Does 2-Methoxyestradiol Represent the New and Improved Hormone Replacement Therapy for Atherosclerosis?

Dantas, Ana Paula; Sandberg, Kathryn

doi:10.1161/01.res.0000236802.00855.cd

Cited by 13 publications

(12 citation statements)

References 36 publications

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“…We do not know the exact reason of these discrepant findings. Since the different method and/or timing of administration of estrogen results in the different effects, these discrepancy might be derived from different study condition [25]. However, low-dose 2-ME treatment did not affect body weight, serum lipid parameters, or blood pressure, and high-dose 2-ME modestly reduced body-weight gain only.…”

Section: Discussionmentioning

confidence: 98%

2-Methoxyestradiol Reduces Monocyte Adhesion to Aortic Endothelial Cells in Ovariectomized Rats

et al. 2007

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Abstract. 2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with no affinity for estrogen receptors. It inhibits cell proliferation, thus is a potentially useful drug to block the progression of atherosclerosis. As a first step to examining the anti-atherosclerotic effects of 2-ME, we investigated monocyte adhesion to aortic endothelial cells, which is considered a prerequisite to atherosclerosis in vivo. Eight-week-old Sprague-Dawley rats were ovariectomized then treated by slow-release pellets with placebo, 17-β-estradiol (5 µg/day), low-dose 2-ME (10 µg/day), or high-dose 2-ME (100 µg/day). After 6 weeks, enface analysis showed an increased number of monocytes adhering to endothelial cells of the thoracic aorta in ovariectomized rats compared with sham-operated controls. This increase was predominantly inhibited by treatment with 17β-estradiol, and low-dose or high-dose 2-ME. The observed effects were unrelated to changes in serum lipids, blood glucose, or blood pressure. Our data suggested that 2-ME mediates the anti-atherosclerotic actions of estradiol at least in part by preventing monocyte adhesion to the aortic endothelium. CARDIOVASCULAR disease is a major cause of morbidity and mortality in modern societies. In women, menopause increases the risk of cardiovascular disease [1, 2], probably due to reduced estrogen levels [3][4][5]. Hormone replacement therapy is reported to delay the onset of cardiovascular disease in postmenopausal women [6,7]. In contrast, two major randomized prospective clinical trials, the Heart and Estrogen/progestin Replacement Study (HERS) [8] and the Women's Health Initiative Study (WHI) [9], found that hormone replacement therapy increased the risk of cardiovascular disease following menopause. This discrepancy might reflect differences in study conditions. The efficacy of hormone replacement therapy to protect against atherosclerosis seems dependent on the atherosclerotic state, type of estrogen used, and the coadministration of progestin [10]. Research into the anti-atherosclerotic effect of estrogen is thus needed to establish a better method to deliver estrogen to postmenopausal women. The endogenous estrogen 17β-estradiol (E 2 ) binds to both estrogen receptor (ER) α and β. Activation of ERα and β has been linked with some, but not all, antiatherosclerotic effects of estrogen [11][12][13]. 2-methoxyestradiol (2ME), a metabolite of estradiol with no affinity for estrogen receptors, is a potent inhibitor of cell proliferation, tumor growth, and angiogenesis, and might, at least in part, mediate anti-atherosclerotic effects of estrogen [14][15][16][17]. Abbreviations: E 2 : 17β-estradiol, ER: estrogen receptor, FFA: free fatty acid, 2-ME: 2-methoxyestradiol, NEMOes: New enface method for optimal observation of endothelial surface, TC: total cholesterol, TG: triglyceride.

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Section: Discussionmentioning

confidence: 98%

2-Methoxyestradiol Reduces Monocyte Adhesion to Aortic Endothelial Cells in Ovariectomized Rats

et al. 2007

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“…An additional clinically relevant basis for choosing 2ME2 was the recent proposal that 2ME2 might represent "new and improved hormone replacement therapy for atherosclerosis" that "could be used clinically to prevent or treat cardiovascular disease." 34 However, 2ME2 does not bind to estrogen receptors but instead inhibits HIF-1␣ expression by destabilizing microtubules. 33 Most importantly, our data indicate that 2ME2 has the potential to exacerbate rather than to prevent ischemic cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Effects of Aging and Hypoxia-Inducible Factor-1 Activity on Angiogenic Cell Mobilization and Recovery of Perfusion After Limb Ischemia

Bosch–Marcé

Okuyama

Wesley

et al. 2007

Circulation Research

268

303

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Abstract-Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function impair the expression of multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. We show that HIF-1 directly activates transcription of the gene encoding stem cell factor and that mice lacking the cognate receptor C-KIT have impaired recovery from ischemia. Administration of AdCA5, an adenovirus encoding a constitutively active form of HIF-1␣, improved the recovery of perfusion in older mice to levels similar to those in young mice. Injection of AdCA5 into nonischemic limb was sufficient to increase the number of circulating angiogenic cells. These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1␣ gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.

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“…and oxidation of low-density lipoproteins in vitro (8,14), and increases cyclooxygenase-2 expression and prostacyclin generation (11,23), all participants in atherogenesis (10,24,25).…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanism of action of 2-methoxyestradiol requires additional clarification, it appears to be independent of the classical estrogen receptors (9,10).…”

mentioning

confidence: 99%

The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

et al. 2007

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Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slowrelease pellets with placebo, 17␤-estradiol (6 g/d), or 2-methoxyestradiol [6.66 g/d (low-dose) or 66.6 g/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high-and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P ‫؍‬ 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo.

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Does 2-Methoxyestradiol Represent the New and Improved Hormone Replacement Therapy for Atherosclerosis?

Cited by 13 publications

References 36 publications

2-Methoxyestradiol Reduces Monocyte Adhesion to Aortic Endothelial Cells in Ovariectomized Rats

2-Methoxyestradiol Reduces Monocyte Adhesion to Aortic Endothelial Cells in Ovariectomized Rats

Effects of Aging and Hypoxia-Inducible Factor-1 Activity on Angiogenic Cell Mobilization and Recovery of Perfusion After Limb Ischemia

The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

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