Geronimo F R B, Barter P J, Rye K A, Heather A K, Shearston K D, Rodgers K J
The Heart Research Institute, Sydney, Australia.
School of Medical Sciences, University of New South Wales, Australia.
Atherosclerosis. 2016 Aug;251:39-46. doi: 10.1016/j.atherosclerosis.2016.04.019. Epub 2016 May 7.
Apolipoprotein (apo) A-IV, the third most abundant HDL-associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo.
Plaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD.
In the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p < 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity.
ApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model.
载脂蛋白（apo）A-IV是高密度脂蛋白（HDL）中含量第三丰富的蛋白质，具有抗动脉粥样硬化作用，与apoA-I具有相似特性。我们之前报道过，HDL中含量最丰富的载脂蛋白apoA-I可抑制小鼠模型中的斑块破裂。我们旨在研究apoA-IV对体内斑块稳定性标志物的影响。
对16周龄载脂蛋白E基因敲除的C57BL/6小鼠头臂动脉内的斑块进行研究，在高脂饮食（HFD）10周后观察其成分变化。在HFD的第9周和第10周，动物每周接受两次人无脂apoA-IV（1mg/kg，n = 31）或磷酸盐缓冲液（PBS，n = 32）注射。
在接受apoA-IV治疗的小鼠中，出血性斑块破裂明显减少（9/31 vs. 18/32，p < 0.05），纤维帽更厚，脂质核心更小，巨噬细胞与平滑肌细胞比例更低，MMP-9蛋白更少，胶原蛋白更多，增殖细胞更少。在给予apoA-IV的小鼠斑块中，单核细胞趋化蛋白-1（MCP-1）、血管细胞黏附分子-1（VCAM-1）和诱导型一氧化氮合酶（iNOS）也显著降低。根据裂解的聚（ADP-核糖）聚合酶（PARP）阳性和末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）阳性斑块细胞核的百分比，apoA-IV可减少细胞凋亡。在人单核细胞来源的巨噬细胞（HMDMs）中，apoA-IV使MMP-9 mRNA表达降低一半，使金属蛋白酶组织抑制因子1（TIMP1）mRNA水平增加一倍，并降低MMP-9活性。
在该小鼠模型中，apoA-IV治疗与更稳定的斑块表型以及急性破裂发生率降低有关。
