Alcohol Consumption in Combination with an Atherogenic Diet Increased Indices of Atherosclerosis in Apolipoprotein E/Low-Density Lipoprotein Receptor Double-Knockout Mice
Alcohol Consumption in Combination with an Atherogenic Diet Increased Indices of Atherosclerosis in Apolipoprotein E/Low-Density Lipoprotein Receptor Double-Knockout Mice
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DOI：
10.1111/acer.13925
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发表时间：
2019-02-01
影响因子：
3.2
通讯作者：
Fujimiya，Tatsuya
中科院分区：
文献类型：
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作者：
Furuta，Yuzo;Liu，Jinyao;Fujimiya，Tatsuya
背景：酒精滥用和坚持致动脉粥样硬化饮食（AD;低碳水化合物-高蛋白饮食）与心血管疾病呈正相关。此外，临床上已经证明，在饮酒的日子里，饮食摄入量会增加。在此，在载脂蛋白E/低密度脂蛋白受体双敲除（KO）小鼠中研究了乙醇（EtOH）和AD对动脉粥样硬化（心血管疾病的主要潜在原因）的累加效应。的机制，特别是主动脉氧化应激损伤，highlighted.MethodsTwelve-week-old的雄性KO小鼠AD与或不与乙醇治疗繁殖4个月。年龄匹配的雄性C57 BL/6 J小鼠，以标准食物饮食，不含EtOH处理作为对照。使用超声生物显微镜，组织病理学和荧光免疫组织化学检查，蛋白质印迹，和polymerase chain reaction.ResultsKO小鼠AD与乙醇治疗显示主动脉最大内膜中层厚度，低回声斑块形成，平均油红O含量增加。这些结果与主动脉8-羟基-2 ′-脱氧鸟苷（8-OHdG）免疫阳性面积与金属硫蛋白（MT）免疫阳性面积的比值增加以及AD诱导的上调的血管Mt 1、Mt 2和上游刺激因子1 mRNA表达的抑制有关。此外，8-OHdG在CD 31-和α平滑肌肌动蛋白免疫阳性细胞的细胞核中表达，结论酒精滥用和坚持AD可能促进主动脉氧化应激和抗氧化应激平衡向氧化应激优势和抗氧化应激降低的方向转变，并可能导致主动脉一氧化氮合酶3和血小板源性生长因子的mRNA表达上调。结论：高脂血症小鼠动脉粥样硬化的发生与应激有关，其机制可能是细胞生物学水平上MT的减少和基因水平上MT的下调，进而在高脂血症小鼠血管内皮功能障碍相关基因和血管平滑肌细胞增殖相关基因的表达上调以及动脉粥样硬化的进展中发挥作用。
BackgroundAlcohol abuse and adherence to atherogenic diet (AD; a low‐carbohydrate–high‐protein diet) have been positively associated with cardiovascular disease. In addition, it has been demonstrated clinically that dietary intake is increased on days when alcohol is consumed. Here, the additive effects of ethanol (EtOH) and AD on atherosclerosis, a major underlying cause of cardiovascular disease, were investigated in apolipoprotein E/low‐density lipoprotein receptor double‐knockout (KO) mice. The mechanisms, especially aortic oxidative stress damage, were highlighted.MethodsTwelve‐week‐old male KO mice on AD with or without EtOH treatment were bred for 4 months. Age‐matched male C57BL/6J mice on a standard chow diet without EtOH treatment served as controls. Analyses were conducted using ultrasound biomicroscopy, histopathological and fluorescence immunohistochemical examinations, Western blots, and polymerase chain reaction.ResultsKO mice on AD with EtOH treatment showed increases in aortic maximum intima media thickness, hypoechoic plaque formation, and mean Oil‐Red‐O content. These results were associated with enhanced ratio of aortic 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG)‐immunopositive area to the metallothionein (MT) immunopositive area and suppression of AD‐induced up‐regulated aorticMt1,Mt2, and upstream stimulatory factor 1 mRNA expressions. Moreover, 8‐OHdG was expressed in the nuclei of CD31‐ and alpha smooth muscle actin‐immunopositive cells, and the up‐regulated mRNA expressions of aortic nitric oxide synthase 3 and platelet‐derived growth factors were only observed in the KO mice on AD with EtOH treatment.ConclusionsAlcohol abuse and adherence to AD may promote the shift of aortic oxidative stress and antioxidative stress balance toward oxidative stress predominance and reduced antioxidative stress, which may be partly due to the decrease in MT at the cell biological level and down‐regulation ofMtat the gene level, which in turn could play a role in the up‐regulation of endothelial dysfunction‐related and vascular smooth muscle cell proliferation‐related gene expression and the progression of atherosclerosis in mice with hyperlipidemia.