Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: novel detection by dual-target fluorescence molecular imaging.
Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: novel detection by dual-target fluorescence molecular imaging.
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吡格列酮在鼠颈动脉粥样硬化中抑制体内炎症：通过双靶荧光分子成像进行新的检测。
DOI：
10.1161/atvbaha.110.206342
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Jaffer FA
中科院分区：
文献类型：
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作者：
Chang K;Francis SA;Aikawa E;Figueiredo JL;Kohler RH;McCarthy JR;Weissleder R;Plutzky J;Jaffer FA
过氧化物酶体增殖物激活受体-γ激动剂如吡格列酮的抗炎作用可能是其抑制动脉粥样硬化的基础，但尚不完全清楚。这项分子影像研究探讨了吡格列酮对体内斑块基质金属蛋白酶(MMPs)和巨噬细胞反应的影响。在体外，吡格列酮可抑制小鼠腹膜巨噬细胞基质金属蛋白酶-9mRNA的表达(P<；0.05)。为了评估吡格列酮对斑块炎症的影响，接受高胆固醇饮食的非糖尿病载脂蛋白−/−小鼠接受了基质金属蛋白酶激活的荧光显像剂和光谱清晰的巨噬细胞亲和荧光纳米颗粒。24小时后，小鼠接受存活的双靶点活体荧光显微镜(IVFM)观察颈动脉斑块。然后，这些小鼠被随机分为HCD或HCD+PIO 0.012%组，持续8周，随后对相同的颈动脉斑块进行第二次IVFM研究。在HCD组，体内基质金属蛋白酶和巨噬细胞靶-背景比(TBR)增加相似(P<；0.01与基线相比)。相反，吡格列酮降低了基质金属蛋白酶和巨噬细胞的总胆红素含量(P<；0.01 vs HCD)。基质金属蛋白酶和巨噬细胞信号的变化具有很强的相关性(r值≥为0.75)。显微镜显示，在吡格列酮治疗的小鼠，基质金属蛋白酶和巨噬细胞减少，以及PIO调节的斑块胶原增加。系列光学分子成像显示，随着高胆固醇血症，体内的斑块和巨噬细胞活性增强，而吡格列酮治疗则降低。
Anti-inflammatory actions of peroxisome proliferator-activated receptor (PPAR)-γ agonists such as pioglitazone (PIO) may underlie their reported but incompletely understood repression of atherosclerosis. This molecular imaging study investigated the effects of pioglitazone on plaque matrix metalloproteinase (MMP) and macrophage responses in vivo. In vitro, pioglitazone suppressed MMP-9 mRNA expression in murine peritoneal macrophages (P<0.05). To assess pioglitazone's effects on plaque inflammation, nondiabetic apoE−/− mice on high-cholesterol diet (HCD) received a MMP-activatable fluorescence imaging agent and a spectrally-distinct macrophage-avid fluorescent nanoparticle. After 24 hours, mice underwent survival dual-target intravital fluorescence microscopy (IVFM) of carotid arterial plaques. These mice were then randomized to HCD or HCD+PIO 0.012% for 8 weeks, followed by a second IVFM study of the same carotid plaque. In the HCD group, in vivo MMP and macrophage target-to-background ratios (TBRs) increased similarly (P<0.01 vs. baseline). In contrast, pioglitazone reduced MMP and macrophage TBRs (P<0.01 vs. HCD). Changes in MMP and macrophage signals correlated strongly (r-values≥0.75). Microscopy demonstrated MMP and macrophage reductions in pioglitazone-treated mice, as well as a PIO-modulated increase in plaque collagen. Serial optical molecular imaging demonstrates that plaque MMP and macrophage activity in vivo intensify with hypercholesterolemia and are reduced by pioglitazone therapy.