Paik Jisun, Kwok Fiona, Seamons Audrey, Brabb Thea, Kim Jinkyu, Sullivan Brittany, Hsu Charlie, O'Brien Kevin D, Maggio-Price Lillian
The Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
The Department of Medicine, University of Washington, Seattle, Washington, USA.
Comp Med. 2015 Apr;65(2):114-22.
We previously reported that murine norovirus (MNV), a virus prevalent in United States research institutions, increased atherosclerotic lesion size in Ldlr(-/-) mice when the mice were infected 8 wk after feeding an atherogenic diet. To determine whether the timing of MNV infection relative to atherosclerosis development altered the disease phenotype and to examine potential mechanisms by which MNV influences the disease process, we fed Ldlr(-/-) mice an atherogenic diet for 16 wk. Three days after initiating the atherogenic diet, half of the mice received MNV4 and the other half vehicle only (clarified cell-culture lysate; controls). Both groups of mice developed large aortic sinus lesions (control compared with MNV4: 133 ± 8 × 10³ μm² compared with 140 ± 7 × 10³ μm²) that were not significantly different in size. Because the timing of MNV infection relative to atherosclerosis development and hypercholesterolemia differed between our previous and the current studies, we examined whether hypercholesterolemia altered MNV4-induced changes in bone-marrow-derived macrophages. MNV4 infection increased the potential of macrophages to take up and store cholesterol by increasing CD36 expression while suppressing the ABCA1 transporter. Thus, the effects of MNV4 infection on atherosclerotic lesion size appear to be dependent on the timing of the infection: MNV4 infection promotes only established lesions. This effect may be due to MNV4's ability to increase cholesterol uptake and decrease efflux by regulating CD36 and ABCA1 protein expression.
我们之前报道过，鼠诺如病毒（MNV）在美国研究机构中普遍存在，当喂食致动脉粥样硬化饮食8周后感染Ldlr（-/-）小鼠时，会增加其动脉粥样硬化病变大小。为了确定MNV感染时间相对于动脉粥样硬化发展是否会改变疾病表型，并研究MNV影响疾病进程的潜在机制，我们给Ldlr（-/-）小鼠喂食致动脉粥样硬化饮食16周。在开始致动脉粥样硬化饮食三天后，一半小鼠接受MNV4，另一半仅接受载体（澄清的细胞培养裂解物；对照组）。两组小鼠均出现了大的主动脉窦病变（对照组与MNV4组相比：133±8×10³μm²与140±7×10³μm²），病变大小无显著差异。由于我们之前的研究与当前研究中MNV感染时间相对于动脉粥样硬化发展和高胆固醇血症的情况不同，我们研究了高胆固醇血症是否会改变MNV4诱导的骨髓来源巨噬细胞的变化。MNV4感染通过增加CD36表达同时抑制ABCA1转运蛋白，增强了巨噬细胞摄取和储存胆固醇的能力。因此，MNV4感染对动脉粥样硬化病变大小的影响似乎取决于感染时间：MNV4感染仅促进已形成的病变。这种作用可能是由于MNV4能够通过调节CD36和ABCA1蛋白表达来增加胆固醇摄取并减少流出。
