Co-treatment of Pitavastatin and Dexamethasone Exacerbates the High-fat Diet-induced Atherosclerosis in apoE-deficient Mice.
Co-treatment of Pitavastatin and Dexamethasone Exacerbates the High-fat Diet-induced Atherosclerosis in apoE-deficient Mice.
复制标题
匹伐他汀和地塞米松联合治疗会加剧 apoE 缺陷小鼠的高脂饮食诱导的动脉粥样硬化
DOI：
10.1097/fjc.0000000000000264
复制
发表时间：
2015
影响因子：
3
通讯作者：
Duan Yajun
中科院分区：
文献类型：
--
作者：
Zhang Wenwen;Wang Xue;Hu Wenquan;Liu Lipei;Li Xiaoju;Han Jihong;Chen Yuanli;Duan Yajun
巨噬细胞脂肪细胞脂肪酸结合蛋白(FABP4)的激活导致动物模型动脉粥样硬化的发生。我们先前报道了他汀类药物抑制巨噬细胞FABP4的表达，而地塞米松则激活了FABP4的表达。然而，他汀类药物和地塞米松联合处理巨噬细胞可以协同诱导FABP4的表达，这意味着这种联合处理可能会加重高脂饮食(HFD)诱导的动脉粥样硬化。在本研究中，我们给载脂蛋白E缺陷(apoE−/−)小鼠喂饲高脂饲料或含地塞米松和/或匹伐他汀的高脂饲料，为期16周。与单纯HFD相比，Pitavastatin或地塞米松对面动脉和主动脉根部横断面的损伤几乎没有影响。然而，联合治疗加剧了HFD诱导的损伤。此外，联合治疗还降低了胶原含量，扰乱了病损盖骨的完整性。血清总胆固醇和低密度脂蛋白水平分别被匹伐他汀降低和地塞米松升高。然而，联合治疗对总胆固醇和低密度脂蛋白水平几乎没有影响，表明病变的恶化与总胆固醇或低密度脂蛋白水平无关。联合治疗可显著诱导大鼠主动脉病变部位FABP4的表达，提示FABP4的激活是导致病变的主要因素。总而言之，我们的研究表明，匹伐他汀和地塞米松联合治疗会加剧HFD诱导的动脉粥样硬化，并定义了在临床上对患者使用双重治疗的潜在风险。
Activation of macrophage adipocyte fatty acid-binding protein (FABP4) induces development of atherosclerosis in animal models. We previously reported that statin inhibited while dexamethasone activated macrophage FABP4 expression. However, co-treatment of macrophages with statin and dexamethasone induced FABP4 expression in a synergistic manner, which implies that this co-treatment may exacerbate high-fat diet (HFD)–induced atherosclerosis. In this study, we fed apoE-deficient (apoE−/−) mice with HFD or HFD containing dexamethasone or pitavastatin or both for 16 weeks. Compared with HFD alone, pitavastatin or dexamethasone had little effect on lesions in both en face aortas and aortic root cross sections. However, the co-treatment exacerbated HFD-induced lesions. In addition, the co-treatment decreased collagen content and disturbed the integrity of lesion caps. Both serum total cholesterol and LDL cholesterol levels were reduced by pitavastatin and increased by dexamethasone, respectively. However, the co-treatment had little effect on both total cholesterol and LDL cholesterol levels, indicating that the exacerbation of lesions is independent of total cholesterol or LDL cholesterol levels. FABP4 expression in aortic lesion area was significantly induced by the co-treatment, suggesting that activation of FABP4 expression is a main contributor to lesions. In conclusion, our study demonstrates that co-treatment of pitavastatin and dexamethasone exacerbates HFD-induced atherosclerosis and defines a potential risk to use the dual treatment for patients in clinics.