Showing papers by "Sridevi Devaraj published in 2005"

Vitamin e, oxidative stress, and inflammation

Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, alpha-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine-kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.

Hyperglycemia Induces Monocytic Release of Interleukin-6 via Induction of Protein Kinase C-α and -β

Abstract: Diabetes confers an increased propensity to atherosclerosis. Inflammation is pivotal in atherogenesis, and diabetes is a proinflammatory state. Interleukin (IL)-6, in addition to inducing the acute-phase response, contributes to insulin resistance. Monocytes from type 2 diabetic patients secrete increased IL-6. The aim of this study was to examine molecular mechanisms for increased IL-6 release from monocytes under hyperglycemia. Monocytic cells (THP-1) were cultured in the presence of 5.5 mmol/l (normal) or 15 mmol/l (high) glucose and mannitol. Secreted IL-6, intracellular IL-6, and IL-6 mRNA were significantly increased with hyperglycemia ( P

Binding and Internalization of C-Reactive Protein by Fcgamma Receptors on Human Aortic Endothelial Cells Mediates Biological Effects

Abstract: Objective— In addition to being a cardiovascular risk marker, recent studies support a role for CRP in atherothrombosis. Several investigators have reported that CRP binds to Fcgamma receptors on l...

Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role.

Abstract: PURPOSE OF REVIEW C-reactive protein (CRP) is the prototypic downstream marker of inflammation High levels of CRP predict future cardiovascular risk in apparently healthy men and women Recent evidence from different cell types suggests that CRP is not only a risk marker but may also be a participant in atherogenesis This review will focus on the effects of CRP on different cells involved in atherosclerosis RECENT FINDINGS CRP is shown to induce matrix metalloproteinase-1 (MMP-1) expression through the Fc gamma RII and extracellular signal-related kinase pathway in U937 cells MMPs are implicated in plaque instability A recent report shows that CRP does not induce tissue factor in human monocytes directly, disputing the previous concept that CRP induces tissue factor in monocytes CRP is shown to upregulate interleukin-8 in human aortic endothelial cells via nuclear factor-kappa B CRP promotes monocyte chemoattractant protein-1-mediated chemotaxis by upregulating CC-chemokine receptor 2 expression in human monocytes Also CRP is shown to attenuate endothelial progenitor cell survival, differentiation, and function via inhibiting nitric oxide Human CRP transgenic animal models show that CRP promotes atherothrombosis and increases plasminogen activator inhibitor-1 Also, the classic dogma that CRP is produced exclusively in liver is challenged by recent data on the extrahepatic production of CRP in different cells including atherosclerotic lesions SUMMARY All this recent evidence along with earlier reports support a role for CRP in atherosclerosis

Macrophage Conditioned Medium Induces the Expression of C-Reactive Protein in Human Aortic Endothelial Cells : Potential for Paracrine/Autocrine Effects

Abstract: C-reactive protein (CRP) is a risk marker for cardiovascular events in apparently healthy persons. Cogent data show that, aside from the liver, CRP is produced in atherosclerotic lesions, kidney, neurons, and alveolar macrophages. Because several proatherogenic effects of CRP have been documented in endothelial cells, we examined human aortic endothelial cells (HAEC) for CRP production. We detected the presence of CRP mRNA by RT-PCR and in situ hybridization, intracellular protein by Western blot and secreted protein by ELISA. Coincubation with the cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor alone and in combination showed that the most potent agonist for CRP production from HAEC is the combination of IL-1 and IL-6 (P < 0.05). To mimic the in vivo situation, we examined whether vascular smooth muscle cell (VSMC) and/or macrophage conditioned media (MCM) could augment CRP production by HAEC. While VSMC-conditioned media had no effect, incubation with MCM resulted in a significant twofold increase in the synthesis of both intracellular and secreted CRP (P < 0.05). The effect of MCM could be reversed by inhibiting both IL-1 and IL-6. Thus, stimulated synthesis and secretion of CRP by cells in the atherosclerotic lesion by paracrine/autocrine loops could result in local concentrations of CRP far in excess of plasma concentrations and could contribute to proinflammatory, proatherogenic effects.

C-Reactive Protein Decreases Tissue Plasminogen Activator Activity in Human Aortic Endothelial Cells Evidence that C-Reactive Protein Is a Procoagulant

Abstract: Objective— C-reactive protein (CRP) can promote atherothrombosis by decreasing endothelial nitric oxide synthase and prostacyclin, and by stimulating both plasminogen activator inhibitor-1 in endothelial cells and tissue factor in mononuclear cells. Plasminogen activator-1, a marker of fibrinolysis, is the primary inhibitor of tissue plasminogen activator (tPA). Thus, we tested the effect of CRP on tPA in human aortic endothelial cells. Methods and Results— Incubation of human aortic endothelial cells with CRP (≥12.5 μg/mL) significantly decreased tPA antigen and activity. Adenyl cyclase inhibitors, an endothelin receptor antagonist, superoxide dismutase, and a nitric oxide donor failed to reverse the effect of CRP on tPA. CRP increased interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Neutralization of both IL-1β and TNFα reversed the inhibition of tPA by CRP. Furthermore, in volunteers that have high CRP levels, euglobulin clot lysis time was significantly increased compared with those that have low CRP levels, providing further evidence that high CRP levels are associated with a procoagulant state. Conclusions— CRP inhibits tPA activity via generation of proinflammatory cytokines (IL-1β and TNFα). This study provides additional novel data that CRP is a procoagulant and has implications for atherothrombosis.

Development of an In Vitro Screening Assay to Test the Antiinflammatory Properties of Dietary Supplements and Pharmacologic Agents

Abstract: Background: Monocytes and macrophages are critical in atherosclerosis and on stimulation secrete proinflammatory, proatherogenic cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, which have been shown to be present in atherosclerotic lesions. The aim of this study was to develop a rapid in vitro screening assay to test the antiinflammatory effects of different compounds. Methods and Results: THP-1 cells (human monocytic cell line) were stimulated with different concentrations of lipopolysaccharide (LPS; 0 to 1000 μg/L) and for different times (4, 12, and 24 h), and the secretion of proinflammatory cytokines (IL-1, IL-6, and TNF-α) was assessed. TNF-α secretion was maximum at the lowest LPS concentration (100 μg/L) and at shortest duration of incubation (4 h). Maximum secretion of IL-1β and IL-6 was achieved at 24 h with higher doses of LPS. Treatment of THP-1 with various test compounds such as dietary supplements (α-tocopherol, N -acetylcysteine, catechin and epigallocatechin gallate) as well as pharmacologic agents (statins, peroxisome proliferator-activated receptor-γ agonists, and an angiotensin II receptor blocker) significantly inhibited LPS-stimulated TNF-α release. Conclusions: The release of TNF-α after stimulation of THP-1 cells with LPS is a valid model system to test novel compounds for potential antiinflammatory effects.

Defining the proinflammatory phenotype using high sensitive C-reactive protein levels as the biomarker.

Abstract: Context: Inflammation is pivotal in atherosclerosis. The prototypic marker of inflammation is C-reactive protein (CRP). Numerous studies have confirmed that high CRP levels in normal volunteers predict cardiovascular events. Objective: The objective of this study was to define proximal and associated abnormalities of the proinflammatory phenotype using CRP levels as the biomarker. Design and Subjects: Two groups of normal, healthy subjects, selected by stringent criteria from an initial cohort of 252, were studied over the period of 12 months. Group 1 included subjects with consistently low CRP ( 2.0 or >0.016 μm to <10 mg/liter or <0.085 μm; high CRP group; n = 13). Main Outcome Measures: Fasting blood (50 ml) was obtained, and the following parameters were assayed: high sensitivity CRP, fibrinogen, lipid profile, insulin, whole blood cytokines after stimulation with lipopolysaccharide (LPS; 100 ng/m...

Scientific Evidence to Support a Vitamin E and Heart Disease Health Claim: Research Needs

Abstract: In addition to epidemiologic studies suggesting a benefit for high intakes of alpha-tocopherol, studies following supplementation in humans have clearly shown that alpha-tocopherol decreases lipid peroxidation, platelet aggregation, and functions as a potent anti-inflammatory agent. However, prospective human clinical trials with alpha-tocopherol alone and in combination with other antioxidants have been largely negative. In this review, we critically appraise the various clinical trials and provide recommendations for future research.

Failure of vitamin E in clinical trials : Is gamma-tocopherol the answer?

Abstract: Oxidative stress and inflammation play a crucial role in atherosclerosis. However, prospective clinical trials of dietary antioxidants with anti-inflammatory properties, such as α-tocopherol (AT), have not yielded positive results. AT supplementation decreases γ-tocopherol (GT) levels. GT is an antioxi-dant with potent anti-inflammatory activity, and plasma GT levels are inversely associated with cardiovascular diseases. Thus, studies using pure GT, alone or in conjunction with AT, will elucidate its utility in cardiovascular disease prevention .

Methods for reducing c-reactive protein

Abstract: The present disclosure is directed to a method for reducing the level of c-reactive protein comprising administering to a subject in need thereof a c-reactive protein level reducing amount of at least one phytosterol.