Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition.
Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition.
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NADPH 氧化酶抑制抗氧化治疗对晚期动脉粥样硬化的炎症和血小板粘附作用的分子成像
DOI：
10.1161/circimaging.112.975193
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Lindner JR
中科院分区：
文献类型：
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作者：
Liu Y;Davidson BP;Yue Q;Belcik T;Xie A;Inaba Y;McCarty OJ;Tormoen GW;Zhao Y;Ruggeri ZM;Kaufmann BA;Lindner JR
在动脉粥样硬化中，局部产生的活性氧放大了炎症反应，并导致斑块脆弱性。我们使用分子成像来测试用夹竹桃麻素抑制NADPH氧化酶是否会减少内皮炎性激活和内皮-血小板相互作用，从而中断向高危斑块表型的进展。在30周龄时研究了LDL受体和Apobec-1缺陷的小鼠，并在10周后再次研究了有或没有夹竹桃麻素治疗（口服10或50 mg/kg/天）的小鼠。采用靶向超声造影（CEU）分子成像技术，对大鼠胸主动脉血管细胞粘附分子1（VCAM-1）、P-选择素（P-selectin）和血小板GPIbα进行了在体分子成像。使用超高频超声和有创血流动力学测量来评估动脉弹性模量和脉搏波传导时间。通过组织学评估斑块大小和组成。未治疗小鼠的分子成像检测到P-选择素表达、VCAM-1表达和血小板粘附在30至40周龄之间增加了2倍。夹竹桃麻素以剂量依赖性方式减少所有这些内皮事件（低剂量和高剂量夹竹桃麻素在40周时信号减少25%和50%）。夹竹桃素还降低主动脉弹性模量，增加脉搏传导时间。在组织学上，夹竹桃麻素以剂量依赖性方式减少总单核细胞积聚以及血小板粘附，尽管仅在高剂量夹竹桃麻素治疗组中总斑块面积减少。在晚期动脉粥样硬化中抑制NADPH氧化酶可降低内皮活化和血小板粘附;这可能是阻止斑块生长和改善血管机械性能的原因。
In atherosclerosis, local generation of reactive oxygen species amplifies the inflammatory response and contributes to plaque vulnerability. We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial-platelet interactions, thereby interrupting progression to high-risk plaque phenotype. Mice deficient for both the LDL receptor and Apobec-1 were studied at 30 weeks of age and again after 10 weeks with or without apocynin treatment (10 or 50 mg/kg/day orally). In vivo molecular imaging of VCAM-1, P-selectin and platelet GPIbα in the thoracic aorta was performed with targeted contrast-enhanced ultrasound (CEU) molecular imaging. Arterial elastic modulus and pulse wave transit time were assessed using ultra-high frequency ultrasound and invasive hemodynamic measurements. Plaque size and composition were assessed by histology. Molecular imaging in non-treated mice detected a 2-fold increase in P-selectin expression, VCAM-1 expression, and platelet adhesion between 30 and 40 wks of age. Apocynin reduced all of these endothelial events in a dose-dependent fashion (25% and 50% reduction in signal at 40 weeks for low- and high-dose apocynin). Apocynin also decreased aortic elastic modulus and increased the pulse transit time. On histology, apocynin reduced total monocyte accumulation in a dose-dependent manner as well as platelet adhesion, although total plaque area was reduced in only the high-dose apocynin treatment group. Inhibition of NADPH oxidase in advanced atherosclerosis reduces endothelial activation and platelet adhesion; which are likely responsible for the arrest of plaque growth and improvement of vascular mechanical properties.