Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer's disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a "smoke-sensor" of the body.
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PMID:Transcription factor NF-kappaB: a sensor for smoke and stress signals. 1638 90

Obesity is associated with vascular endothelial cell dysfunction (ECD). Studies on nitric oxide (NO) production of vascular system in these subjects may help delineate the pathogenesis of obesity-associated ECD. In this study, we recruited 69 severely obese patients who were treated with gastric partition surgery for weight reduction and 69 matched healthy controls for comparison. The following parameters were obtained in the healthy control subjects and in the obese subjects both before and after gastric partition surgery: body mass index, blood pressure, serum lipids, high sensitivity C-reactive protein (hs-CRP), adiponectin, total nitrite and nitrate (NO(x)), and 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), and insulin resistance index (as measured by homeostasis model assessment (HOMA-IR). At baseline, serum lipids, glucose, insulin, hs-CRP and 8-iso-PGF2alpha and HOMA-IR were all higher while adiponectin lower in the obese group than in the control group. The serum NO(x) levels were not different between the two groups. In the obese subjects, the adiponectin levels were significantly elevated but NO(x) markedly decreased after surgery. All other measurements, except for systolic blood pressure, were decreased after surgery. For healthy controls, the serum NO(x) levels were negatively associated with HOMA-IR and positively associated with serum adiponectin levels as analyzed by multiple linear regression analysis. In obese patients, the baseline serum NO(x) was positively associated with the serum TG levels. The changes of serum NO(x) levels after weight reduction surgery were positively associated with the changes of body mass index and serum TG levels. These observations suggested that, in the extremely obese patients, there might be excessive production and/or inactivation of NO and, after weight reduction surgery, the NO production was down-regulated. In conclusion, in the severely obese patients, the apparently normal NO production might be due to over-expression of iNOS. After gastric partition surgery, the NO production was significantly decreased which might be reflecting the usual status of NO production in obese subjects. The positive correlation between NO(x) and serum TG level might suggest that the metabolism of TG plays a role in the regulation of NO production.
Atherosclerosis 2007 Feb
PMID:Nitric oxide production is paradoxically decreased after weight reduction surgery in morbid obesity patients. 1654 95

Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.
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PMID:Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" effect--a Chinese concept for a worldwide pandemic. 1663 54

Nitric oxide plays a central role in the physiology and pathology of diverse tissues including the immune system. It is clear that the levels of nitric oxide must be carefully regulated to maintain homeostasis. Appropriate levels of nitric oxide derived from iNOS assist in mounting an effective defense against invading microbes. Conversely, inability to generate nitric oxide results in serious, even fatal, susceptibility to infections. Further, dysregulation or overproduction of nitric oxide has been implicated in the pathogenesis of many disorders, including atherosclerosis, neurodegenerative diseases, inflammatory autoimmune diseases, and cancer. Therefore, depending upon the levels of nitric oxide generated, the potential exists for nitric oxide to behave like a "double-edged" biological sword. Taking these issues into consideration, it is thus pivotal to understand the regulation of nitric oxide. Nitric oxide is regulated by many endogenous factors including hormones such as estrogens. While the effects of estrogen on the generation of nitric oxide in non-immune tissues are relatively well documented, the effect of estrogen on iNOS/nitric oxide in immune cells is only now becoming apparent. Our laboratory has recently shown that estrogen treatment of mice markedly upregulates the levels of iNOS mRNA, iNOS protein, and nitric oxide in activated splenocytes. This upregulation of nitric oxide is in part mediated through interferon-gamma (IFN-gamma), a pro-inflammatory cytokine that is enhanced by estrogen. These findings are important considering that estrogens are not only involved in regulation of normal immune responses, but also are implicated in many autoimmune and inflammatory diseases. To date, there are no reviews on the effects of estrogen on immune tissue-derived nitric oxide and therefore this review will address this critical gap in the literature. Given the increasing importance of immune-tissue-derived iNOS in health and disease, studies on estrogen-induced regulation of iNOS may offer a better understanding of diseases and aid in devising new therapeutic interventions.
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PMID:Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis. 1664 69

Macrophage activation in atherosclerotic plaques plays a role in plaque destabilization, rupture and subsequent atherothrombosis. Platelet phagocytosis that occurs within human atherosclerotic plaques can activate macrophages and it has been suggested that the platelet constituent amyloid precursor protein (APP) is involved. Recent studies show that amyloid beta (Abeta), a peptide extensively studied in Alzheimer's disease and that is cleaved from APP by beta- and gamma-secretase, and/or Abeta-like peptides are also present in human atherosclerotic plaques, in particular in activated, inducible nitric oxide synthase (iNOS) expressing perivascular macrophages that had phagocytized platelets. In vitro studies confirm that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Abeta-like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMG-CoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Abeta formation in Alzheimer's disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter gamma-secretase activity in Alzheimer's disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of Abeta-containing peptides. From the statins investigated (fluvastatin, atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin) only fluvastatin and atorvastatin selectively inhibit macrophage activation after platelet phagocytosis, possibly through inhibition of Rho activity. Taken together, these new findings point to the involvement of platelet-derived APP in macrophage activation in atherosclerosis and suggest a biochemical link between atherosclerosis and Alzheimer's disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.
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PMID:Processing of amyloid precursor protein as a biochemical link between atherosclerosis and Alzheimer's disease. 1672 33

Whereas stress is known to be one of the risk factors of stroke, few experimental studies have examined the possible mechanisms by which stress may affect stroke outcome. Most of the knowledge on the effects of stress on cerebrovascular disease in humans is restricted to catecholamines and glucocorticoids effects on blood pressure and/or development of atherosclerosis. By using an experimental paradigm consisting of the exposure of Fischer rats to repeated immobilization sessions (1 h daily during seven consecutive days) prior to permanent middle cerebral artery occlusion (MCAO), we have found that stress worsens behavioral outcome and increases infarct size after MCAO. These changes occur concomitantly to an increase in inducible nitric oxide synthase (iNOS) expression and to the accumulation of lipid peroxidation markers in brain tissue. The possible regulatory role of TNFalpha was studied by looking at the mechanisms of release of this cytokine as well as to the expression of its receptors (TNFR1 and 2). The results of the present study suggest an increase in TNFalpha expression and release after stress, as well as an increase in the expression of TNFR1. Pharmacological blockade of TNFalpha with anti-TNFalpha led to a decrease in the infarct size as well as in the oxidative/nitrosative biochemical parameters seen after ischemia. In summary, our results indicate that TNFalpha accounts, at least partly, for the worsening of MCAO consequences in brain of rats exposed to stress. Furthermore, the data presented here provide evidence that stress can increase brain ischemic damage and support a possible protective effect of treatment of stressful situations before and during the development of the brain ischemia.
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PMID:The role of tumor necrosis factor-alpha in stress-induced worsening of cerebral ischemia in rats. 1684 5

Our previous studies have proven that crocetin (CCT), extracted from Gardenia jasminoides Ellis, possesses the anti-atherosclerotic effect. Because endothelial dysfunction strongly contributes to the initiation and progression of atherosclerosis, the present study aims to investigate whether CCT is capable of improving this dysfunction and to explore the possible mechanisms. Endothelial dysfunction was induced by in vivo feeding high cholesterol diet (HCD) to rabbit and by in vitro treating bovine aortic endothelial cells (BAECs) with oxidized LDL (oxLDL). Endothelium-dependent relaxation (EDR) evoked by acetylcholine (Ach) and endothelium-independent relaxation (RIDR) mediated by sodium nitroprusside (SNP) of thoracic aorta isolated from rabbit were measured. The results indicated that the EDR in HCD alone treated rabbits was seriously impaired and the maximal relaxation induced by Ach (10(-5.5) M) was only 54% that in control rabbit fed with regular diet. Oral complementation with CCT (15, 30 mg/kg) dose-dependently improved this impairment and restored the maximal relaxation to 68% and 80% that in control group, respectively. However, the EIDR maintained comparable in all groups. Complementation with CCT (15, 30 mg/kg) simultaneously increased serum level of nitric oxide (NO), upregulated vessel activity and mRNA expression of endothelial NO synthase (eNOS) as well as vessel cyclic GMP (cGMP) content compared with those in rabbit treated with HCD alone. Inducible NOS (iNOS) activity remained unchangeable in all groups. In BAECs, oxLDL treatment decreased NO production, downregulated both activity and mRNA expression of eNOS. While those decrease or downregulation were inhibited by co-treatment with CCT (0.1, 1, 10 microM) in a dose-dependent manner. These findings suggested that CCT significantly restored the EDR of thoracic aorta in hypercholesterolemic rabbit, which might be explained by its action to increase the vessel eNOS activity, leading to elevation of NO production.
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PMID:Crocetin improves endothelium-dependent relaxation of thoracic aorta in hypercholesterolemic rabbit by increasing eNOS activity. 1687 66

The aim of the present study was to analyze the early events in atherogenesis and the role of pro- or anti-atherosclerotic proteins in the development of atherosclerotic lesions. We used apolipoprotein E-deficient (E(0)) mice that spontaneously develop hypercholesterolemia and atherosclerotic lesions in the aorta in a time-dependent manner. Aortas of mice aged 6, 8, 10 and 12 weeks were examined to determine histopathological changes. In mice aged 8-12 weeks, developing atherosclerotic lesions were present in different regions of the aortas. These lesions protruded into the lumen of the vessel and showed lipid deposits, lipid-filled macrophages and extensive accumulation of collagen and elastic fibers throughout the entire arterial wall. A parallel immunohistochemical study included analysis of three proteins known to be involved in atherosclerosis, i.e. inducible nitric oxide synthase (iNOS, NOS2), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP2). Increased immunolabelling of iNOS and VEGF accompanied atherosclerosis development in E(0) mice aged 8, 10 and 12 weeks. On the contrary, immunolabelling for MMP2 was negative in E(0) mice aged 10 and 12 weeks. Our results indicate morphological alterations in the Tunica intima and Tunica media of atherosclerotic aortas and possible protective roles for iNOS and VEGF proteins against atherosclerosis development. These data may be relevant for developing therapeutic strategies for atherosclerosis development.
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PMID:Atherosclerosis and the protective role played by different proteins in apolipoprotein E-deficient mice. 1704 51

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.
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PMID:Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation. 1707 26

Atherosclerosis, an inflammatory disease, is closely associated with hyperglycemia, major sign of diabetes mellitus. Caveolae are vesicular invaginations of the plasma membrane that mediate the intracellular transport of lipids such as cholesterol. We evaluated the relationship between the expression of caveolin-1 and the number of caveolae in macrophages under conditions of high glucose concentration. Increased superoxide production, induction of inducible nitric oxide synthase (iNOS), and decreased caveolin-1 were observed in a concentration-dependent manner in THP-1 derived macrophages with high glucose concentrations. Mannitol, used as an osmotic control, showed no effects. Furthermore, co-localization of the NADPH oxidase component, p47(phox), and caveolin was confirmed by confocal microscopy. An atomic force microscopy (AFM) study showed that high glucose concentrations reduced the number and size of the caveolae. The percentage of cells with fragmented DNA was increased in cells grown in hyperglycemic media. Taken together, high glucose concentrations suppress the levels of caveolin-1 expression and reduce the number of caveolae. This might be due to the actions of superoxide via the activation of NADPH oxidase by translocation of its component and uncoupling of induced iNOS in macrophages. Furthermore, the apoptosis of macrophages might occur with high glucose concentrations, leading to the spreading of lipids from macrophages into intracellular spaces in the vessel wall.
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PMID:High glucose downregulates the number of caveolae in monocytes through oxidative stress from NADPH oxidase: implications for atherosclerosis. 1724 Jan 21


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