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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional changes of the vessel wall--specifically dysfunction of endothelial cells--may precede the formation of frank plaques at the initiation of atherosclerosis. Clinically endothelial function and dysfunction can be measured by angiography or ultrasound techniques. Another possibility is the measurement of circulating markers of endothelial dysfunction in human plasma, such as the endogenous NOS inhibitor ADMA (asymmetric dimethylarginine). In our recent studies we were able to show that ADMA accumulates in the presence of metabolic changes such as hyperhomocysteinemia, insulin resistance and type-2 diabetes, and that these elevations of plasma ADMA correlate well with the amount of endothelial dysfunction and with NO bioavailability. Furthermore ADMA was shown to be dynamically regulated and to play an important patho-physiologic role in myocardial ischemia and reperfusion. Thus, measurements of plasma ADMA in patients could help to screen for manifestations of atherosclerosis. Moreover attempts to reduce plasma and tissue ADMA could potentially play an important role in the treatment of endothelial dysfunction, atherosclerosis, but also of ischemia reperfusion injury.
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PMID:[Asymmetric dimethyl arginine (ADMA): a novel cardiovascular risk factor?]. 1734 60

The present study was designed in order to: (a) compare ET-1 and ADMA levels, between women with PCOS (n=106) and healthy controls (n=30); (b) determine the effects of treatment with estrogens and anti-androgens on the hormonal features of PCOS, insulin resistance, ET-1 and ADMA levels. Women with PCOS were randomized in five therapeutic protocols: (I) 17beta-estradiol+cyproterone acetate 50mg; (II) conjugated estrogen+CA 50 mg; (III) ethinyl estradiole+CA 2mg; (IV) EE+CA 52 mg; (V) EE+desogestrel. In all women, gonadotropin, PRL, androgen, SHBG, insulin, glucose, ET-1 and ADMA levels were determined; in women with PCOS, testosterone, SHBG, ET-1 and ADMA levels were measured again after 3, 6, 12 months of treatment and insulin and glucose levels after 12 months. ET-1 and ADMA concentrations were higher in women with PCOS, and they were positively correlated with each other. ADMA levels were decreased and IR was increased with treatment. Treatment with synthetic estrogens (EE) resulted in a more pronounced increase in SHBG and a more pronounced decrease in FAI, compared to natural estrogens. Conclusively, PCOS is associated with endothelial dysfunction, which is ameliorated by the administration of estrogens and anti-androgens, independent of IR.
Atherosclerosis 2008 Feb
PMID:The administration of estrogens, combined with anti-androgens, has beneficial effects on the hormonal features and asymmetric dimethyl-arginine levels, in women with the polycystic ovary syndrome. 1741 49

The conditionally essential amino acid L-arginine is the substrate for nitric oxide (NO) synthesis, a key second messenger involved in physiological functions including endothelium-dependent vascular relaxation and inhibition of platelet adhesion and aggregation. Extracellular L-arginine transport seems to be essential for the production of NO by the action of NO synthases (NOS), even when the intracellular levels of L-arginine are available in excess (L-arginine paradox). Chronic renal failure (CRF) is a complex clinical condition associated with accelerated atherosclerosis and thrombosis leading to cardiovascular events. Various studies document that markers of malnutrition and inflammation, such as low body mass index (BMI), C-reactive protein (CRP) and interleukin-6 (IL-6), are strong independent predictors of cardiovascular mortality in patients with end-stage renal disease (ESRD). There is considerable literature demonstrating that a disturbance in the nitric oxide control mechanism plays a role in mediating the haemodynamic and haemostatic disorders present in CRF. Endogenous analogues of L-arginine, ADMA and L-NMMA, which can inhibit NO synthesis and L-arginine transport, are increased whilst L-arginine is reduced in plasma from all stages of CRF patients. In this context, the uptake of L-arginine in blood cells is increased in undialysed CRF patients and in patients treated by CAPD and haemodialysis. In platelets obtained from haemodialysis patients, the activation of L-arginine transport and NO production was limited to well-nourished patients. Impairment in nitric oxide bioactivity, coupled with malnutrition and inflammation, may contribute to increased incidence of atherothrombotic events in CRF. This article summarizes the current knowledge of L-arginine-nitric oxide pathway and malnutrition in CRF and briefly describes possible therapeutic interventions.
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PMID:Nitric oxide, malnutrition and chronic renal failure. 1743 Jan 38

Atherosclerosis is a chronic disease triggered by lipid disturbances, endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to initiate inflammatory immunity. We investigated the role of statins and the mevalonate pathway on DC invasion. DC incubation with atorvastatin (ATV; 0.05-1 microM) for 24h decreased DC adhesion capacity. DC invasion (adhesion/transmigration) was decreased after exposing DCs to low and moderate concentrations of statins, which was reversible by mevalonate (but not geranyl- or farnesyl-pyrophosphate) and cholesterol. Inhibition of the phosphoinositide 3-kinase (with wortmannin) and inhibition of the NO-synthase (with asymmetric dimethyl ADMA) partially reversed statin-mediated effects. High-dose statins markedly decreased DC invasion, which was reversible by adding geranyl pyrophosphate and cholesterol. Inhibition of geranylgeranyltransferase but not inhibition of farnesyltransferase significantly decreased DC invasion. Statin-mediated alteration in DC-cholesterol synthesis and subsequent activation of the Akt/NOS pathway accounts for the statin-induced decrease in DC invasion at low-moderate concentrations (0.05-0.5 microM). Additionally, at high statin concentrations (1 microM) DC invasion is reduced by inhibition of protein geranylgeranylation. As DCs control immunity, regulating DC/endothelial cell interaction by statins may have relevance to inflammation and atherogenesis.
Atherosclerosis 2008 Mar
PMID:Dual mode of HMG-CoA reductase inhibition on dendritic cell invasion. 1788 31

An elevated urinary albumin excretion is associated with an increased risk of cardiovascular disease due to atherosclerosis, but the pathophysiological mechanism underlying this association is poorly understood. We studied 217 diabetic patients, that is, 121 normoalbuminuric patients, 71 microalbuminuric patients, and 25 macroalbuminuric patients. We evaluated flow-mediated dilatation of brachial artery (%FMD, one endothelial function marker associated with endogenous NO production), von Willebrand factor (vWF, endothelial activation marker), high-sensitive CRP (hsCRP, a low-grade inflammation marker), asymmetric dimethyl arginine (ADMA, an endogenous inhibitor of NO synthesis), and insulin sensitivity by steady-state plasma glucose method. %FMD was apparently decreased in microalbuminuric and macroalbuminuric patients compared with normoalbuminuric patients (p<0.001). Moreover, %FMD was significantly correlated with the degree of albuminuria (r=-0.38, p<0.05). On the other hand, vWF and hsCRP did not show significant difference between normoalbuminuric patients and microalbuminuric patients. In diabetic patients with macroalbuminuria, ADMA was significantly elevated compared to those with normoalbuminuria. Insulin sensitivity was significantly associated with urinary albumin excretion rate. These results suggested that endothelial dysfunction which may be due to impaired NO production and insulin resistance underlie the association between diabetic nephropathy and atherosclerosis in diabetic patients.
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PMID:Impaired flow-mediated vasodilatation and insulin resistance in type 2 diabetic patients with albuminuria. 1790 44

Dimethylated L-arginine analogs have been attracting the attention of both basic researchers and clinicians for 15 years since 1992 when Vallance et al. were first to observe several fold elevations of asymmetric and symmetric dimethyl-L-arginine levels (ADMA and SDMA, respectively) in plasma of hemodialyzed patients. ADMA - in contrast to SDMA - competes with L-arginine at the level of NO synthase with consequent inhibition of NO generation. Later studies have revealed excessive ADMA accumulation in the presence of atherosclerotic risk factors and endothelial dysfunction even in patients free of clinical evidence of atherosclerosis. Moreover, ADMA concentrations were elevated also in proportion to the severity of carotid, coronary and peripheral atherosclerosis. Additionally, in vitro studies have shown the ability of proinflammatory cytokines and oxidized low-density lipoproteins to increase liberation of ADMA by cultured endothelial cells. This evidence has provoked a hypothesis that ADMA may accelerate atherogenesis by inhibition of endothelial NO synthase. Indeed, ADMA concentration proved to be an independent adverse outcome predictor in end-stage renal disease and in coronary artery disease. On the other hand, it remains an intriguing issue how ADMA is able to exert any biological effects in the presence of saturating L-arginine concentrations which are well above the Michaelis-Menten constant of endothelial NO synthase for L-arginine. Recent years have brought novel fascinating findings in the field of research on dimethylated L-arginine analogs. First, ADMA has been shown to accelerate replicative senescence of endothelial cells via inhibition of the activity of telomerase, an enzyme counteracting telomere attrition, a molecular "clock". Second, ADMA impairs the mobilization and activity of bone marrow-derived endothelial progenitor cells that participate in continuous endothelial renewal and neovascularization of ischemic tissues. Third, SDMA - previously considered an inactive stereoisomer of ADMA - has been demonstrated to inhibit NO synthesis via competition with L-arginine uptake by endothelial cells. As SDMA rises in earlier stages of renal dysfunction than ADMA, it may contribute to excessive cardiovascular morbidity in chronic kidney disease.
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PMID:L-arginine analogs--inactive markers or active agents in atherogenesis? 1885 43

Vascular endothelium plays a crucial role in ensuring normal function and morphology of blood vessels, and many risk factors of atherosclerosis act via their effects on endothelial cells. However, endothelial dysfunction is induced by very different pathomechanisms. In principle, it is caused by an impaired bioavailability of nitric oxide (NO) due to an inhibited synthesis (eg, by asymmetric dimethylarginine [ADMA]) or increased consumption of formed NO (by reactive oxygen species [ROS]). ROS can be synthesized in the organism (eg, by different enzymes) or can be administered from the environment (eg, by cigarette smoking), whereas ADMA is the subject of endogenous metabolism only. Many studies have elucidated the system of pathomechanisms and targeted some as potential goals for therapeutic interventions. This review demonstrates roles of ROS, NO, ADMA, endothelin, and estrogen in endothelial function and dysfunction focusing on homocysteinemia and diabetes mellitus and provide examples for the medical treatment of endothelial dysfunction.
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PMID:Roles of oxidants, nitric oxide, and asymmetric dimethylarginine in endothelial function. 1894 74

Platelet hyporesponsiveness to the anti-aggregatory effects of nitric oxide (NO) occurs commonly in association with myocardial ischemia and coronary risk factors, often co-exists with endothelial dysfunction and represents an independent marker of long-term cardiovascular risk. We sought to determine whether polycystic ovary syndrome (PCOS), which has been postulated as a cardiovascular risk factor in women, is independently associated with this phenomenon. Twenty-four young women with PCOS (mean age 32.1+/-1.3) were evaluated in lean (n=12) and obese (n=12) subgroups, and compared with age-matched lean normals (n=12). Platelet aggregation and its inhibition by the nitric oxide donor sodium nitroprusside (SNP) were assessed and compared with vascular endothelial function. Plasma concentrations of malondialdehyde (MDA), N(G),N(G)-dimethyl-L-arginine (ADMA) and hs-CRP were measured as markers of oxidative stress, endothelial dysfunction and inflammation, respectively. Circulating endothelial progenitor cell (EPC) counts were also documented. In both PCOS subgroups, which demonstrated hyperaggregability to ADP, responses to SNP inhibition of aggregation (the principal end-point of the study) were significantly impaired (P<0.01 for both), as were their endothelium-dependent vascular responses to salbutamol (P<0.05 for both). However, vasomotor responses to nitroglycerin and circulating EPC counts did not vary between groups. PCOS subjects also had significantly elevated ADMA, MDA and hs-CRP levels relative to normals (all P<0.05). Impairment of SNP response remained unaltered after mean 30+/-2.4 months follow-up in PCOS subjects. We conclude that in PCOS subjects, independent of obesity and associated insulin resistance, profound and reproducible impairment of platelet responsiveness to NO is an additional component of cardiovascular homeostatic disturbance.
Atherosclerosis 2009 Jun
PMID:Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. 1902 16

The prevalence of type 2 diabetes mellitus is growing. Vascular disease is here the main cause of morbidity and mortality, and accelerated atherosclerosis is responsible for about 80% of mortality and for about 75% of hospitalizations. In diabetics there is 2-4 times greater risk of ischemic heart disease in comparison to non-diabetics, and this risk is even greater in diabetic-females. Authors put greater attention to pathophysiology of diabetic vascular disease (inflammation and adipose tissue, metabolic and other--AGEs, ADMA--abnormalities, their contribution to endothelial dysfunction). The main concern is devoted to the treatment possibilities of diabetic vascular disease.
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PMID:[Diabetes and vascular diabetic disease]. 1978 77

N(omega)-Carboxymethyl-arginine (CMA), N(omega)-carboxyethyl-arginine (CEA) and N(delta)-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) have been identified as L-arginine-derived advanced glycation end products (AGEs) formed by non-enzymatic reactions between reducing sugars such as glucose and amino groups in proteins. These AGEs are structurally analogous to endogenous inhibitors of nitric oxide synthases (NOS) including N(G)-monomethyl-L-arginine (L-NMMA) and asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA). Increased plasma levels of these NOS inhibitors, and thus impaired generation of NO in vivo has been associated with the pathogenesis of vascular complications such as kidney failure and atherosclerosis. For these reasons we examined whether L-arginine-derived AGEs inhibit the activities of three L-arginine metabolizing enzymes including three isoforms of NOS (endothelium, neuronal and inducible NOS), dimethylarginine dimethylaminohydrolase (DDAH) that catalyzes the hydrolytic degradation of L-NMMA and ADMA to L-citrulline, and arginase that modulates intracellular L-arginine bioavailability. We found that AGEs inhibited the in vitro activities of endothelium type NOS weakly (IC(50) values of CMA, CEA and MG-H1 were 830, 3870 and 1280 microM, respectively) and were also potential endogenous inhibitors for arginase (IC(50) values of CMA and CML were 1470 and 1060 microM), but were poor inhibitors for DDAH. These results suggest that the tested L-arginine- and L-lysine-derived AGEs appear not to impair NO biosynthesis directly.
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PMID:Inhibition of L-arginine metabolizing enzymes by L-arginine-derived advanced glycation end products. 2021 51


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