Raloxifene Inhibits Aortic Accumulation of Cholesterol in Ovariectomized, Cholesterol-Fed Rabbits

Bjarnason, Nina H.; Haarbo, Jens; Byrjalsen, I.; Kauffman, Raymond F.; Christiansen, Claus

doi:10.1161/01.cir.96.6.1964

Cited by 132 publications

(62 citation statements)

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“…13,29 Second, raloxifene inhibits the accumulation of cholesterol in ovariectomized cholesterolfed rabbits and inhibits macrophage lipid oxidation. 30,31 Third, raloxifene acutely dilates rabbit coronary arteries via NO-and calcium influx-dependent pathways and increases uterine and coronary blood flow in ovariectomized ewes. 14,32 However, it has not yet been elucidated whether long-term treatment with raloxifene leads to reduced blood pressure and improved vascular function in hypertensive males.…”

Section: Discussionmentioning

confidence: 99%

Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production

Waßmann

Laufs²,

Stamenkovic³

et al. 2002

Circulation

115

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Section: Discussionmentioning

confidence: 99%

Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production

Waßmann

Laufs²,

Stamenkovic³

et al. 2002

Circulation

115

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“…9 However, the chemical structure of raloxifene differs considerably from that of tamoxifen, and the effects of raloxifene on atherosclerosis are uncertain. 10,11 Droloxifene is a structural analogue of tamoxifen with tissue-specific estrogen agonistic/antagonistic effects. 12 In ovariectomized rodents, it prevents bone loss and lowers cholesterol without causing uterine hypertrophy.…”

mentioning

confidence: 99%

Cardiovascular Effects of Droloxifene, a New Selective Estrogen Receptor Modulator, in Healthy Postmenopausal Women

Herrington

Pusser

Riley

et al. 2000

ATVB

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Abstract-Selective estrogen receptor modulators, like tamoxifen and related compounds, have mixed estrogen agonistic/ antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of tamoxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unknown. We enrolled 24 healthy postmenopausal women in a randomized, double-blind, 2-period crossover trial comparing the effects of droloxifene (60 mg/d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fibrinolytic factors, and brachial flow-mediated vasodilator responses were measured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low density lipoprotein cholesterol (PϽ0.001) and 13.2% and 9.5% reductions, respectively, in lipoprotein(a) (PϽ0.05). In contrast, estrogen, but not droloxifene, increased high density lipoprotein (18.5%, PϽ0.001). Droloxifene also reduced fibrinogen by 17.8% versus a 7.3% reduction with estrogen (Pϭ0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen produced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilation (percent change from baseline, PϽ0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodilation but, unlike estrogen, has no effect on high density lipoprotein/triglyceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit. Key words: droloxifene Ⅲ hormone replacement therapy Ⅲ women Ⅲ estrogen Ⅲ cardiovascular disease E strogen replacement therapy favorably influences several domains of vascular health, including lipid metabolism, endothelial function, and aspects of hemostasis. 1 However, estrogen replacement also carries an increased risk of endometrial 2 and possibly breast 3 carcinoma. The recent Heart and Estrogen/Progestin Study trial 4 also raises questions about whether the favorable effects of estrogen on the cardiovascular system may be offset by other, previously unrecognized, adverse cardiovascular effects, resulting in no overall clinical cardiovascular benefit.Selective estrogen receptor modulators (SERMs), like tamoxifen, are compounds with mixed estrogen agonistic/antagonistic effects. Other benzothiophene derivatives, such as raloxifene, and other structurally unrelated compounds, such as soy phytoestrogens and tibolone, have variable degrees of estrogen agonistic and antagonistic effects. 5 Tamoxifen lowers cholesterol, 6 and in trials in women with breast cancer, it was associated with 15% to 63% fewer cardiovascular events. 7 However, tamoxifen also increases the risk for endometrial ...

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“…41 Multiple animal studies have demonstrated that raloxifene reduces the size of atherosclerotic lesions, 8,9 and pursuant to these other studies, perhaps the marginal changes in lipid parameters (LDL reduction, HDL elevation) may have contributed to the differences in lipid deposition seen in this experiment. Alternatively, the atheroma regression may have occurred completely independent of systemic cholesterol levels and may have been mediated via the anti-inflammatory effects seen in vascular wall.…”

Section: Discussionmentioning

confidence: 74%

“…6,7 The mechanism of raloxifene's potential effects upon atherosclerotic lesions is not completely understood. Pre-clinical animal models have shown that raloxifene, similar to HT, inhibits atherosclerosis, 8,9 but its effect upon vascular calcification is unknown. HT results in less calcified plaques 10 without clear reduction in cardiovascular events, 11 yet statins, a therapy with clear reductions in cardiovascular events, increase calcification.…”

mentioning

confidence: 99%

Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model

et al. 2008

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Objective-Osteoporosis trials suggest raloxifene decreased cardiovascular events in women with preexisting atherosclerosis. We assessed the hypothesis that selective estrogen receptor modulation induces plaque stability in "menopausal" animals.Methods and Results-Atherosclerosis was induced in 42 ovariectomized New Zealand White rabbits by cholesterol feeding and mechanical injury. Animals were imaged by magnetic resonance (MRI) for baseline atherosclerosis, and randomized to control (OVX, n=12), raloxifene 35-60 mg/kg/day by diet admixture (RLX, n=24), or immediate sacrifice (n=6) for immunohistopathologic correlation of MRI. Six months later, rabbits underwent repeat MRI then sacrifice for micro-computed tomography (μCT) and molecular analysis. Unlike OVX, RLX reduced atheroma volume. Analysis for lesion inflammation revealed reductions in COX-2, MMP-1, MCP-1 expression and macrophage infiltration in RLX vs. OVX with concomitant upregulation of estrogen receptor α. μCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63 ± 7° vs. 33 ± 6° in OVX), the predicted result of a 53% increase in BMP-2. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conclusions-Raloxifene NIH Public Access Author ManuscriptAtherosclerosis. Author manuscript; available in PMC 2012 July 02. Recent efforts at female-specific pharmacologic therapies have focused on selective estrogen receptor modulators (SERMs). Most pertinently, post-hoc analysis from an osteoporosis treatment trial in post-menopausal women (the Multiple Outcomes of Raloxifene Evaluation, MORE) found that those women at high-risk for coronary artery disease (i.e., a secondary prevention population most likely to have established atherosclerotic lesions) treated with the SERM raloxifene had 40 percent fewer cardiovascular events than those on placebo. 5 The Raloxifene Use for the Heart (RUTH) study, which was a double-blind, placebo-controlled, randomized clinical trial of this SERM's use in a patient population without pre-specified osteoporosis did not confirm this benefit. 6, 7The mechanism of raloxifene's potential effects upon atherosclerotic lesions is not completely understood. Pre-clinical animal models have shown that raloxifene, similar to HT, inhibits atherosclerosis, 8, 9 but its effect upon vascular calcification is unknown. HT results in less calcified plaques 10 without clear reduction in cardiovascular events, 11 yet statins, a therapy with clear reductions in cardiovascular events, increase calcifi...

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Raloxifene Inhibits Aortic Accumulation of Cholesterol in Ovariectomized, Cholesterol-Fed Rabbits

Abstract: Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

Cited by 132 publications

References 28 publications

Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production

Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production

Cardiovascular Effects of Droloxifene, a New Selective Estrogen Receptor Modulator, in Healthy Postmenopausal Women

Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model

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