The Cholesterol Metabolite 27-Hydroxycholesterol Promotes Atherosclerosis via Proinflammatory Processes Mediated by Estrogen Receptor Alpha

Umetani, Michihisa; Ghosh, Pritam; Ishikawa, Takaaki; Umetani, Junko; Ahmed, Mohamed H.; Mineo, Chieko; Shaul, Philip W.

doi:10.1016/j.cmet.2014.05.013

Cited by 158 publications

(132 citation statements)

References 62 publications

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“…Several oxysterols have been identified in humans and atherosclerotic animal models. 9,12 Although there are several nonhuman studies suggesting a detrimental role of 7-KC 35 and 27-hydroxycholesterol 36,37 on endothelial function, this study shows the association of oxysterols with endothelial dysfunction in humans. Treatment with ezetimibe was associated with the inhibition of sterol absorption and decreases of both enzymatic (intrinsic) and nonenzymatic oxysterols through the inhibition of sterol absorption.…”

Section: Cholesterol Absorption and Lipid Oxidationcontrasting

confidence: 46%

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Takase

Matoba

Nakashiro

et al. 2017

ATVB

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Objectives-We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. Approach and Results-We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6-to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. Conclusions-The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction afterCoronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels. From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan (S.T., T.M., S.N., T.H., K. Egashira, K. Sunagawa); Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan (S.T., T.M., S.N., Y.M., S.I., K.O., T.H., S.K., M.T., K. Sunagawa); Japanese Red Cross Fukuoka Hospital, Japan (N.S.); St. Mary's Hospital, Kurume, Japan (K. Eshima); Japan Community Health Care Organization, Kyushu Hospital, Fukuoka, Japan (K.M.); Harasanshin Hospital, Fukuoka, Japan (M.Y.); Hamanomachi Hospital, Fukuoka, Japan (M.U.); Saga-ken Medical Centre Koseikan, Saga, Japan (K. Sadamatsu); National Hospital Organization Kyushu Medical Centre, Fukuoka, Japan (S.S.); Saiseikai Futsukaichi Hospital, Chikushino, Japan (T.K.); Saiseikai Fukuoka General Hospital, Japan; Fukuoka City Hospital, Japan (K.H.); Graduate School of ...

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Section: Cholesterol Absorption and Lipid Oxidationcontrasting

confidence: 46%

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Takase

Matoba

Nakashiro

et al. 2017

ATVB

View full text Add to dashboard Cite

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“…It has been reported that long-term feeding of cholesterol to rodents may affect cerebral microcirculation [21] and induce cerebral inflammatory markers [12,22]. Also, 27OH has recently been shown to promote atherosclerosis and inflammatory changes in mice [23].…”

Section: General Conclusionmentioning

confidence: 99%

27-Hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice

Heverin

Maioli

Pham

et al. 2015

Behavioural Brain Research

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“…27HC was discovered to bind to estrogen receptors (ER) and act as a selective ER modulator (SERM) eliciting system-specific adverse effects. In the vascular wall, 27HC functioned as an ER antagonist and inhibited estrogenrelated cardioprotection (Umetani et al, 2007(Umetani et al, , 2014; Umetani and Shaul, 2011). Conversely, in breast tumors, 27HC served as a partial ER agonist and stimulated tumor growth in several mouse models of breast cancer (Nelson et al, 2013;Wu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

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Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6-and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

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The Cholesterol Metabolite 27-Hydroxycholesterol Promotes Atherosclerosis via Proinflammatory Processes Mediated by Estrogen Receptor Alpha

Cited by 158 publications

References 62 publications

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

27-Hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

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