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)

Extensively oxidized low density lipoprotein (ox-LDL), a modulator of atherogenesis, down-regulates the lipopolysaccharide (LPS)-induced activation of transcription factor NF-kappaB. We investigated whether 4-hydroxynonenal (HNE), a prominent aldehyde component of ox-LDL, represents one of the inhibitory substances. NF-kappaB activation by stimuli such as LPS, interleukin (IL)-1beta, and phorbol ester, but not tumor necrosis factor (TNF), was reversibly inhibited by HNE in a dose-dependent manner in human monocytic cells, whereas AP-1 binding was unaffected. Using similar HNE concentrations, LPS-induced kappaB- and TNF or IL-8 promoter-dependent transcription was prevented. Furthermore, pretreatment with HNE suppressed TNF production but not lactate dehydrogenase levels. Under these conditions the binding of LPS to monocytic cells was not significantly affected. However, induced proteolysis of the inhibitory proteins IkappaB-alpha, IkappaB-beta, and, at a later time point, IkappaB-epsilon was prevented. This is not due to inhibition of the proteasome, the major proteolytic activities of which remain unaffected, but rather to a specific prevention of the activation-dependent phosphorylation of IkappaB-alpha. This is the first report which demonstrates that HNE specifically inhibits the NF-kappaB/Rel system. Down-modulation of NF-kappaB-regulated gene expression may contribute at certain stages of atherosclerosis to low levels of chronic inflammation and may also be involved in other inflammatory/degenerative diseases.
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PMID:4-Hydroxynonenal prevents NF-kappaB activation and tumor necrosis factor expression by inhibiting IkappaB phosphorylation and subsequent proteolysis. 1020 70

About 50 mg of silver leaf (metallic silver) was given daily by mouth to 30 healthy volunteers for 20 days. A statistically significant hypophospholipidemic, hypotriglyceridemic, hypocholesterolemic and hypoglycemic effect was observed. This was accompanied by a less marked fall in total lipids and significant rise in HDL-cholesterol. In addition, a decrease in plasma enzymes - alkaline phosphatase (ALP), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), creatine phosphokinase (CPK), gamma glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH) was noted. This was statistically significant for all enzymes except CPK. The safety of ingested silver foil is indicated by absence of pathology in urine and unaltered levels of protein and albumin in the plasma. These observations suggest that silver could be beneficial in conditions like diabetes mellitus, obesity and atherosclerosis.
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PMID:Effect of silver leaf on circulating lipids and cardiac and hepatic enzymes. 1023 75

We examined the effect of acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on intracellular cholesterol stores in primary human monocyte-derived macrophages (HMMs) during foam cell formation. HMMs were exposed to acetylated low density lipoprotein (acLDL, 500 microg protein per mL) with or without 58-035 (1 to 10 microg/mL) or CI-976 (2 microg/mL) for 2 to 48 hours. Total cholesterol (TC) and esterified cholesterol (EC) mass was significantly lower while unesterified cholesterol (UC) increased slightly in cells incubated with acLDL plus ACAT inhibitors. Sterol mass was also measured in cells coincubated with acLDL (500 microg protein per mL) with or without 58-035 (2 microg/mL), high density lipoprotein (HDL, 400 microg protein per mL), or HDL+58-035 for 48 hours. TC and EC were 23% and 55% lower, respectively (P<0.0004), while UC was 11% higher (P<0.04) in cells incubated with acLDL plus 58-035. In contrast, coincubation with HDL alone did not significantly affect TC, EC, or UC mass compared with acLDL alone. The effect of 58-035 could not be explained by cytotoxicity, because adenine release, secreted lactate dehydrogenase, glucose utilization, and cell protein were similar in cells exposed to acLDL regardless of the presence of 58-035. We investigated several potential mechanisms for the decreased TC mass, including increased UC efflux and decreased acLDL binding and uptake. Efflux was measured in cells exposed to [1,2-(3)H]cholesteryl oleate-labeled acLDL, unlabeled control acLDL, and native untreated acLDL (500 microg protein per mL) with or without 58-035 (5 microg/mL) for 24 or 48 hours. UC efflux increased in a time-dependent manner from cells exposed to acLDL plus 58-035 compared with cells exposed to acLDL alone (P<0. 04). High-affinity binding was measured in cells exposed to (125)I-acLDL (5 microg protein per mL) with or without excess unlabeled acLDL (100 or 500 microg protein per mL) for 4 hours at 4 degrees C. Specific acLDL binding, uptake, and total degradation were significantly lower when 58-035 was present during cholesterol enrichment compared with cells exposed to acLDL alone (P<0.001). Unlike the effects of ACAT inhibitors on foam cell formation in rodent macrophages, these compounds lowered TC accumulation in HMMs during foam cell formation by limiting the uptake of acLDL and enhancing UC efflux. They may offer promise as drug therapies for atherosclerosis.
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PMID:Novel effects of the acyl-coenzyme A:Cholesterol acyltransferase inhibitor 58-035 on foam cell development in primary human monocyte-derived macrophages. 1047 63

The factors responsible for the marked gender difference in the risk of coronary heart disease and remain controversial. Several clinicians and basic scientists support the hypothesis that a protective effect of endogenous estrogen is the key, however epidemiological data failed to prove this trend. The role of endogenous androgens or sex steroid hormones on the development of atherosclerosis has received little attention over the years. The specific objectives of this study are: 1) to deliver testosterone (T), dihydrotestosterone (DHT), or androstenedione (AED) at sustained levels by tricalcium phosphate lysine (TCPL) ceramic delivery devices, and 2) to quantify major biochemical markers levels such as lactate dehydrogenase activity (LDH), total cholesterol, thiobarbituric reactive species associated with sustained delivery of androgens and 3) to evaluate the histopathological changes in vital and reproductive organs associated with excess androgens delivery in adult intact male rats. A total of sixteen male rats were randomly divided into four equal groups. Rats in group I served as intact controls, and animals in groups II-IV were implanted with a single TCPL delivery device contained T (40 mg), DHT (40 mg), or AED (40 mg), respectively. Animals in all groups were weighed and blood was drawn biweekly for cholesterol, LDH and TBAR analysis. At the end of ninety days post implantation, the animals were sacrificed and the organs removed, processed embedded, sectioned and screened for morphological changes. The results of this study suggest that: 1) sustained deliver of androgens caused a statistically significant increase (p < 0.05) in the prostate and the seminal vesicle weights, while the epididymis weights remained similar to control intact animals, 2) decreases in adrenal gland weight was detected in animals treated with androgens compared to control animals, 3) kidney weights increased in all androgen groups compared to control, 4) no differences were observed in heart, spleen, or body weights between the groups, 5) TBAR analysis, as well as LDH activity were not different between androgen treated animals and control animals, and 6) total cholesterol was significantly reduced in T and DHT treated groups compared with control and AED treated animals. The decrease in total cholesterol and reduction in adrenal gland weight may suggest impairment of cholesterol synthesis. In conclusion, this study provides information on the effects of sustained release of DHT, T and AED on the reproductive organs, vital organs, as well as physiological parameters such as TBARS (cellular damage) and total cholesterol.
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PMID:Physiological responses associated with sustained delivery of T, DHT, and AED in male rats. 1083 34

Cardiovascular disease (CVD) is the leading cause of death in the USA and other industrialized countries. A large number of epidemiological studies have established a direct correlation between diet and the development and progression of atherosclerosis. Several studies have shown the incidence of CVD to be lower in populations consuming a predominantly plant-based diet, as compared to meat-based diets. Besides being low in fat and cholesterol, vegetarian and Asian diets contain a large variety of phytochemicals, which may function in the body. For example, phytosterols (PS) are plant sterols that interfere with the absorption of cholesterol from the intestine when present in adequate amounts. Although PS may also function at a cellular level in the body, there are few studies examining the action of PS on cells involved in atherosclerosis. The purpose of this study was to examine the effect of dietary PS on vascular smooth muscle cell (VSMC) growth and function, since VSMC play a central role in the development of atherosclerosis. VSMC were treated with 16 microM cholesterol, 25-hydroxycholesterol, campesterol and beta-sitosterol (SIT) using an ethanol as a vehicle. Cell growth was determined by cell counting and cell proliferation by DNA synthesis, which was measured by [(3)H]-thymidine incorporation. Cholesterol supplementation had no effect on cell growth and proliferation. 25-Hydroxycholesterol decreased cell growth by 68% and DNA synthesis by 99%. SIT was found to inhibit VSMC growth more effectively than campesterol. Of the two PS, campesterol decreased cell growth by 16% and SIT decreased cell growth by 30%. DNA synthesis was decreased 25% by SIT supplementation but was not influenced by campesterol or cholesterol supplementation. Cholesterol, campesterol and SIT were not cytotoxic to VSMC and did not significantly alter cell viability. 25-Hydroxycholesterol, however, was cytotoxic and decreased cell viability by 45% as determined by lactate dehydrogenase release and a trypan blue dye exclusion test. De novo cholesterol synthesis was decreased 28% by campesterol, 49% by SIT and 23% by cholesterol. Beta-sitosterol exhibited a greater effect on cholesterol synthesis than campesterol or cholesterol supplementation. Measurement of cell sterol content demonstrated incorporation of PS into VSMC at the expense of cholesterol. Campesterol decreased VSMC cholesterol content by 36%, representing 40% of the total sterol content following treatment. Beta-sitosterol decreased VSMC cholesterol by 41% following supplementation and represented 49% of the total sterol amount. Cholesterol treatment did not alter the cholesterol content of the cells. Prostacyclin production was significantly altered by PS treatment. Basal prostacyclin release was increased 43% by campesterol and 81% by SIT. A23187 stimulated prostacyclin release was increased 25% by campesterol and 54% by SIT. SIT supplementation induced a greater effect on prostacyclin release from VSMC than cholesterol or campesterol supplementation. The in vitro results presented here suggest that dietary PS, especially SIT, may offer protection from the VSMC hyperproliferation found in atherosclerosis. Further in vivo research is needed to support these observations.
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PMID:Plant sterols regulate rat vascular smooth muscle cell growth and prostacyclin release in culture. 1142 42

Reactive oxygen species (ROS) hydrogen peroxide (H(2)O(2)) and hypochlorite (HOCl) participate in the pathogenesis of ischemia/reperfusion injury, inflammation, and atherosclerosis. Both NO and ROS are important modulators of vascular tone and architecture and of adhesive interactions between leukocytes, platelets, and vascular endothelium. We studied the effect of H(2)O(2) and HOCl on receptor-dependent (bradykinin [10(-6) mol/L] and ADP [10(-4) mol/L]) and receptor-independent mechanisms (calcium ionophore A23187 [10(-6) mol/L]) of NO production by porcine aortic endothelial cells (ECs). Changes in the level of EC cGMP (the second messenger of NO) were used as a surrogate of NO production. EC cGMP increased 300% in response to bradykinin and A23187 and 200% in response to ADP. Exposure of ECs to H(2)O(2) (50 micromol/L) for 30 minutes significantly impaired cGMP levels in response to ADP, bradykinin, and the receptor-independent NO agonist A23187. In contrast, preincubation with HOCl (50 micromol/L) impaired cGMP production only in response to ADP and bradykinin but not A23187. These concentrations of H(2)O(2) and HOCl did not result in increased EC lethality as assessed by lactate dehydrogenase release. Neither H(2)O(2) nor HOCl affected EC cGMP production in response to NO donor sodium nitroprusside, which suggests that guanylate cyclase is resistant to these oxidants. We also demonstrated that neither H(2)O(2) nor HOCl affects endothelial NO synthase (eNOS) catalytic activity as measured by conversion of L-arginine to L-citrulline in EC homogenates supplemented with eNOS cofactors. The present studies show that H(2)O(2) impairs NO production in response to both receptor-dependent and receptor-independent agonists and that these effects are due, at least in part, to inactivation of eNOS cofactors, whereas HOCl inhibits NO production by interfering with receptor-operated mechanisms at the level of the cell membrane. Concentrations of H(2)O(2) and HOCl used in the present studies have been shown to be generated in vivo during inflammation and ischemia/reperfusion. Therefore, we infer that these effects of H(2)O(2) and HOCl on EC NO production may contribute to disregulated vascular tone and altered leukocyte-EC interactions that occur in vascular injury as a result of those causes in which ROS generation is involved.
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PMID:Effects of the reactive oxygen species hydrogen peroxide and hypochlorite on endothelial nitric oxide production. 1164 2

Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P<0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41 micromol/g of protein respectively; mean difference -2.66 micromol/g; 95% confidence intervals -5.10 to -0.22 micromol/g; P<0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.
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PMID:Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum. 1167 56

Freshly solubilized A beta peptides synergistically increase the magnitude of the constriction induced by endothelin-1 (ET-1), via the activation of a pro-inflammatory pathway. We report that mevinolin and mevastatin, two inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are able to completely abolish the vasoactive properties of A beta in rat aortae. Mevinolin also appears to oppose the increased vascular reactivity to ET-1 induced by interleukin 1-beta and phospholipase A(2) suggesting that statins display some anti-inflammatory properties. We show that freshly solubilized A beta stimulates prostaglandin E(2) and F(2 alpha) production (by 6 and 3.6 times, respectively) in isolated rat aortae and that mevinolin completely antagonizes this effect confirming the anti-inflammatory action of mevinolin ex vivo in rat aortae. In addition, we observed that A beta vasoactivity is not mediated nor modulated by mevalonic acid suggesting that the anti-inflammatory action of the statins are not related to an inhibition of HMG-CoA reductase activity. Differentiated human neuroblastoma cells (IMR32) were used to assess the neurotoxic effect of pre-aggregated A beta by quantifying the release of lactate dehydrogenase (LDH) in the cell culture medium. A beta appears to enhance LDH release by 30% in IMR32 cells, an effect that can be completely opposed by mevastatin. Taken together these data show that statins can antagonize the effect of A beta in different assays and provide new clues to understand the prophylactic action of the statins against Alzheimer's disease.
Atherosclerosis 2002 Apr
PMID:Statins inhibit A beta-neurotoxicity in vitro and A beta-induced vasoconstriction and inflammation in rat aortae. 1188 11

The migration and proliferation of vascular smooth muscle cells (SMCs) are known to play roles in the pathogenesis of atherosclerosis. Therapy with a reductase inhibitor of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) ("statin") produces significant alterations in various SMC functions. The objectives of the present study were to determine whether pitavastatin, a new chemically synthesized and powerful statin, can affect angiotensin II (Ang II)- and platelet-derived growth factor (PDGF)-induced migration and proliferation of cultured rat vascular SMCs. The effect of pitavastatin on cell viability was also examined in these cells. Migration was evaluated by the Boyden's chamber method using microchemotaxis chambers. As expected, Ang II and PDGF BB potently stimulated cell migration in a concentration-dependent manner. Pitavastatin significantly inhibited Ang II (10(-6) mol/l)-induced migration at the concentrations of 10(-8) and 10(-7) mol/l. Pitavastatin also inhibited PDGF BB (1 ng/ml)-induced migration at concentrations between 10(-9) and 10(-8) mol/l in a relatively concentration-dependent manner. This statin modestly but significantly inhibited Ang II (10(-6) mol/l)- and PDGF BB (1 ng/ml)-induced DNA synthesis at concentrations between 10(-9) and 10(-7) mol/l. In addition, pitavastatin clearly inhibited Ang II (10(-6) mol/l)- and PDGF BB (1 ng/ml)-induced increases of cell number at concentrations between 10(-9) and 10(-7) mol/l. Pitavastatin did not affect lactate dehydrogenase release from these cells at the concentrations used in this experiment. In a trypan blue exclusion test, dead cells stained with trypan blue were not found 24 h after treatment with 10(-9), 10(-8) or 10(-7) mol/l of pitavastatin. These findings suggest that pitavastatin suppresses the migration and proliferation stimulated by Ang II and PDGF BB without affecting cell viability. Pitavastatin may exert an anti-atherogenic effect, in part, through these mechanisms.
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PMID:Inhibition of migration and proliferation of rat vascular smooth muscle cells by a new HMG-CoA reductase inhibitor, pitavastatin. 1204 44

Ebselen (2-phenyl-1, 2-benzisoselenazol-3[2H]-one) is a seleno-organic compound exhibiting both glutathione peroxidase and antioxidant activity. Although it has been reported that ebselen is effective against hydrogen peroxide (H(2)O(2))-induced cell death in several cell types, its effect on endothelial cell damage has not yet been elucidated. In the present study, we examined the effect of ebselen on H(2)O(2)-induced human umbilical vein endothelial cells (HUVECs) death, and its intracellular mechanism. Our findings showed that pretreatment of HUVECs with ebselen resulted in a significant recovery from H(2)O(2)-induced cell death in a concentration-dependent manner. In addition to the inhibition of lactate dehydrogenase (LDH) leakage, ebselen inhibited H(2)O(2)-induced cytochrome c release and caspase-3 activation and the resultant apoptosis in HUVECs. Moreover, it was observed that H(2)O(2) significantly stimulated activation of mitogen-activated protein (MAP) kinases, i.e., p38 MAP kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2). Ebselen inhibited H(2)O(2)-induced p38 MAP kinase, but not JNK or ERK1/2 activation. Furthermore, SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]-1H-imidazole), a specific p38 MAP kinase inhibitor, inhibited H(2)O(2)-induced p38 MAP kinase phosphorylation, cytochrome c release, caspase-3 activation, as well as cell death in HUVECs. These findings suggest that ebselen attenuates H(2)O(2)-induced endothelial cell death through the inhibition of signaling pathways mediated by p38 MAP kinase, caspase-3, and cytochrome c release. Thus, inhibition of p38 MAP kinase by ebselen may imply its usefulness for prevention and/or treatment of endothelial cell dysfunction, which was suggested to be the first step in the development of atherosclerosis.
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PMID:Ebselen inhibits p38 mitogen-activated protein kinase-mediated endothelial cell death by hydrogen peroxide. 1475 32


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