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Background Platelet-endothelial interactions are thought to contribute to early atherogenesis. These interactions are potentiated by oxidative stress. We used in vivo molecular imaging to test the hypothesis that platelet-endothelial interactions occur at early stages of plaque development in obese, insulin-resistant nonhuman primates, and are suppressed by NADPH-oxidase-2 inhibition. Methods and Results Six adult rhesus macaques fed a Western-style diet for a median of 4.0 years were studied at baseline and after 8 weeks of therapy with the NADPH-oxidase-2-inhibitor apocynin (50 mg/kg per day). Six lean control animals were also studied. Measurements included intravenous glucose tolerance test, body composition by dual-energy X-ray absorptiometry, carotid intimal medial thickness, carotid artery contrast ultrasound molecular imaging for platelet GPIbα (glycoprotein- Ibα) and vascular cell adhesion molecule-1, and blood oxidative markers on mass spectrometry. Compared with lean controls, animals on a Western-style diet were obese (median body mass: 16.0 versus 8.7 kg, =0.003; median truncal fat: 49% versus 20%, =0.002), were insulin resistant (4-fold higher insulin-glucose area under the curve on intravenous glucose tolerance test, =0.002), had 40% larger carotid intimal medial thickness (=0.004), and exhibited oxidative signatures on proteomics. In obese but not lean animals, signal enhancement on molecular imaging was significantly elevated for GPIbα and vascular cell adhesion molecule-1. The signal correlated modestly with intimal medial thickness but not with the degree of insulin resistance. Apocynin significantly (<0.01) reduced median signal for GPIbα by >80% and vascular cell adhesion molecule-1 signal by 75%, but did not affect intimal medial thickness, body mass, or intravenous glucose tolerance test results. Conclusion In nonhuman primates, diet-induced obesity and insulin resistance leads to platelet-endothelial adhesion at early atherosclerotic lesion sites, which is associated with the expression of pro-inflammatory adhesion molecules. These responses appear to be mediated, in part, through oxidative pathways.

背景

血小板-内皮细胞相互作用被认为有助于早期动脉粥样硬化的形成。这些相互作用会被氧化应激增强。我们使用体内分子成像技术来测试这样一个假设，即在肥胖、胰岛素抵抗的非人类灵长类动物的斑块形成早期阶段，就会发生血小板-内皮细胞相互作用，而 NADPH 氧化酶-2 抑制可抑制这种相互作用。

方法和结果

对 6 只接受西方饮食喂养的成年恒河猴进行了研究，中位时间为 4.0 年。这些猴子在基线时和接受 NADPH 氧化酶-2 抑制剂阿朴肉桂酸（50mg/kg/天）治疗 8 周后进行了研究。同时还对 6 只瘦猴进行了研究。测量包括静脉葡萄糖耐量试验、双能 X 射线吸收法测量的身体成分、颈动脉内膜中层厚度、颈动脉血管对比超声分子成像以检测血小板 GPIbα（糖蛋白 Ibα）和血管细胞黏附分子-1、以及质谱法检测血液氧化标志物。与瘦猴相比，西方饮食组的猴子肥胖（中位数体重：16.0 公斤与 8.7 公斤，=0.003；中位数躯干脂肪：49%与 20%，=0.002）、胰岛素抵抗（静脉葡萄糖耐量试验中胰岛素-葡萄糖曲线下面积增加 4 倍，=0.002）、颈动脉内膜中层厚度增加 40%（=0.004），且蛋白质组学显示存在氧化特征。在肥胖但不瘦的猴子中，GPIbα 和血管细胞黏附分子-1 的分子成像信号增强显著升高。该信号与内膜中层厚度中度相关，但与胰岛素抵抗程度无关。阿朴肉桂酸显著（<0.01）降低 GPIbα 的中位数信号超过 80%，降低血管细胞黏附分子-1 的信号超过 75%，但不影响内膜中层厚度、体重或静脉葡萄糖耐量试验结果。