Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Cellular oxidation of protein and lipoproteins is believed to contribute to the pathology associated with both acute and chronic inflammatory processes. Enzymatic, myeloperoxidase and lipoxygenase, and non- enzymatic oxidation of low density lipoprotein, LDL, has been implicated in foam cell formation and the progression of atherosclerotic changes within the arterial wall. In the present study, the in vitro protective role of the selective estrogen receptor modulator, raloxifene, in these oxidant triggered processes has been investigated. Raloxifene, as with estrogen was observed to inhibit both copper mediated LDL oxidation as well as the cellular modification of LDL by murine peritoneal macrophages. Raloxifene was, however, a more potent inhibitor of LDL oxidation than 17 beta-estradiol. The inhibition of macrophage LDL modification by raloxifene was not due to a non-specific effect on all effector functions as phagocytosis of opsonized yeast was comparable with control macrophage cultures. In addition to the protective effects on LDL oxidation, raloxifene also inhibited tyrosyl radical formation catalyzed by myeloperoxidase. The inhibition of myeloperoxidase activity was observed for both the isolated enzyme and in phorbol ester stimulated murine peritoneal neutrophils. In contrast, raloxifene was a weaker inhibitor of horseradish peroxidase. These results demonstrate a potential protective role for raloxifene as an anti-oxidant in in vitro assays designed to evaluate oxidant mediated radical formation and tissue damage.
Atherosclerosis 1996 Sep 27
PMID:Inhibition of LDL oxidation and myeloperoxidase dependent tyrosyl radical formation by the selective estrogen receptor modulator raloxifene (LY139481 HCL). 887 35

Raloxifene has been shown to have estrogen agonist effects on bone and cholesterol metabolism while having estrogen antagonist effects on mammary gland and uterus. Reported here are the results of a study to determine whether raloxifene had the estrogen agonist effect of inhibiting coronary artery atherogenesis and to compare its effects with those of traditional conjugated equine estrogens (CEE) treatment. Ovariectomized (surgically postmenopausal) cynomolgus monkeys were fed a moderately atherogenic diet and treated with a placebo, raloxifene (1 mg/kg x day), raloxifene (5 mg/kg x day), or CEE (Premarin) at a dose that mimicked that of 0.625 mg/day in women. The effects of raloxifene on plasma lipid concentrations were generally comparable to those reported in postmenopausal women treated with raloxifene: reductions in low density lipoprotein cholesterol concentrations and no significant effects on high density lipoprotein cholesterol. We found no evidence that raloxifene had an estrogen agonist effect on coronary arteries. Treatment with CEE resulted in about a 70% reduction in coronary artery plaque size relative to that in the placebo group, whereas neither the low nor the high dose of raloxifene had an effect on coronary artery plaque size. The low dose raloxifene group had about 2 times more atherosclerosis and the high dose group had about 3 times more atherosclerosis than the CEE group.
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PMID:Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. 970 84

Epidemiological observations, clinical studies, and basic laboratory research suggest that oestrogen replacement therapy is associated with beneficial cardiovascular effects in postmenopausal women. Oestrogen has a multitude of biological effects that may account for this apparent benefit (which remain to be proven in randomized clinical trials), including favourable effects on the lipid profile, a direct effect on the vascular endothelium with increased nitric oxide bioactivity, and improved fibrinolysis. However, long-term oestrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the oestrogen receptor, is a selective oestrogen receptor modulator, producing oestrogen-agonistic effects in some tissues (liver, bone), and oestrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis and its associated risk factors who might benefit from oestrogen therapy. This review updates the current knowledge of the biological effects of oestrogen and selective oestrogen receptor modulators of potential cardiovascular importance in postmenopausal women.
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PMID:Effects of oestrogens and selective oestrogen receptor modulators on serum lipoproteins and vascular function. 986 94

Raloxifene hydrochloride binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators (SERMs). Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonist effects on bone and lipids and estrogen antagonist effects on the breast and uterus. In addition to its well established effects on osteoporosis, recent preclinical and clinical findings suggest that raloxifene also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene has been shown to reduce total and low-density lipoprotein cholesterol concentrations in plasma, an effect similar to that produced by estrogens. Unlike estrogens, however, raloxifene does not increase high-density lipoprotein cholesterol and triglyceride levels in plasma. Endothelium is thought to play an important role in the genesis of atherosclerosis. Several lines of evidence suggest that an intervention with endothelial function might influence the progression of coronary disease and the incidence of cardiovascular events. Raloxifene increases the nitric oxide/endothelin-1 ratio, and improves endothelium-dependent vasomotion in post-menopausal women to the same extent as estrogens. Furthermore, in two randomized trials on post-menopausal women raloxifene reduced homocysteine levels, another independent risk factor for the development of cardiovascular disease. Although estrogens remain the drugs of choice in the hormonal therapy of most postmenopausal women, raloxifene may represent and alternative in women who are at risk of coronary artery disease.
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PMID:Cardiovascular effects of raloxifene hydrochloride. 1131 1

Despite biologically plausible mechanisms whereby estrogen may confer cardioprotection as well as observational data suggesting cardiovascular benefit, data from the sole randomized controlled clinical outcomes trial reported on the benefit of hormone use. A trend was observed in the Heart and Estrogen/progestin Replacement Study (HERS) of an early increase in coronary events with possible late benefit, and in a recent angiographic trial, the Estrogen Replacement and Atherosclerosis trial (ERA) where no benefit was seen. Furthermore, selective estrogen receptor modulators may enable dissociation of estrogen risks and benefits; the selective estrogen replacement modulator raloxifene is under study in a large randomized clinical outcomes trial entitled the Raloxifene Use for the Heart trial (RUTH). (c) 2000 by CVRR, Inc.
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PMID:Hormonal and Nonhormonal Therapies for the Postmenopausal Woman: What is the Evidence for Cardioprotection? 1141 67

The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5+/-10.7 micromol/L and increased to 36.3+/-11.4 micromol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreased to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.
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PMID:Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. 1155 81

Epidemiological observations, clinical mechanistic studies, and basic laboratory research suggest that estrogen therapy is associated with beneficial cardiovascular effects in postmenopausal women. Estrogen has a multitude of biological effects that may account for this apparent benefit (which remains to be proved in randomized clinical trials), including favorable effects on the lipid profile, increased endothelial nitric oxide bioactivity, and enhanced fibrinolysis. However, long-term estrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the estrogen receptor, is a selective estrogen receptor modulator, producing estrogen-agonist effects in some tissues (liver, bone) and estrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis or its risk factors. This review updates the current knowledge of the biological effects of selective estrogen receptor modulators of potential cardiovascular importance in postmenopausal women.
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PMID:Selective estrogen receptor modulator effects on serum lipoproteins and vascular function in postmenopausal women and in hypercholesterolemic men. 1179 50

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.
Atherosclerosis 2003 Mar
PMID:Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women. 1261 76

Vascular endothelial senescence is involved in human atherosclerosis. Telomerase activity is known to be critical in cellular senescence and its level is modulated by regulation of telomerase catalytic subunit (telomerase reverse transcriptase (TERT)) at both the transcriptional and post-transcriptional levels. Since the cardioprotective effect of estrogen itself has not been ruled out, we examined that of raloxifene, which has been classified as a selective estrogen receptor modulator, on the proliferation and telomerase activity of human umbilical vein endothelial cells (HUVECs). Raloxifene, like estrogen, clearly induced the telomerase activity and human TERT (hTERT) expression via estrogen receptor (ER) alpha and ERbeta. Treatment with raloxifene for 5 days significantly induced cell growth, and either cotreatment with a telomerase inhibitor, 3'-azido-3'-deoxythymidine, or transfection with hTERT-specific small interfering RNA significantly attenuated the raloxifene-induced cell growth. Raloxifene also induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase inhibitor, LY294002, significantly attenuated the raloxifene-induced telomerase activity. In addition, raloxifene induced both the phosphorylation of hTERT and IkappaB. Moreover, cotreatment with an IkappaBalpha phosphorylation inhibitor, BAY-11-7082, or a specific NFkappaB nuclear translocation inhibitor, SN50, significantly attenuated the raloxifene-induced telomerase activity and the association of NFkappaB with hTERT. These results show that raloxifene induced the up-regulation of telomerase activity not only by the transcriptional regulation of hTERT but also by post-translational regulation of the phosphorylation of Akt and hTERT and the association of hTERT with NFkappaB in HUVECs. Thus, the up-regulation of telomerase activity in vascular endothelial cells might be one mechanism contributing to the potential atheroprotective effect of raloxifene.
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PMID:Raloxifene increases proliferation and up-regulates telomerase activity in human umbilical vein endothelial cells. 1679 46

Coronary heart disease (CHD) is the leading cause of death in women in most countries. Atherosclerosis is the main biological process determining CHD. Clinical data support the notion that CHD is sensitive to estrogens, but debate exists concerning the effects of the hormone on atherosclerosis and its complications. Selective estrogen receptor modulators (SERMs) are compounds capable of binding the estrogen receptor to induce a functional profile distinct from estrogens. The possibility that SERMs may shift the estrogenic balance on cardiovascular risk towards a more beneficial profile has generated interest in recent years. There is considerable information on the effects of SERMs on distinct areas that are crucial in atherogenesis. The complexity derived from the diversity of variables affecting their mechanism of action plus the differences between compounds make it difficult to delineate one uniform trend for SERMs. The present picture, nonetheless, is one where SERMs seem less powerful than estrogens in atherosclerosis protection, but more gentle with advanced forms of the disease. The recent publication of the Raloxifene Use for The Heart (RUTH) study has confirmed a neutral effect for raloxifene. Prothrombotic states may favor occlusive thrombi at sites occupied by atheromatous plaques. Platelet activation has received attention as an important determinant of arterial thrombogenesis. Although still sparse, available evidence globally suggests neutral or beneficial effects for SERMs.
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PMID:Selective estrogen receptor modulators and risk for coronary heart disease. 1745 58


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