Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Abstract

Macrophage CD36 binds and internalizes oxidized low density lipoprotein (oxLDL) to facilitate foam cell formation. CD36 expression is activated by peroxisome proliferator-activated receptor ␥ (PPAR␥). Tamoxifen, an anti-breast cancer medicine, has demonstrated pleiotropic functions including cardioprotection with unfully elucidated mechanisms. In this study, we determined that treatment of ApoE-deficient mice with tamoxifen reduced atherosclerosis, which was associated with decreased CD36 and PPAR␥ expression in lesion areas. At the cellular level, we observed that tamoxifen inhibited CD36 protein expression in human THP-1 monocytes, THP-1/PMA macrophages, and human blood monocyte-derived macrophages. Associated with decreased CD36 protein expression, tamoxifen reduced cellular oxLDL accumulation in a CD36-dependent manner. At the transcriptional level, tamoxifen decreased CD36 mRNA expression, promoter activity, and the binding of the PPAR␥ response element in CD36 promoter to PPAR␥ protein. Tamoxifen blocked ligand-induced PPAR␥ nuclear translocation and CD36 expression, but it increased PPAR␥ phosphorylation, which was due to that tamoxifen-activated ERK1/2. Furthermore, deficiency of PPAR␥ expression in macrophages abolished the inhibitory effect of tamoxifen on CD36 expression or cellular oxLDL accumulation both in vitro and in vivo. Taken together, our study demonstrates that tamoxifen inhibits CD36 expression and cellular oxLDL accumulation by inactivating the PPAR␥ signaling pathway, and the inhibition of macrophage CD36 expression can be attributed to the anti-atherogenic properties of tamoxifen.Tamoxifen (Nolvadex) and its immediate metabolite, 4-hydroxytamoxifen, belong to the class of drugs called selective estrogen receptor modulators (1). Dependent on target tissue/ molecules, tamoxifen can function either as an estrogen receptor (ER) 5 antagonist, such as in the mammary tissue, or as an ER agonist, such as in the endometrium (2). In the breast tissue, inactivation of ER by tamoxifen inhibits the growth of breast cancer cells. Therefore, tamoxifen is the most commonly used anti-hormonal drug for adjuvant treatment of patients with ERpositive breast cancer (2). In addition, tamoxifen has been determined to have a preventive function on breast cancer in the population of women with a high risk of developing this disease (3).Besides the effect on breast cancer, several lines of evidence have demonstrated the cardioprotective effects of tamoxifen. In animal models, tamoxifen reduces atherosclerosis in wild type mice and pro-atherogenic animal models, such as ApoE deficient (ApoE Ϫ/Ϫ ) mice and surgically postmenopausal monkeys (4 -6). In humans, tamoxifen lowers the incidence of fatal myocardial infarction, reduces the intima-media thickness of the common carotid artery in the postmenopausal women, and promotes the endothelium-dependent flow-mediated dilation in male patients with advanced atherosclerosis (7-9).Atherosclerosis is one of the major causes of coronary heart disease and a chronic patholo...

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

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High Glucose Promotes CD36 Expression by Upregulating Peroxisome Proliferator-Activated Receptor γ Levels to Exacerbate Lipid Deposition in Renal Tubular Cells

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Cd36 knockout mice are protected against lithogenic diet-induced gallstones

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