Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA.
Toxicology. 2012 Sep 28;299(2-3):133-8. doi: 10.1016/j.tox.2012.05.015. Epub 2012 Jun 1.
Plasma lipoproteins play important roles in the development and progression of atherosclerosis. Two widely used mouse models of experimental atherosclerosis, apolipoprotein E-deficient (ApoE -/-) and LDL receptor-deficient (LDLr -/-) mice, have major differences in lipoprotein characteristics. These include differences in lipoprotein cholesterol distribution, lipoprotein compositions, apoliporoteins distribution, and susceptibility to oxidation. In the present study, we compared pulmonary and cardiovascular responses of ApoE -/- and LDLr -/- mice to sidestream cigarette smoke (SSCS) exposure to determine if strain differences influence their predisposition to SSCS-mediated promotion of atherosclerosis. Female ApoE -/- and LDLr -/- mice were maintained on a saturated fat enriched diet and exposed to SSCS in whole body exposure chambers for 15 weeks (4h/day, 5 days/week). At terminations, the levels of pulmonary injury markers in bronchoalveolar lavage (BAL) fluids from 6 mice per group and atherosclerotic lesion formation in 14 mice per group were analyzed. Total BAL cells and polymorphonuclear leukocytes were not significantly altered by SSCS exposure in both mouse models. Total protein, LDH, and cytokine concentrations in cell-free BAL fluids were also not significantly affected by chronic SSCS exposure in either mouse strain. SSCS significantly reduced surfactant protein D levels in both strains to a similar extent. However, SSCS exposure increased significantly the percent atherosclerotic lesion areas covering aortic intimal surfaces of ApoE -/- (control-25.3±1.52 vs. SSCS-31.9±2.02, p=0.012) as well as in LDLr -/- (control-30.97±1.1 vs. SSCS-36.61±1.7, p=0.028) mice. In contrast, the serum cholesterol concentrations of SSCS-exposed ApoE -/- mice were similar to that of controls (control-1255±85 vs. SSCS-1190±61mg/dl, p=0.552) but increased significantly in SSCS-exposed LDLr -/- mice (control-998±114 vs. SSCS-1577±142mg/dl, p=0.008). These results showing different effects of identical SSCS exposure on plasma cholesterol concentrations in these two mouse models suggest a role of multiple mechanisms in SSCS-induced atherosclerosis.
血浆脂蛋白在动脉粥样硬化的发生和发展中起着重要作用。两种广泛应用的实验性动脉粥样硬化小鼠模型，载脂蛋白 E 缺陷（ApoE-/-）和 LDL 受体缺陷（LDLr-/-）小鼠，在脂蛋白特征方面存在主要差异。这些差异包括脂蛋白胆固醇分布、脂蛋白组成、载脂蛋白分布以及易氧化性的差异。在本研究中，我们比较了 ApoE-/-和 LDLr-/-小鼠对侧流香烟烟雾（SSCS）暴露的肺和心血管反应，以确定品系差异是否影响其对 SSCS 介导的动脉粥样硬化促进的易感性。雌性 ApoE-/-和 LDLr-/-小鼠维持在富含饱和脂肪的饮食中，并在全身暴露室中接受 SSCS 暴露 15 周（每天 4 小时，每周 5 天）。在每组 6 只小鼠的终止时，分析了每组 14 只小鼠的支气管肺泡灌洗液（BAL）中肺损伤标志物的水平和动脉粥样硬化病变的形成。在两种小鼠模型中，SSCS 暴露并没有显著改变 BAL 细胞中的总细胞和嗜中性粒细胞。细胞游离 BAL 液中的总蛋白、LDH 和细胞因子浓度也没有因慢性 SSCS 暴露而受到显著影响。SSCS 显著降低了两种品系的表面活性蛋白 D 水平，降低程度相似。然而，SSCS 暴露显著增加了 ApoE-/-（对照组-25.3±1.52 对 SSCS-31.9±2.02，p=0.012）以及 LDLr-/-（对照组-30.97±1.1 对 SSCS-36.61±1.7，p=0.028）小鼠主动脉内膜表面的动脉粥样硬化病变面积百分比。相比之下，SSCS 暴露的 ApoE-/-小鼠的血清胆固醇浓度与对照组相似（对照组 1255±85 对 SSCS 1190±61mg/dl，p=0.552），但在 SSCS 暴露的 LDLr-/-小鼠中显著增加（对照组 998±114 对 SSCS 1577±142mg/dl，p=0.008）。这些结果表明，两种小鼠模型中相同的 SSCS 暴露对血浆胆固醇浓度有不同的影响，表明 SSCS 诱导的动脉粥样硬化存在多种机制的作用。
