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)

It is proposed that metabolic syndrome X is initiated in the perinatal period as a low-grade systemic inflammatory condition. Increased consumption of energy-dense diets by pregnant women and lactating mothers suppresses the activities of Delta-6 and Delta-5 desaturases not only in maternal tissues but also in fetal liver and the placenta, resulting in decreased plasma and tissue concentrations of long-chain polyunsaturated fatty acids omega-6 arachidonic acid (AA), omega-3 eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). EPA, DHA, and AA have negative feedback control on tumor necrosis factor-alpha and IL-6 synthesis. Hence, EPA, DHA, and AA deficiencies induced by an energy-dense diet increase generation of tumor necrosis factor-alpha and interleukin-6, markers of inflammation that in turn decrease production of endothelial nitric oxide and adiponectin to induce insulin resistance in maternal and fetal tissues. Increased concentrations of tumor necrosis factor-alpha and interleukin-6 enhance expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 enzyme, which produces abdominal obesity, insulin resistance, hyperlipidemia, hyperphagia, and hyperleptinemia, characteristic features of metabolic syndrome X. Continued consumption of an energy-dense diet in childhood aggravates these molecular events. This implies that supplementation of long-chain polyunsaturated fatty acids (especially AA, EPA, and DHA in appropriate ratios) from the perinatal period through adulthood could prevent, arrest, or postpone development of metabolic syndrome X.
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PMID:Pathophysiology of metabolic syndrome X and its links to the perinatal period. 1592 3

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

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating substances, including vasodilator prostaglandins, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). Since the first report for the existence of EDHF, several substances/mechanisms have been proposed for the nature of EDHF, including epoxyeicosatrienoic acids (metabolites of arachidonic P450 epoxygenase pathway), K ions, and electrical communications through myoendothelial gap junctions. We have recently demonstrated that endothelium-derived hydrogen peroxide (H(2)O(2)) is an EDHF in mouse and human mesenteric arteries and in porcine coronary microvessels. For the synthesis of H(2)O(2) as an EDHF, endothelial Cu,Zn-superoxide dismutase plays an important role in mesenteric arteries of mice and humans. We also have demonstrated that EDHF-mediated responses are attenuated by several arteriosclerotic risk factors, including diabetes mellitus and hyperlipidemia and their combination in particular. Recent studies have indicated that endothelium-derived H(2)O(2) plays an important protective role in coronary autoregulation and myocardial ischemia/reperfusion injury in vivo. Indeed, our H(2)O(2)/EDHF theory demonstrates that endothelium-derived H(2)O(2), another reactive oxygen species in addition to NO, plays an important role as a redox signaling molecule to cause vasodilatation as well as cardioprotection. In this review, we summarize our knowledge on H(2)O(2)/EDHF regarding its identification, mechanisms of synthesis, and clinical implications.
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PMID:Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. 1612 55

Atherosclerosis and hyperlipidemia impair endothelium-dependent nitric oxide (NO)-mediated dilations in conducting arteries. In addition to NO, the endothelium releases an endothelium-derived hyperpolarizing factor (EDHF) in response to acetylcholine (ACh), which is particularly important in microvessels and initiates a dilation that conducts along the vessel through gap junctional communication. The expression of connexins is, however, altered by hypercholesterolemia. Therefore, we studied endothelium-dependent dilations and their conduction in murine hypercholesterolemic models. Dilations were assessed by intravital microscopy in arterioles with a diameter of approximately 35 microm in ApoE and LDL receptor (LDLR(-/-))-deficient mice after superfusion or locally confined application of ACh. ACh induced comparable concentration-dependent dilations in wild-type, LDLR(-/-), and ApoE(-/-) mice fed a normal or high-cholesterol diet, however EC(50) was slightly higher in ApoE(-/-) mice. Furthermore, the NO donor sodium-nitroprusside dilated arterioles to a similar extent (approximately 60%). Locally initiated ACh dilations (approximately 68%) conducted up to a distance of 1,100 microm without significant attenuation even under severe hypercholesterolemic conditions. Since ACh dilation in the arterioles of mice is mainly mediated via EDHF, we conclude that hypercholesterolemia does not alter EDHF release and efficacy. This conclusion is confirmed by an intact conducted response since EDHF is a prerequisite for this response. The intact conduction also suggests that gap-junctional communication is functionally preserved in these models.
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PMID:Intact endothelium-dependent dilation and conducted responses in resistance vessels of hypercholesterolemic mice in vivo. 1615 63

Metabolic syndrome is a cluster of metabolic abnormalities, including hypertension, hyperlipidemia, hyperinsulinemia, glucose intolerance and obesity. In such lifestyle-related diseases, impairment of nitric oxide (NO) production or bioactivity has been reported to lead to the development of atherogenic vascular diseases. Therefore, in the present study we investigated changes in the NO/cyclic guanosine monophosphate (cGMP) system in aortas of SHR/NDmcr-cp (cp/cp) rats (SHR-cp), a model of the metabolic syndrome. In aortas of SHR-cp, endothelium-dependent relaxations induced by acetylcholine and endothelium-independent relaxations induced by sodium nitroprusside were significantly impaired in comparison with Wistar-Kyoto rats. Furthermore, protein levels of soluble guanylyl cyclase and cGMP levels induced by sodium nitroprusside were significantly decreased. In contrast, protein levels of endothelium NO synthase and cGMP levels induced by acetylcholine were significantly increased, and plasma NO2 plus NO3 levels were also increased. The levels of lipid peroxide in plasma and the contents of 3-nitrotyrosine, a biomarker of peroxynitrite, in aortas were markedly increased. These findings indicate that in the aortas of SHR-cp, NO production from the endothelium is augmented, although the NO-induced relaxation response is impaired. Enhanced NO production may be a compensatory response to a variety of factors, including increases in oxidative stress.
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PMID:Disturbances in nitric oxide/cyclic guanosine monophosphate system in SHR/NDmcr-cp rats, a model of metabolic syndrome. 1618 78

Diabetic vascular disease is accompanied by decreased formation of the vasodilators, nitric oxide (NO), and prostacyclin and increased formation of vasoconstrictor eicosanoids, which exacerbate the progression of vascular disease. Similarities between the dysfunction introduced by short-term effects of elevated glucose and long-term effects of diabetes suggest that the alteration in endothelial factors in diabetes primarily results from exposure of endothelial cells to elevated glucose, although undoubtedly hyperlipidemia contributes as well. A key alteration in endothelial cell phenotype is increased formation of reactive oxygen species. This is in part due to uncoupling of endothelial NO synthase such that it generates superoxide anion in addition to NO. This is responsible for NO synthase to produce peroxynitrite, a damaging molecule. Peroxynitrite inactivates prostacyclin synthase leading to the accumulation of inflammatory and prothrombotic eicosanoids. This not only helps to explain the impairment of endothelial vasodilator mechanisms, but also increased progression of vascular disease. Many of these cellular abnormalities can be prevented by adequate scavenging of oxygen-derived free radicals or by blocking the actions of the eicosanoids at thromboxane (TP) receptors. Exposure to elevated glucose also gives rise to oxidants in smooth muscle, and recent studies indicate that oxidation of cysteine thiols under these conditions may prevent physiological NO signaling. As a result, the responsiveness to NO is impaired and accounts in part for abnormal endothelium-dependent vasodilation.
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PMID:Role of nitric oxide in diabetic complications. 1628 Jun 43

Endothelial dysfunction contributes to mechanisms of atherogenesis and its clinical manifestations, including coronary heart disease. Cardiovascular risk factors have been linked directly to a loss of endothelial function, such as endothelium-dependent nitric oxide (NO) release, resulting in abnormal vasodilation in response to various stimuli. There is evidence that multiple risk factors, including hypertension and hyperlipidemia, lead to a synergistic effect on endothelial dysfunction, likely through oxidative stress mechanisms. Damage to the endothelium leads to reduced NO bioavailability and facilitates vessel wall permeability to low-density lipoprotein. Certain agents, including the antihypertensive drug amlodipine and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) atorvastatin, are known to influence endothelial function and NO bioavailability directly; these properties may contribute to clinical benefits. Recent experimental evidence at the cellular level indicates that these agents stimulate NO release from human endothelial cells in a highly synergistic fashion. The clinical implications of these observations are discussed in this article in the context of cardiovascular risk factor management strategies.
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PMID:A rationale for combination therapy in risk factor management: a mechanistic perspective. 1635 9

Coronary artery disease (CAD) and erectile dysfunction (ED) are both highly prevalent conditions that frequently coexist. Additionally, they share mutual vascular risk factors, suggesting that they are both manifestations of systemic vascular disease. The role of endothelial dysfunction in CAD is well established. Normal erectile function is primarily a vascular event that relies heavily on endothelially derived, nitric oxide-induced vasodilation. Accordingly, endothelial dysfunction appears to be a common pathological etiology and mechanism of disease progression between CAD and ED. The risk factors of diabetes mellitus, hypertension, hyperlipidemia, obesity and tobacco abuse contribute to endothelial dysfunction. This article reviews the role of vascular endothelium in health, the abnormalities resulting from vascular risk factors, and clinical trials evaluating the role of endothelial dysfunction in ED.
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PMID:Linking erectile dysfunction and coronary artery disease. 1639 38

cGMP-dependent protein kinase (PKG) is the major intracellular receptor for cyclic guanosine monophosphate (cGMP). Two forms of PKG, PKG-I and PKG-II, occur in mammalian tissues. PKG may mediate nitric oxide-cGMP-induced vasodilation through decreasing intracellular calcium concentration by the activation of calcium-activated potassium channel on the cell membrane and phosphorylation of phospholamban (PLB) and IP3 receptor-associated PKG-I substrate (IRAG) on the sarcoplasmic reticulum. PKG may also decrease the sensitivity of myosin to calcium by stimulating the activity of myosin light chain phosphatase and by inhibiting Rho kinase activity. PKG plays an important role in regulating the gene expression, phenotype, and proliferation of vascular smooth muscle cells. PKG activation inhibits platelet aggregation and myocardial hypertrophy. Recent studies indicate that the alternations of PKG expression and activity are closely related with the pathogenesis of atherosclerosis, restenosis, hypertension, hyperlipemia as well as nitrate tolerance.
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PMID:[Role of cGMP-dependent protein kinase in the cardiovascular system]. 1640 66

Effect of dietary supplementation of two types of rice bran fraction on blood pressure (BP), lipid profile, and glucose metabolism in stroke-prone spontaneously hypertensive rats was studied. Male 4-week-old rats were divided into one group fed the AIN-93M-based control (C) diet and two groups fed diet supplemented with 60 g/kg of Driselase and ethanol fractions (DF and EF, respectively) of rice bran. After 8 weeks feeding, the BP decreased in the DF and EF groups in comparison with the C group (p < 0.01). Plasma ACE inhibitory activity, BUN, BUN/creatinine ratio, albumin, triglyceride, and glucose levels were lower in the DF and EF groups than in the C group (p < 0.01). Plasma nitric oxide and urinary 8-hydroxy-2'-deoxyguanosine levels were lower in the DF and EF groups than in the C group (p < 0.01). Rice bran fractions appear to have a beneficial dietary component that improves hypertension, hyperlipidemia, and hyperglycemia.
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PMID:Rice bran fractions improve blood pressure, lipid profile, and glucose metabolism in stroke-prone spontaneously hypertensive rats. 1650 53


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