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)

Inflammation and oxidative processes are key components of atherosclerosis, from fatty streak formation to plaque rupture and thrombosis. Recent basic and clinical studies have identified a number of inflammatory and oxidative processes that appear to play a direct role in atherothrombosis and identify potentially clinically useful markers of inflammation and oxidative stress. In this review, we highlight recent results on several of the more promising markers of inflammation for cardiovascular disease risk assessments, such as C-reactive protein, myeloperoxidase, and soluble CD40 ligand and nitrotyrosine, as well as other potential markers.
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PMID:Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. 1506 50

In addition to hypercholesterolemia, proinflammatory and prothrombotic markers have been suggested to play an important role in atherogenesis. We examined whether heparin-mediated extracorporeal low-density lipoprotein precipitation (HELP) therapy modulates the circulating levels of proinflammatory and prothrombotic markers. Twenty-two coronary heart disease (CHD) patients undergoing regular HELP-apheresis (18 males, 4 females, mean age 57.3 +/- 10.9 years) were enrolled in this study. A single HELP therapy treatment significantly decreased the circulating levels of high sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin, lipopolysaccharide binding protein (LBP), endothelin-1 (ET-1), and monocyte chemoattractant protein-1 (MCP-1) on average by 67, 37, 24, 27, 24, and 15%, respectively. Prothrombotic factors including fibrinogen, tissue factor (TF), soluble CD40 ligand (sCD40L), and homocysteine were decreased by 66, 27, 16, and 22%, respectively. In accordance with previous studies HELP therapy reduced total cholesterol, low density lipoprotein (LDL) cholesterol, and Lp(a) mass by 50, 61, and 62%, respectively. Our data suggest that simultaneous reduction of proinflammatory and prothrombotic factors together with atherogenic lipoproteins by HELP-apheresis may contribute to improvement of endothelial dysfunction and thereby inhibit progression of atherosclerotic lesions and stabilize the existing plaque.
Atherosclerosis 2004 Jul
PMID:Effects of heparin-mediated extracorporeal low-density lipoprotein precipitation beyond lowering proatherogenic lipoproteins--reduction of circulating proinflammatory and procoagulatory markers. 1518 59

Ligation of endothelial cell (EC) CD40 induces the expression of several proinflammatory cytokines as well as angiogenesis factors, including vascular endothelial growth factor (VEGF). Moreover, despite the reported importance of CD40 in cell-mediated immunity, little is known of the CD40-induced signaling pathways in EC. In this study, we have investigated the function of the Ras signaling pathway(s) for CD40-induced overexpression of VEGF. EC were transiently transfected with a full-length VEGF promoter-luciferase construct and a dominant-inhibitory mutant of Ras (Ras17N). Following transfection, ligation of CD40 with soluble CD40 ligand resulted in a significant increase in VEGF transcriptional activation, and the inhibitory mutant of Ras blocked this CD40-induced VEGF overexpression. Using EMSA and Western blot analysis, we demonstrated that CD40-dependent binding of nuclear protein(s) to the VEGF promoter and CD40-induced VEGF protein expression in EC were also inhibited by the Ras mutant. Immunoprecipitation studies revealed that ligation of CD40 on EC promoted an increased association of Ras with its effector molecules Raf, Rho, and phosphatidylinositol 3-kinase (PI3K). But, cotransfection of effector-loop mutants of Ras determined that only PI3K was functional for Ras-induced VEGF transcription. Also, wortmanin and a dominant-inhibitory mutant of PI3K inhibited CD40-induced overexpression of VEGF. Together these findings demonstrate that both Ras and PI3K are intermediaries in CD40-induced regulation of VEGF in EC. We believe our findings are of importance in several chronic inflammatory diseases, including atherosclerosis and allograft rejection associated with both CD40-CD40 ligand signaling as well as VEGF expression and function.
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PMID:The CD40-induced signaling pathway in endothelial cells resulting in the overexpression of vascular endothelial growth factor involves Ras and phosphatidylinositol 3-kinase. 1518 29

Atherosclerosis is currently considered a chronic inflammatory disease combined with a disorder of lipid metabolism and deposition. Risk factors for coronary disease, as well as circulating cytokines, are involved in endothelial activation, leading to an adhesive and dysfunctional endothelium. The CD40 receptor (CD40) and its counterpart, the CD40 ligand (CD40L/CD154), were originally found to regulate T cell-dependent B cell differentiation. Meanwhile, several studies clearly demonstrate that the CD40/CD40L system plays an important role not only in cellular immunity and inflammation, but also in the pathophysiology of atherosclerosis. This is evidenced by the finding that inhibition of CD40/CD40L interaction prevents atherogenesis in animal models. Thus, the regulation of proatherogenic factors including CD40L may provide novel therapeutic options to treat inflammatory disorders such as atherosclerosis.
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PMID:CD40 and vascular inflammation. 1519 19

Endothelial cells, platelets, and oxidized LDL could play very important roles in the development of atherosclerosis in diabetes patients. The levels of plasma endothelial cell-derived microparticles (EDMP), platelet-derived microparticles (PDMP), platelet-P-selectin (plt-PS), soluble CD40 ligand (sCD40L), and anti-oxidized LDL antibody were measured and compared to develop a better understanding of their potential contribution to diabetic vascular complications. The concentrations of EDMP, PDMP, plt-PS, and sCD40L in diabetic patients were significantly higher than those in normal subjects. The number of EDMPs in patients with diabetes complicated by nephropathy was significantly higher than that in those without complications. Levels of anti-oxidized LDL antibody were also higher in type 2 diabetic patients than in control subjects. In addition, anti-oxidized LDL antibody levels correlated with EDMP, PDMP, plt-PS, and sCD40L levels in nephropathy patients. In the nephropathy group treated with sarpogrelate hydrochrolide, a 5-HT(2A) receptor antagonist, EDMP, PDMP, plt-PS, and sCD40L levels were decreased significantly. Oxidized LDL increased expression of plt-PS, and also promoted shedding of PDMP. Furthermore, oxidized LDL promoted a dose-dependent release of 5-hydroxytriptamine. On the other hand, activated platelets and PDMP promoted endothelial cells and THP-1 (monocytic cell line) interaction, and membrane vesiculation occurred in the presence of oxidized LDL. These findings suggest that activated platelets and oxidized LDL induce EDMP generation, and that elevated EDMPs may be a sign of vascular complications in type 2 diabetic patients, particularly those who suffer from diabetes-associated nephropathy.
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PMID:Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes. 1524 77

The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state. Advances in predictive capabilities of vascular events using a number of these biomarkers are beginning to remodel our clinical practice in the use of medications such as statins and angiotensin receptor blockers for stroke prevention. Although the general inflammatory features of atherosclerosis are becoming widely recognized, factors resulting in individual variability in plaque formation and instability remain poorly defined. Emerging literature points toward several acquired and innate susceptibility factors in the immune pathways that may provide insight into why many plaques rapidly evolve from a "stable" to an "unstable" or symptomatic state. First, exposure of plaque memory T-lymphocytes to infectious or endogenous antigens may result in rapid clonal expansion of T-cell variable beta chain subtypes and stimulate macrophages to release MMPs, causing plaque destabilization. The effects of infectious agents can further be influenced by an individual's major histocompatibility complex class II molecule profiles, which can affect susceptibility to specific organisms. Second, functional polymorphisms of genes that regulate the immune pathway can predispose patients to a more robust inflammatory expression after risk factor exposure. Identification of a susceptibility gene profile and immunologic mediators that promote T-cell activation provides a unique opportunity for early identification of stroke risk and targets for future therapy.
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PMID:Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation. 1547 6

Inflammation within coronary plaques may cause an acute coronary syndrome by promoting rupture and erosion. It was the aim of this study to examine whether markers of inflammation derive from a cardiac or extracardiac source and how their levels develop over time. Blood samples were taken from patients with acute coronary syndromes (ACS) with proven atherosclerotic lesion(s) of the left coronary artery (n=13) and from control patients without coronary artery disease (n=13). Blood was taken from the femoral vein and the coronary sinus vein before and after coronary angioplasty (day 0) and on days 1 and 120. Levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1-receptor antagonist (IL-1 ra) and soluble CD40 ligand (sCD40L) were higher in ACS patients as compared to controls and remained elevated up to day 120. In the long-term time course these markers of inflammation and plaque remodeling slightly decreased in ACS patients. There were no statistically significant differences detectable in the levels of TNF-alpha, IL-6, IL-1 beta, IL-10, IL-1 ra, sCD40L and monocyte chemoattractant protein-1 (MCP-1) in the blood of ACS patients taken from a cardiac source as compared to an extracardiac source (coronary sinus vs. femoral vein). This study demonstrates the importance of a systemic inflammatory condition in patients with ACS, in whom markers of inflammation are increased as compared to controls. During long-term follow-up the pro-inflammatory activity remains elevated in ACS patients, supporting the concept of a systemic rather than a local vascular inflammation contributing to the development of atherosclerosis.
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PMID:Time course of systemic markers of inflammation in patients presenting with acute coronary syndromes. 1555 72

Atherosclerosis is a pathological process caused by vascular remodeling. It symbolizes one of the major causes for morbidity and mortality in the western world. The causes for these vascular problems are manifold and different etiologies have been discussed. Since the 1980s the role of chronic inflammation has been considered and is now confirmed by many studies and experimental data. Several inflammatory pathways have been shown to participate in the atherosclerotic process. Different markers for inflammation have been found to predict the future risk for developing cardiovascular disease. Among these, high sensitivity C-reactive protein has been the most extensively validated. Newer markers such as CD40 ligand appear also to provide important information regarding risk stratification. Medications have been found to lower levels of inflammatory markers and perhaps decrease the associated clinical risk. Statins particularly appear to have anti-inflammatory mediated benefits, though other classes of drugs are also being evaluated. Lipid-lowering therapy in general has been found to be associated with reductions in inflammatory markers. Antithrombotic therapy, such as intravenous glycoprotein lIb/IIIa inhibitors and clopidogrel, has also been demonstrated to reduce inflammatory marker release. Peroxisome proliferator-activated receptor agonists are being evaluated for possible roles in targeting arterial inflammation. Angiotensin-converting enzyme inhibitors may also have anti-inflammatory properties. In this article we review the existing data in the inflammatory model of atherosclerosis. Furthermore, we discuss the prognostic value of different inflammatory markers and the potential benefit of anti-inflammatory therapies in cardiovascular disease.
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PMID:The role of inflammation in atherothrombosis: current and future strategies of medical treatment. 1556 94

Patients with rheumatoid arthritis (RA) have a two to five times increased risk of developing premature cardiovascular disease that shortens life expectancy by 5-10 years. Traditional risk factors known to promote and accelerate the progression of atherosclerotic lesions however, are often absent in patients with RA. Many similarities have emerged between the paradigm of inflammation in the pathogenesis of atherosclerosis and the well-established mechanisms of inflammation in the pathogenesis of RA. Hence it is intriguing to speculate that inflammation in RA is not confined to the joints but also present in the vessel wall. Indeed, low-grade inflammation and endothelial dysfunction play pivotal roles in the initiation, progression and propagation of the atherosclerotic process. While the healthy endothelium prevents adhesion of mononuclear cells, the defence mechanisms cease under the influence of cardiovascular risk factors and inflammation and they express adhesion molecules (selectins, vascular adhesion molecule-([VCAM-]1, intercellular adhesion molecule-[ICAM-]1) that promote the adherence of monocytes. This expression is induced by pro-inflammatory cytokines such as interleukin-(IL-)1beta and tumor necrosis factor-(TNF-)alpha, by C-reactive protein (CRP), and CD40/CD40 ligand interactions. As all of these factors are present at increased levels in the systemic circulation in RA, it appears possible that they might impact the endothelium as well. Further similarities include proteolytic enzymes such as matrix metalloproteinases (MMPs) that play a role in joint destruction as well as in destabilization and rupture of vulnerable atherosclerotic plaques. In addition, coagulation factors such as increased levels of tissue factor (TF), van Willebrand factor (vWF) and plasminogen activator inhibitor-(PAI-)1 are important in both, RA and CAD. Endothelial dysfunction has shown to correlate with cardiovascular prognosis in several studies, which indicates its clinical relevance. Endothelial function measurement is performed in the coronary or peripheral circulation (by venous occlusion plethysmography or flow-mediated dilation). Recent studies have demonstrated impaired endothelial function in patients with RA, already at early stages of the disease. Similar results are found in patients with systemic lupus erythematosus (SLE), indicating that inflammation per se may impair altering vascular function. This and more evidence supports the notion that inflammation plays a pivotal role in vascular dysfunction and may by these mechanisms explain at least part of the excess morbidity and mortality observed in RA and SLE. In light of the growing evidence of increased cardiovascular morbidity and mortality mostly independent of traditional risk factors, treatment strategies in RA should not only aim at relieving symptoms and inhibiting joint destruction but should have a beneficial effect on the vasculature to reduce cardiovascular events. Indeed, an improvement in endothelial function in RA was recently demonstrated by anti-TNF-alpha therapy and statins. Whether and to what degree the effects of anti-inflammatory strategies to improve endothelial function, which although clinically well established is still a surrogate, translate into clinical benefit for our patients with rheumatologic diseases needs to be determined in large-scale clinical trials some of which are now already under way.
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PMID:[Rheumatoid arthritis, inflammation, and atherosclerosis]. 1559 72

Inflammation plays a pivotal role in atherosclerosis and coronary heart disease. Inflammatory processes of the coronary arterial wall are involved in plaque formation, progression and, finally, plaque instability consecutively leading to the clinical manifestations of stable coronary artery disease or acute coronary syndromes (unstable angina, non-ST elevation and ST elevation myocardial infarction). Acute coronary syndromes result from plaque rupture or erosion leading to local thrombus formation with consecutive necrosis of myocytes due to ischemia, which is associated with widespread and diffuse pancoronary and panmyocardial inflammation. Accordingly, markers of myocardial necrosis (e. g., cardiac troponins) do have crucial diagnostic and prognostic value. In case of troponin-negative acute coronary syndromes, however, markers of inflammation emerged as potentially useful tools for risk stratification. C-reactive protein has been shown to serve as a powerful predictor of future cardiovascular events following acute coronary syndromes, even if troponins are not (yet) positive. Moreover, a variety of pro- (soluble CD40 ligand, placental growth factor, interleukin-6, pregnancy-associated plasma protein A, myeloperoxidase, monocyte chemoattractant protein-1) and anti-inflammatory markers (interleukin-10, activin A) have been suggested to provide relevant prognostic information in patients with acute coronary syndrome. However, the clinical utility of these novel markers has not been established so far.
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PMID:[Acute coronary syndrome and inflammation. Biomarkers for diagnostics and risk stratification]. 1559 73


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