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)

1. Overproduction of superoxide anions in the vascular wall contributes to endothelial dysfunction in vascular disease. A superoxide-generating reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major source of oxidative radicals in vascular tissues. We studied the effects of a synthetic manganese-containing superoxide dismutase (SOD) mimetic, M40403, on NADPH oxidase-dependent superoxide generation and on endothelial dysfunction. 2. In rat aortic smooth muscle cells, NADPH (100 micro M) markedly stimulated superoxide production as detected by lucigenin (5 micro M)-enhanced chemiluminescence. M40403 reduced NADPH oxidase-dependent superoxide production in a concentration-dependent manner, with IC(50) being 31.6 micro M. In contrast, native Cu/Zn SOD (up to 300 U ml(-1)) had no effect. Angiotensin II (100 nM) increased the NADPH oxidase activity by 70%, and treatment with M40403 (10 micro M) reduced this increased superoxide to the control level. 3. In aortae from apolipoprotein(E)-deficient mice (apoE(0)) with hyperlipidemia and atherosclerosis, superoxide production is largely derived from NADPH oxidase. The attenuation of endothelial nitric oxide vasodilator function parallels the increase in vascular superoxide production at different stages of the disease. Acute incubation of such aortic rings with M40403 significantly suppressed superoxide production and improved endothelium-dependent vasorelaxation to a level comparable to that in wildtype control mice. 4. In summary, the cell-permeable SOD mimetic M40403 was found to reverse endothelial dysfunction in apoE(0) aorta ex vivo by decreasing NADPH oxidase-dependent superoxide levels. The advantages of synthetic SOD mimetics over the native Cu/Zn SOD enzyme, such as greater cell permeability and stability, confer significant therapeutic potential in vascular disease.
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PMID:Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)-deficient mice. 1287 23

Dietary flavonoids are thought to protect against cardiovascular disease. We have studied the effects of bioactive isoflavone metabolites on hyperlipidemia, endothelial dysfunction and the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE(0)) mice fed a Western high-fat diet. Supplementation with dihydrodaidzein (DiD), dehydroequol (DeE) (both 25 mg kg(-1) x day(-1)) and their combination (D/D; 12.5 mg kg(-1) x day(-1) for each) for 24 weeks reduced plasma high-density lipoprotein (HDL) and non-HDL cholesterol. D/D also reduced the triglyceride level. In the abdominal aorta of apoE(0) mice, these compounds significantly increased endothelial nitric oxide (NO)-mediated vasorelaxations induced by acetylcholine, but had a minor effect on relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine. Isoflavone treatment for 24 weeks had no effect on the total area of atherosclerotic plaques in the whole aorta, but DeE reduced the plaque thickness in the aortic arch by 29%, although this did not reach statistical significance. The endothelial dysfunction in apoE(0) mice is associated with hyperlipidemia and increased vascular oxidative stress measured as increased superoxide production. Both isoflavones have superoxide-scavenging activities in vitro. We suggest that chronic supplementation with bioactive isoflavone metabolites may protect endothelial NO function in apoE(0) mice, through both lipid-lowering and antioxidant actions.
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PMID:Cardiovascular protective effects of synthetic isoflavone derivatives in apolipoprotein e-deficient mice. 1290 40

Shosaikoto, a Kampo medicine used clinically to treat patients with chronic hepatitis or cirrhosis in Japan, displays immunoregulatory effects, especially on macrophage functions. Oral administration of shosaikoto influences the synthesis of humoral factors such as the interleukins, nitric oxide and prostaglandins in macrophages. In addition, phagocytic activity is enhanced by treatment with shosaikoto, resulting in an antigen that is effectively presented to T lymphocytes to produce more antibodies. The role of macrophages in the pathogenesis of atherosclerosis is well recognized, although a therapeutic agent targeted at macrophages has not yet been developed. When shosaikoto was administered to atherosclerotic rabbits, it did not exhibit antihyperlipidemic effects but did reduce the formation of atherosclerotic lesions. In addition, treatment with shosaikoto suppressed intimal hyperplasia in apoE-deficient mice fed a cholesterol-enriched diet for nine weeks. Biochemical studies demonstrated that the mechanism of the antiatherosclerotic effect was partly due to the increase of oxidized low-density lipoprotein (oxLDL) elimination by macrophages, resulting from stimulation of oxLDL uptake through scavenger receptors, activation of acyl-CoA:cholesterol acyltransferase and neutral cholesteryl ester hydrolase, and increase of cholesterol elimination by high-density lipoprotein. Furthermore, shosaikoto is able to reverse the depression of macrophage functions caused by hyperlipidemia. These results indicate the potential of this medicine as a new type of preventive or therapeutic agent for atherosclerosis.
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PMID:Shosaikoto as a potential antiatherosclerotic agent. 1293 13

Cardiac stress adaptation is deteriorated in hyperlipidemia possibly due to deterioration of nitric oxide (NO) metabolism. However, inhibition of HMG-CoA reductase, a key enzyme in the mevalonate pathway, was shown to increase the level of endothelial NO-synthase (eNOS) mRNA. Here we studied the effect of dietary and pharmacologic modulation of the mevalonate pathway on cardiac NO synthesis. Rats were fed 2% cholesterol-enriched or normal diet for 8 weeks. Normal and cholesterol-fed animals were treated with farnesol, a major metabolite of the mevalonate pathway (2.2 mg/kg i.p.) or with the HMG-CoA reductase inhibitor lovastatin (3 x 5 mg/kg per os for 3 days, n = 5-6 in each group). Cardiac NO content was significantly decreased in cholesterol-fed rats as assessed by electron spin resonance spectroscopy, however, other treatments did not influence cardiac NO content. Cardiac activity of Ca(2+)-dependent NOS was unaffected by cholesterol-diet and by treatment with either farnesol or lovastatin, as assessed by (14)C-citrullin assay. Ca(2+)-independent NOS activity was negligible in all groups. Cardiac eNOS protein content measured by Western blotting was also unchanged in all groups. We conclude that cholesterol-diet decreases cardiac NO content, however, cholesterol diet-induced inhibition of the mevalonate pathway does not account for the decreased NO level in the heart, and that the mevalonate pathway does not influence cardiac NO biosynthesis.
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PMID:Role of cholesterol-enriched diet and the mevalonate pathway in cardiac nitric oxide synthesis. 1295 3

I investigated whether metabolism of essential fatty acids and the concentrations of their long-chain metabolites (long-chain polyunsaturated fatty acids [LCPUFAs]) are altered in fetal or perinatal growth retardation, maternal hypercholesterolemia, low-grade systemic inflammation, insulin resistance, and atherosclerosis, conditions that predispose to the development of coronary heart disease (CHD).I critically reviewed the literature pertaining to the metabolism of essential fatty acids in CHD and conditions that predispose to it.LCPUFAs enhance endothelial nitric oxide synthesis, suppress the production of the proinflammatory cytokines tumor necrosis factor and interleukin-6, attenuate insulin resistance, and have antiatherosclerotic properties. Low-birthweight infants have decreased concentrations of LCPUFAs, especially arachidonic acid. Neonatal arachidonic acid status is related to intrauterine growth, and LCPUFAs improve fetal and postnatal growth. LCPUFAs are useful in the management of hyperlipidemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, and may mediate the beneficial actions of statins. Plasma concentrations of various LCPUFAs are low in diabetes mellitus, hypertension, and CHD and in populations at high risk of CHD. Breast milk is rich in LCPUFAs, and this may explain why and how adequate (6 mo to 1 y) breast feeding protects against the development of obesity, hypertension, insulin resistance, and CHD.LCPUFAs are essential for the growth and development of the fetus and infant. LCPUFAs can prevent various conditions that predispose to the development of CHD. The low incidence of CHD seen in adequately breast-fed infants can be linked to the LCPUFA content of breast milk. Based on this evidence, I suggest that provision of LCPUFAs during critical periods of growth, especially from the second trimester of pregnancy to age 5 y, prevents CHD in adult life.
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PMID:A perinatal strategy to prevent coronary heart disease. 1462 57

In glomerular and tubulointerstitial disease, polymorphonuclear- and monocyte-derived reactive oxygen species may contribute to oxidative modification of proteins, lipids, and nucleic acids. In part, the processes instigated by reactive oxygen species parallel events that lead to the development of atherosclerosis. Myeloperoxidase (MPO), a heme protein and catalyst for (lipo)protein oxidation is present in these mononuclear cells. The ability of MPO to generate hypochlorous acid/hypochlorite (HOCl/OCl-) from hydrogen peroxide in the presence of chloride ions is a unique and defining activity for this enzyme. The MPO-hydrogen peroxide-chloride system leads to a variety of chlorinated protein and lipid adducts that in turn may cause dysfunction of cells in different compartments of the kidney. The aim of this article is to cover and interpret some experimental and clinical aspects in glomerular and tubulointerstitial diseases in which the MPO-hydrogen peroxide-chloride system has been considered an important pathophysiologic factor in the progression but also the attenuation of experimental renal disease. The colocalization of MPO and HOCl-modified proteins in glomerular peripheral basement membranes and podocytes in human membranous glomerulonephritis, the presence of HOCl-modified proteins in mononuclear cells of the interstitium and in damaged human tubular epithelia, the inflammation induced and exacerbated by MPO antibody complexes in necrotizing glomerulonephritis, and the presence of HOCl-modified epitopes in urine following hyperlipidemia-induced renal damage in rodents suggest that MPO is an important pathogenic factor in glomerular and tubulointerstitial diseases. Specifically, the interaction of MPO with nitric oxide metabolism adds to the complexity of actions of oxidants and may help to explain bimodal partly detrimental partly beneficial effects of the MPO-hydrogen peroxide-chloride system in redox-modulated renal diseases.
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PMID:Myeloperoxidase in kidney disease. 1463 18

Several studies have suggested that hypertriglyceridemia is a common risk factor for coronary heart disease. Although increasing serum levels of triglyceride correlate with hypercoagulability, little is known about the contribution of hypertriglyceridemia to vascular function. We successfully segregated two lines of rabbits with genetically-determined severely high (TGH; 2764 +/- 413 mg/dl) and moderately high (TGL; 191 +/- 12 mg/dl) levels of triglyceride, but with comparable levels of total cholesterol, from Watanabe heritable hyperlipidemic rabbits. To determine whether hypertriglyceridemia was involved in alterations of vascular function, we conducted isometric tension studies and analyzed protein expression on thoracic aortic rings isolated from young (3-4 month) TGH, TGL and Japanese White rabbit (JW). No difference in percentage of plaque area in the thoracic aorta was found between TGH and TGL. Relaxing responses, evoked by sodium nitroprusside were similar in JW, TGL and TGH, but endothelium-dependent relaxation to acetylcholine was impaired in TGH compared with JW or TGL (maximal relaxation in JW; 83.5 +/- 2.7%, TGL; 79.9 +/- 5.3%, TGH; 59.1 +/- 5.7%, p<0.05). Relaxation to A23187 was also attenuated in TGH compared with JW, but not significantly different between TGL and JW. Endothelium-independent relaxation elicited by isoproterenol in TGH was significantly decreased compared with JW or TGL (maximal relaxation in JW; 95.2 +/- 2.6% TGL; 91.0 +/- 4.9%, TGH; 75.1 +/- 5.2%, p<0.05). Protein expression of angiotensin II type-1 receptor was increased in TGH and that of nitric oxide synthases-3 was attenuated in TGH compared with TGL. This is the first study showing that endothelium-dependent and -independent vascular relaxation under the condition of combined hyperlipidemia was severely impaired as compared to that under only hypercholesterolemia. These results suggest that hypertriglyceridemia aggravates functional impairment induced by hypercholesterolemia in endothelial and smooth muscle cells.
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PMID:Chronic hypertriglyceridemia in young watanabe heritable hyperlipidemic rabbits impairs endothelial and medial smooth muscle function. 1472 98

Evidence has accumulated that impairment of vascular endothelial function is the initial step in the development of atherosclerosis. One important finding is impairment of the release of endothelium-dependent relaxing factor, which is now thought to be nitric oxide or its related substances, from endothelial cells. Flow-mediated dilatation has been known to be endothelium-dependent, and this can be detected during reactive hyperemia by high-resolution ultrasound in superficial arteries. Several coronary risk factors have been reported to be significantly related with decreased flow-mediated dilatation. We studied the association between the accumulation of coronary risk factors (hyperlipidemia, diabetes mellitus, hypertension, and current smoking habitus) and vascular endothelial function. The lower incidence of atherosclerosis in women before the menopause than that in men is an established epidemiological observation. Short-term estrogen therapy improves endothelial function in postmenopausal women. However, there are few reports on its long-term effects on endothelial function. Furthermore, we determined whether a reduced dosage of estrogen may maintain its beneficial effects. A similar improvement was also observed while women were on hormone replacement therapy even at the reduced dosage. Our results indicate that even at half the dose of estrogen, hormone replacement therapy may improve endothelial function in postmenopausal women.
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PMID:New methods to evaluate endothelial function: Non-invasive method of evaluating endothelial function in humans. 1473 9

Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.
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PMID:Anti-lipid deposition effect of HMG-CoA reductase inhibitor, pitavastatin, in a rat model of hypertension and hypercholesterolemia. 1496 17

Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their potent lipid lowering properties. Amongst other factors, inflammation and oxidation are involved in enhanced progression of atherosclerosis and new lesion development. Therefore, research has been initiated focusing on the antioxidant and anti-inflammatory properties of CCBs and statins, beyond their primary effect, in order to evaluate the possible additive effects of combined treatment of CCBs with statins as antiatherosclerotic therapy. Clinical studies (e.g., the International Nifedipine Trial on Antiatherosclerotic Therapy [INTACT]) have demonstrated that the antiatherosclerotic action of CCBs is limited to the attenuation of the first stage of atherosclerogenesis (fatty streak formation or new lesion growth). The lesions that pre-existed at the start of CCB therapy did not demonstrate progression or regression on angiography. However, because the mechanisms of action of lipid-lowering drugs and CCBs, and their role in preventing the progression of atherosclerosis differ, it is conceivable to conclude that these two classes may have an additive or synergic effect, not only on new lesion formation but also on inhibiting the progression of established coronary atherosclerosis. Indeed, this combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has been reported in the Regression Growth Evaluation Statin Study (REGRESS) trial. This beneficial effect of combining CCBs with statins has now been replicated in transgenic atherosclerotic mice, where the combination of amlodipine and atorvastatin produced an additional 60% reduction of atherosclerosis compared with that observed with the statin alone. Serum markers of atherosclerosis and vascular integrity also improved most in the combination group. Synergistic effects of the combination of atorvastatin and amlodipine on acute nitric oxide release/endothelial function, and additive effects of the combination of amlodipine and atorvastatin in the improvement of arterial compliance in hypertensive hyperlipidaemic patients has been demonstrated. Collectively, these studies support the clinical antiatherosclerotic advantages of combination of CCBs and statins and in particular, of atorvastatin with amlodipine beyond their established antihyperlipidaemic and antihypertensive modes of action.
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PMID:Amlodipine and atorvastatin in atherosclerosis: a review of the potential of combination therapy. 1499 41


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