Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation.
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Although the cardiovascular morbidity and mortality induced by cigarette smoking exceed those attributable to lung cancer, the molecular basis of smoking-induced vascular injury remains unclear. To test the link between cigarette smoke, oxidative stress, and vascular inflammation, rats were exposed to the smoke of five cigarettes per day (for 1 wk). Also, isolated arteries were exposed to cigarette smoke extract (CSE; 0 to 40 microg/ml, for 6 h) in organoid culture. We found that smoking impaired acetylcholine-induced relaxations of carotid arteries, which could be improved by the NAD(P)H oxidase inhibitor apocynin. Lucigenin chemiluminescence measurements showed that both smoking and in vitro CSE exposure significantly increased vascular O(2)(*-) production. Dihydroethidine staining showed that increased O(2)(*-) generation was present both in endothelial and smooth muscle cells. CSE also increased vascular H(2)O(2) production (dichlorofluorescein fluorescence). Vascular mRNA expression of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha and that of inducible nitric oxide synthase was significantly increased by both smoking and CSE exposure, which could be prevented by inhibition of NAD(P)H oxidase (diphenyleneiodonium and apocynin) or scavenging of H(2)O(2). In cultured endothelial cells, CSE elicited NF-kappaB activation and increased monocyte adhesiveness, which were prevented by apocynin and catalase. Thus we propose that water-soluble components of cigarette smoke (which are likely to be present in the bloodstream in vivo in smokers) activate the vascular NAD(P)H oxidase. NAD(P)H oxidase-derived H(2)O(2) activates NF-kappaB, leading to proinflammatory alterations in vascular phenotype, which likely promotes development of atherosclerosis, especially if other risk factors are also present. (+info)
Effects of an antiatherogenic diet during pregnancy on markers of maternal and fetal endothelial activation and inflammation: the CARRDIP study.
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OBJECTIVE: To study the effect of an antiatherogenic diet on maternal and cord blood concentrations of systemic biomarkers of endothelial cell activation, haemostasis and inflammation. DESIGN: Single blinded randomised controlled clinical trial. SETTING: Obstetric outpatient clinic and maternity unit of a university hospital in Norway. POPULATION: Nonsmoking pregnant women aged 21-38 years carrying a single fetus and with no previous pregnancy-related complications. METHODS: Subjects (n = 290) were randomised to continue their usual diet or to adopt a diet low in saturated fat and cholesterol from gestational week 17-20 to birth. Soluble forms of cellular adhesion molecules, high-sensitivity C-reactive protein (CRP) and haemostatic markers were measured at 17-20 weeks of gestation (baseline) and subsequently up to week 36. All the above, except CRP, were also measured in cord blood. MAIN OUTCOME MEASURES: Concentrations of maternal and fetal biomarkers and maternal CRP. RESULTS: All biomarkers except CRP levels increased significantly during the study period in both the intervention and control groups. None of the maternal or fetal biomarkers were influenced by the intervention (P > 0.05) except for a tendency to lower concentrations of cord blood tissue plasminogen activator antigen in the intervention group compared with the control group, median (interquartile range) 5.4 ng/ml (3.1-7.7) versus 5.8 ng/ml (3.5-11.8), P = 0.05. CONCLUSION: An antiatherogenic diet in pregnancy did not significantly influence maternal or fetal blood concentrations of a range of biomarkers for inflammation. Thus, the previously reported effects of a cholesterol-lowering diet on maternal lipid profile and preterm delivery (<37 complete weeks of gestation) do not seem to involve changes in the systemic inflammatory responses of pregnancy. (+info)
Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha.
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High levels of triglyceride-rich lipoproteins (TGRLs) in blood are linked to development of atherosclerosis, yet the mechanisms by which these particles initiate inflammation of endothelium are unknown. TGRL isolated from human plasma during the postprandial state was examined for its capacity to bind to cultured human aortic endothelial cells (HAECs) and alter the acute inflammatory response to tumor necrosis factor-alpha. HAECs were repetitively incubated with dietary levels of freshly isolated TGRL for 2 hours per day for 1 to 3 days to mimic postprandial lipidemia. TGRL induced membrane upregulation of the low-density lipoprotein family receptors LRP and LR11, which was inhibited by the low-density lipoprotein receptor-associated protein-1. TGRLs alone did not elicit inflammation in HAECs but enhanced the inflammatory response via a 10-fold increase in sensitivity to cytokine stimulation. This was reflected by increased mitogen-activated protein kinase activation, nuclear translocation of NF-kappaB, amplified expression of endothelial selectin and VCAM-1, and a subsequent increase in monocyte-specific recruitment under shear flow as quantified in a microfabricated vascular mimetic device. (+info)
A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis.
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Lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or 'statins' has dramatically reduced morbidity and mortality in patients with established cardiovascular disease. Recently, there have been multiple studies investigating the role of high-dose statin therapy with more aggressive lipid lowering in this setting. Concomitantly, there is increasing evidence implicating a role of inflammation in the pathogenesis of atherosclerosis. These high-dose statin trials and other studies have also provided a wealth of data suggesting that statins have anti-inflammatory and anti-oxidant properties that go beyond their lipid-lowering effects. In this review, we will provide a brief overview of recent, large-scale, randomized, placebo and active controlled trials of high-dose statin therapy in the setting of stable and unstable coronary artery disease and percutaneous coronary intervention. Further, we will discuss the evidence for effects of high-dose statin therapy on inflammation and C-reactive protein. (+info)
Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo.
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BACKGROUND: Reactive oxygen species (ROS) play a major role in vascular inflammation and pathophysiology of many vascular diseases such as atherosclerosis and injury-induced neointima formation after balloon angioplasty. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses on oxidative and electrophilic stress, and it has been shown to have antiinflammatory effects in vascular cells in vitro. We therefore postulated that Nrf2 gene transfer would have salutary effects on vascular inflammation after angioplasty. METHODS AND RESULTS: Transduction of vascular smooth muscle cells (VSMCs) with Nrf2-expressing adenovirus increased the expression of several antioxidant enzymes including heme oxygenase-1 (HO-1) compared with beta-galactosidase (AdLacZ)-transduced controls. Moreover, Nrf2 gene transfer also inhibited vascular smooth muscle cell (VSMC) proliferation, and the effect was partially reversed by the HO inhibitor Sn(IV) protoporphyrin. In vivo, adenoviral gene transfer effectively reduced oxidative stress determined by antibody staining against oxidized epitopes of LDL, as well as inhibited vascular inflammation assessed by the macrophage cell count and monocyte chemoattractant protein-1 (MCP-1) staining. However, the antiproliferative effects of Nrf2 in vivo were counterbalanced with diminished apoptosis in neointimal VSMCs, resulting in no change in neointimal hyperplasia. CONCLUSIONS: Nrf2 gene transfer or Nrf2-inducing drugs may have therapeutic applications in vascular diseases in which inflammation and oxidative stress play a role. However, the contrasting growth inhibitory and antiapoptotic effects of Nrf2 need to be considered in pathological conditions in which SMC proliferation plays a critical role. (+info)
Restenosis after percutaneous angioplasty: the role of vascular inflammation.
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Restenosis after endovascular treatment of atherosclerotic lesions in the peripheral, cerebrovascular, and coronary circulation is the major drawback of this minimally invasive technique. Although certain advances have been made during recent years to improve patency rates after percutaneous angioplasty, restenosis remains a challenging clinical problem. Understanding factors that contribute to the pathophysiology of late lumen loss is an effective strategy to improving patients' postangioplasty outcome. Vascular inflammation after balloon angioplasty or stent implantation has been identified as a cornerstone of the restenotic process, and several markers of inflammation have been referred to as potential predictors of outcome. This article reviews recent findings on the issue of inflammation and restenosis after percutaneous angioplasty with special attention given to the role of inflammatory parameters as markers for the restenosis risk in the peripheral vessel area. (+info)
Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome.
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OBJECTIVES: We investigated factors for carotid artery inflammation by [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). BACKGROUND: Inflammation is present in some atherosclerotic plaques. The FDG-PET is capable of identifying and quantifying vascular inflammation within atherosclerotic plaques. METHODS: The FDG-PET imaging was performed in 216 consecutive patients (63 +/- 9 years, men:women 147:69) for cancer screening. Vascular inflammation in carotid atherosclerosis was quantified by measuring the standardized uptake value (SUV) of FDG into the artery. RESULTS: Multiple stepwise regression analysis revealed significant relationships between SUV and waist circumference (p < 0.001), hypertensive medication (p < 0.001), carotid intima-media thickness (p < 0.001), high-density lipoprotein cholesterol (p < 0.01, inversely), homeostasis model assessment of insulin resistance (p < 0.05), or high sensitivity C-reactive protein (p < 0.05). Age- and gender-adjusted SUV of FDG was significantly higher (p < 0.0001) in proportion to the accumulation of the number of the components of the metabolic syndrome. Thus, the metabolic syndrome was associated with increased FDG uptake in carotid atherosclerosis. CONCLUSIONS: Our present study may suggest that the metabolic syndrome is associated with inflammation in carotid atherosclerosis. (Detection of Plaque Inflammation by Positron Emission Tomography (PET); http://www.clinicaltrials.gov/ct/show/NCT00114504; NCT00114504). (+info)
Is the anti-inflammatory effect of regular exercise responsible for reduced cardiovascular disease?
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Engaging in regular physical activity reduces the risk of developing CVD (cardiovascular disease), but it is not certain to what degree this may be due to the anti-inflammatory effects of exercise. Following acute exercise, there is a transient increase in circulating levels of anti-inflammatory cytokines, whereas chronic exercise reduces basal levels of pro-inflammatory cytokines. Exercise training also induces the expression of antioxidant and anti-inflammatory mediators in the vascular wall that may directly inhibit the development of atherosclerosis. Limited studies in humans and more comprehensive assessments in animal models have confirmed that exercise is atheroprotective and helped identify a number of the mechanisms to explain these effects. This review explores the relationship between systemic and vascular wall inflammation and the role that the anti-inflammatory effects of exercise have on the development and progression of CVD. (+info)