Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic renal failure (CRF) is associated with a 20-fold increased risk of cardiovascular death, two principal mechanisms being: sudden, arrhythmic death associated with left ventricular hypertrophy, and ischaemic heart disease, associated with accelerated atherosclerosis. In recent years, the vascular endothelium has been recognised as a large and complex endocrine organ, with many important physiological functions including the control of vascular tone. Endothelial dysfunction, commonly characterised by reduced production of the vasodilator nitric oxide (NO), is thought to be a key initial event in the development of atherosclerosis and is present in patients with hypertension and hyperlipidaemia. While these cardiovascular risk factors are also prevalent in CRF, other factors more specific to uraemia such as accumulation of homocysteine and asymmetric dimethylarginine (endogenous inhibitor of NO synthase) may impair endothelial function. Modulation of endothelial function in CRF may offer a novel strategy to reduce cardiovascular disease.
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PMID:The vascular endothelium in chronic renal failure. 1085 70

Endothelial function is abnormal in a variety of diseased states such as hypercholesterolemia and atherosclerosis. This may be secondary to decreased synthesis of nitric oxide (NO) and/or increased degradation of NO due to interaction with superoxide anions. More recent experimental observations demonstrate increased production of superoxide in hyperlipidemia, suggesting that endothelial dysfunction in these states is in part secondary to increased NO metabolism. Enzymes proposed to be involved in increased superoxide production may include xanthine oxidase, the NO synthase, and the NAD(P)H oxidase. Superoxide rapidly reacts with NO to form peroxynitrite (ONOO-), a highly reactive intermediate with cytotoxic properties. Despite experimental evidence for the oxidative stress concept in causing endothelial dysfunction, the results of recent randomized trials to test the influence of antioxidants on coronary event rates and prognosis in patients with coronary artery disease were very disappointing. In all of these studies the use of vitamins such as vitamin E failed to improve the prognosis. In contrast, treatment with angiotensin converting enzyme inhibitors or cholesterol- lowering drugs improved endothelial dysfunction, prevented the activation of superoxide-producing enzymes in cholesterol-fed animals, reduced coronary event rates, and improved prognosis in patients with coronary artery disease. Therefore, inhibition of superoxide production at the enzymatic level rather than symptomatic superoxide scavenging may be the better choice of treatment.
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PMID:Antioxidants and endothelial dysfunction in hyperlipidemia. 1117 9

Supraphysiological increases in serum triglycerides and cholesterol often occur during pregnancy, but their effects on vascular function are poorly understood. Intraperitoneal injection of the nontoxic surfactant poloxamer 407 (P-407) results in sustained elevation of triglycerides and cholesterol. We asked if P-407-induced hyperlipidemia during late pregnancy adversely affects mesenteric resistance artery vasodilator function. On days 13-15 of pregnancy, rats were given a single intraperitoneal injection of P-407, sterile water vehicle, or non-lipid-altering pluronic F-88 (P-88). Four days postinjection, serum triglycerides, cholesterol, free fatty acids, and the lipid peroxidation product malondialdehyde were significantly increased in P-407-treated rats. Mesenteric arteries from P-407-treated rats displayed significant increases in myogenic reactivity (constrictor responses to step increases in intraluminal pressure). The nitric oxide (NO) blocker N(alpha)-methyl-L-arginine increased the myogenic response in control but not in P-407 arteries, normalizing group differences. Endothelial removal increased myogenic reactivity beyond that of prior NO synthase inhibition in controls and potentiated myogenic reactivity in P-407 arteries such that responses again converged. Relaxation responses to the endothelium-dependent vasodilator methacholine did not differ. We conclude that that P-407-induced hyperlipidemia during pregnancy increases myogenic reactivity due to selective attenuation of an NO-mediated vasodilator component of the myogenic response.
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PMID:Endothelial function and myogenic reactivity in small mesenteric arteries of hyperlipidemic pregnant rats. 1155 43

Postprandial hyperlipidemia is frequently associated with diabetes mellitus and considered to be an independent coronary risk factor. Nitric oxide (NO) is a key regulator of glucose uptake in skeletal muscle. The goal of this study was to examine the effects of chronic in vivo competitive antagonism of NO synthase (NOS) by the administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) on glucose and lipid metabolism in diabetic (Otsuka Long-Evans Tokushima Fatty [OLETF]) and nondiabetic rats. Chronic administration of L-NAME to rats induced reduced NO production and hypertension in both strains of rats. No detectable impairment of plasma levels of postprandial triglyceride (TG) or insulin sensitivity in nondiabetic rats was detected by chronic treatment of L-NAME, but significant impairment was observed in the cases of diabetic rats. These results suggest that diabetes, when associated with endothelial dysfunction, results in greater abnormalities in lipid, as well as glucose metabolism.
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PMID:Chronic feeding of a nitric oxide synthase inhibitor induces postprandial hypertriglyceridemia in type 2 diabetic model rats, Otsuka Long-Evans Tokushima Fatty rats, but not in nondiabetic rats. 1203 22

Epidemiological studies have suggested that cardiovascular disease can be decreased by moderate wine consumption, but an overall quantitative estimation of the relationship between wine intake and vascular risk is lacking. A meta-analysis was therefore performed on 19 studies selected on the basis of the availability of specific information on the cardiovascular relative risk (RR) associated with wine consumption. A significant risk reduction (RR: 0.66, 95% CI 0.57-0.75) was associated with moderate (1-2 drinks or 150-300 mL/d) versus no wine consumption. In five studies which excluded ex-drinkers as reference group, the overall RR associated with wine consumption was 0.61 (95% CI 0.57-0.75). A dose-response relation between wine intake and vascular risk resulted in a J-shaped curve, with a significant risk reduction at about 300 mL/d (trend analysis p = 0.032). Two studies were also performed to investigate the effects of wine polyphenols on experimental thrombosis in rats. Supplementation for 10 days with alcohol-free red wine--but not white wine or alcohol--induced a significant reduction of stasis-induced venous thrombosis, an effect blunted by NO synthase inhibitor L-NAME. In rats with diet-induced hyperlipidemia, alcohol-free red wine supplementation significantly delayed the thrombotic occlusion of an artificial prosthesis inserted into the abdominal aorta, but did not affect the increased cholesterol and triglyceride levels. TRAP values were significantly higher in animals receiving alcohol-free wine. Altogether these experimental data support an antithrombotic role of polyphenols in the reduced vascular risk associated with moderate wine consumption in man, as shown by our epidemiological studies.
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PMID:Antithrombotic effect of polyphenols in experimental models: a mechanism of reduced vascular risk by moderate wine consumption. 1207 71

We tested the hypothesis that exercise training (Ex) attenuates the effects of hyperlipidemia on endothelial function by enhancing NO-mediated vasorelaxation in porcine brachial (Br) arteries. Adult female pigs were fed a normal-fat (NF) or high-fat (HF) diet for 20 wk. Four weeks after initiation of the diet, pigs underwent Ex or remained sedentary (Sed) for 16 wk. Relaxation to ACh was impaired by HF (P = 0.03). The combination of HF and Sed impaired ACh-induced relaxation more than HF or Sed alone (P = 0.0002). Relaxation to high doses of bradykinin (BK) was impaired by HF (P = 0.0002). Ex significantly improved ACh-induced relaxation (P = 0.01) and tended to improve relaxation to BK (P = 0.38). To determine the mechanism(s) by which HF and Ex affected relaxation to ACh and BK, relaxation was assessed in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME; to inhibit NO synthase), indomethacin (Indo; to inhibit cyclooxygenase), or l-NAME + Indo. In the presence of l-NAME, Indo, or l-NAME + Indo, ACh-induced relaxation was no longer different between HF and NF arteries; however, relaxation remained greater in Ex than in Sed arteries. In the presence of l-NAME or Indo, BK-induced relaxation was no longer altered by HF but was enhanced by Ex. In the presence of l-NAME + Indo, BK-induced relaxation was enhanced by HF and Ex. These data indicate that hyperlipidemia impairs ACh- and BK-induced relaxation by impairing NO- and PGI(2)-mediated relaxation. Ex attenuates the effects of HF by enhancing a vasodilator mechanism independent of NO and PGI(2).
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PMID:Exercise training preserves endothelium-dependent relaxation in brachial arteries from hyperlipidemic pigs. 1267 52

The endothelial cell layer displays the features of a distributed organ and has a variety of biological functions such as keeping the balance between coagulation and fibrinolysis, expression of adhesion molecules for cells in the immune system, metabolism of noradrenaline and 5-hydroxytryptamine, and conversion of angiotensin I and bradykinin. The endothelium also regulates the underlying smooth muscle layer and vascular tone by release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) as well as vasoconstricting factors such as endothelin, superoxide (O(2)(-)), and thromboxane. We have reviewed the nature, mechanisms of action, and role of these factors in regulation of vascular tone, with special emphasis on NO. By a process catalyzed by NO synthase, NO and citrulline is formed from the substrates molecular O(2) and L-arginine. The main receptor for NO is guanylyl cyclase leading to formation of smooth muscle cyclic guanosinmonophosphate and relaxation. EDHF is an endothelium-derived factor causing vasorelaxation of the underlying smooth muscle layer by hyperpolarization. The nature of EDHF is still unknown, but several candidates for EDHF have been proposed such as potassium ions, hydrogen peroxide, and epoxyeicosatrienoic acids. Prostaglandins such as prostacyclin and prostaglandin E2 binds to specific receptors followed by increases in cyclic adenosinmonophosphate and vasorelaxation, while contractile prostaglandins constrict vessels by activation of thromboxane and endoperoxidase receptors. Superoxide anions induce contraction of vascular smooth muscles cells by scavenging NO. Endothelin is a potent endothelium-derived contractile factor. The synthesis of endothelin-1 is induced by hypoxia, thrombin, interleukin-1, transforming growth factor-beta1, vasopressin, and catecholamines. Cardiovascular risk factors like age, hypertension, and hyperlipidemia are associated with impaired endothelium-dependent vasodilation either as a consequence of increased inactivation of endothelium-derived vasodilators or increased formation of endothelium-derived contracting factors. This imbalance of endothelium-derived factors plays a role for development of atheroslerosis and ischemic vascular diseases.
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PMID:[Role of nitric oxide and other endothelium-derived factors]. 1273 1

The endothelial generation of reactive oxygen species (ROS) is important both physiologically and in the pathogenesis of many cardiovascular disorders. ROS generated by endothelial cells include superoxide (O2-*), hydrogen peroxide (H2O2), peroxynitrite (ONOO-*), nitric oxide (NO), and hydroxyl (*OH) radicals. The O2-* radical, the focus of the current review, may have several effects either directly or through the generation of other radicals, e.g., H2O2 and ONOO-*. These effects include 1) rapid inactivation of the potent signaling molecule and endothelium-derived relaxing factor NO, leading to endothelial dysfunction; 2) the mediation of signal transduction leading to altered gene transcription and protein and enzyme activities ("redox signaling"); and 3) oxidative damage. Multiple enzymes can generate O2-*, notably xanthine oxidase, uncoupled NO synthase, and mitochondria. Recent studies indicate that a major source of endothelial O2-* involved in redox signaling is a multicomponent phagocyte-type NADPH oxidase that is subject to specific regulation by stimuli such as oscillatory shear stress, hypoxia, angiotensin II, growth factors, cytokines, and hyperlipidemia. Depending on the level of oxidants generated and the relative balance between pro- and antioxidant pathways, ROS may be involved in cell growth, hypertrophy, apoptosis, endothelial activation, and adhesivity, for example, in diabetes, hypertension, atherosclerosis, heart failure, and ischemia-reperfusion. This article reviews our current knowledge regarding the sources of endothelial ROS generation, their regulation, their involvement in redox signaling, and the relevance of enhanced ROS generation and redox signaling to the pathophysiology of cardiovascular disorders where endothelial activation and dysfunction are implicated.
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PMID:Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. 1547 99

Hyperhomocyst(e)inemia is associated with an increased risk for atherosclerotic disease and venous thromboembolism. The impact of elevated plasma homocysteine levels seems to be clinically relevant, since the total cardiovascular risk of hyperhomocyst(e)inemia is comparable to the risk associated with hyperlipidemia or smoking. There is substantial evidence for impairment of endothelial function in human and animal models of atherosclerosis, occurring even before development of overt plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of atherosclerotic lesion development and predicts future vascular events. NO is the most potent endogenous vasodilator known. It is released by the endothelium, and reduced NO bioavailability is responsible for impaired endothelium-dependent vasorelaxation in hyperhomocyst(e)inemia and other metabolic disorders associated with vascular disease. Substances leading to impaired endothelial function as a consequence of reduced NO generation are endogenous NO synthase inhibitors such as ADMA. Indeed there is accumulating evidence from animal and human studies that ADMA, endothelial function and homocyst(e)ine might be closely interrelated. Specifically elevations of ADMA associated with impaired endothelium-dependent relaxation were found in chronic hyperhomocyst(e)inemia, as well as after acute elevation of plasma homocyst(e)ine following oral methionine intake. The postulated mechanisms for ADMA accumulation are increased methylation of arginine residues within proteins, as well as reduced metabolism of ADMA by the enzyme DDAH, but they still need to be confirmed to be operative in vivo. Hyperhomocyst(e)inemia, as well as subsequent endothelial dysfunction can be successfully treated by application of folate and B vitamins. Since ADMA seems to play a central role in homocyst(e)ine-induced endothelial dysfunction, another way of preventing vascular disease in patients with elevated homocyst(e)ine concentrations could be supplementation with L-arginine to reverse the detrimental effects of ADMA.
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PMID:Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction. 1572 Feb 2

Cardiovascular diseases have been increasing in association with life style changes and increasing trends of hyperlipidemia and diabetes in Japan. On the other hand, cerebrovascular diseases, which largely comprise of small-vessel diseases such as hypertensive brain hemorrhage and lacunar brain infarction, have been considered to be dependent on aging and hypertension. Recently, however, atherothrombotic brain infarction (ATBI) has been rapidly increasing in Japan, and this increase occurs precedently in urban area such as Kanto and Kansai Districts. The present paper, therefore, summarizes the classification of diverse subtypes of cerebrovascular diseases and their underlying vascular lesions. Furthermore, it also focuses the risk factors for cerebrovascular diseases and the vascular lesions, and aims to clarify the factors and background which may have contributed to the increase of ATBI in Japan. Arteriosclerotic changes of small arteries in the brain parenchyma are considered to play an important role in development of cerebral white matter lesions (leucoaraiosis) and lacunar infarction. Oxidative stresses such as smoking, lipid peroxidation, and others are suggested to give impacts on the lesion formation through the effects on various functions of arterial trees and nitric oxide (NO) production from the arterial endothelial cells. Therefore, This paper presents the data indicating the significant correlation of these oxidative stress markers and polymorphism of endothelial NO synthase gene which may be relating to the pathogenesis of cerebral white matter lesions, and discusses about the usefulness of these new risk factors for cerebrovascular diseases.
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PMID:[Risk factors for cerebrovascular diseases]. 1596 6


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