use , Costs and Cost Analysis , Creatine Kinase/blood , Diltiazem/administration & dosage , Female , Humans , Isosorbide Dinitrate/administration & dosage , Isosorbide Dinitrate/analogs & derivatives , Isosorbide Dinitrate/therapeutic use , Length of Stay , Male , Middle Aged , Nitroglycerin/administration & dosage , Postoperative Complications , Prospective Studies , Radial Artery , Vasodilator Agents/administration & dosage
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