Division of Imaging Science and Biomedical Engineering, King's College London, London, United Kingdom.
J Am Heart Assoc. 2013 Sep 26;2(5):e000402. doi: 10.1161/JAHA.113.000402.
Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magnetic resonance imaging (MRI) using an albumin-binding contrast agent, gadofosveset, could monitor the efficacy of minocycline and ebselen in reducing endothelial permeability and atherosclerotic burden in the brachiocephalic artery of high-fat diet (HFD)-fed ApoE-/- mice.
ApoE-/- mice were scanned 12 weeks after commencement of either a normal diet (controls) or an HFD. HFD-fed ApoE-/- mice were either untreated or treated with minocycline or ebselen for 12 weeks. Delayed-enhancement MRI and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R1, s(-1)) in untreated HFD-fed ApoE-/- mice (R1 = 3.8 ± 0.52 s(-1)) compared with controls (R1 = 2.15 ± 0.34 s(-1), P < 0.001). Conversely, minocycline-treated (R1 = 2.7 ± 0.17 s(-1), P < 0.001) and ebselen-treated (R1 = 2.7 ± 0.23 s(-1), P < 0.001) ApoE-/- mice showed less vessel wall enhancement compared with untreated HFD-fed ApoE-/- mice. Mass spectroscopy showed a lower gadolinium concentration in the brachiocephalic artery of treated (minocycline = 28.5 ± 3 μmol/L, ebselen = 32.4 ± 4 μmol/L) compared with untreated HFD-fed ApoE-/- mice (191 ± 4.8 μmol/L) (P < 0.02). Both interventions resulted in a lower plaque burden as measured by delayed-enhancement MRI (minocycline = 0.14 ± 0.02 mm2, ebselen= 0.20 ± 0.09 mm2), untreated = 0.44 ± 0.01 mm2; P < 0.001) and histology (minocycline = 0.13 ± 0.05 mm2, ebselen = 0.18 ± 0.02 mm2, untreated = 0.32 ± 0.04 mm2; P < 0.002). Endothelium cells displayed fewer structural changes and smaller gap junction width in treated compared with untreated animals as seen by electron microscopy (minocycline=42.3 ± 8.4 nm, ebselen = 56.5 ± 17 nm, untreated = 2400 ± 39 nm; P < 0.001). Tissue flow cytometry of the brachiocephalic artery showed lower monocyte/macrophage content in both ebselen- and minocycline-treated mice (8.06 ± 3.2% and 7.62 ± 1.73%, respectively) compared with untreated animals (20.1 ± 2.2%) (P = 0.03), with significant attenuation of the proinflammatory Ly6Chigh subtype (untreated mice, 42.64 ± 6.1% of total monocytes; ebselen, 14.07 ± 9.5% of total monocytes; minocycline, 26.42 ± 0.6% of total monocytes).
We demonstrate that contrast-enhanced MRI with an albumin-binding contrast agent can be used to noninvasively monitor the effect of interventions on endothelial permeability and plaque burden. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim at restoring endothelial integrity.
内皮功能障碍促进动脉粥样硬化。我们研究了使用结合白蛋白的对比剂gadofosveset 的体内磁共振成像（MRI）是否可以监测米诺环素和艾地苯醌在减少高脂肪饮食（HFD）喂养的 ApoE-/- 小鼠颈总动脉内皮通透性和动脉粥样硬化负担方面的疗效。
在开始正常饮食（对照组）或 HFD 12 周后，对 ApoE-/- 小鼠进行扫描。HFD 喂养的 ApoE-/- 小鼠未治疗或用米诺环素或艾地苯醌治疗 12 周。在注射 gadofosveset 30 分钟后进行颈总动脉延迟增强 MRI 和 T1 映射，与对照组（R1 = 2.15 ± 0.34 s(-1)）相比，未经治疗的 HFD 喂养的 ApoE-/- 小鼠的血管壁增强和弛豫率（R1）增加（R1 = 3.8 ± 0.52 s(-1)，P < 0.001）。相反，米诺环素治疗（R1 = 2.7 ± 0.17 s(-1)，P < 0.001）和艾地苯醌治疗（R1 = 2.7 ± 0.23 s(-1)，P < 0.001）的 ApoE-/- 小鼠与未经治疗的 HFD 喂养的 ApoE-/- 小鼠相比，血管壁增强程度较低。质谱显示，与未经治疗的 HFD 喂养的 ApoE-/- 小鼠（191 ± 4.8 μmol/L）相比，治疗（米诺环素 = 28.5 ± 3 μmol/L，艾地苯醌 = 32.4 ± 4 μmol/L）的颈总动脉中的镧系元素浓度较低（P < 0.02）。两种干预措施均通过延迟增强 MRI（米诺环素= 0.14 ± 0.02 mm2，艾地苯醌= 0.20 ± 0.09 mm2）测量到较低的斑块负担，与未经治疗的 HFD 喂养的 ApoE-/- 小鼠（0.44 ± 0.01 mm2）相比，差异有统计学意义（P < 0.001），并且组织学（米诺环素= 0.13 ± 0.05 mm2，艾地苯醌= 0.18 ± 0.02 mm2，未经治疗= 0.32 ± 0.04 mm2）。与未经治疗的动物相比，电子显微镜显示治疗的内皮细胞结构变化较少，细胞间隙连接宽度较小（米诺环素= 42.3 ± 8.4nm，艾地苯醌= 56.5 ± 17nm，未经治疗= 2400 ± 39nm；P < 0.001）。颈总动脉组织流式细胞术显示，两种艾地苯醌和米诺环素治疗的小鼠单核细胞/巨噬细胞含量均较低（分别为 8.06 ± 3.2%和 7.62 ± 1.73%），与未经治疗的动物（20.1 ± 2.2%）相比，差异有统计学意义（P = 0.03），并且促炎 Ly6Chigh 亚型的含量显著降低（未经治疗的小鼠，总单核细胞的 42.64 ± 6.1%；艾地苯醌，总单核细胞的 14.07 ± 9.5%；米诺环素，总单核细胞的 26.42 ± 0.6%）。
我们证明了使用结合白蛋白的对比剂的对比增强 MRI 可以用于非侵入性监测干预措施对内皮通透性和斑块负担的影响。血液白蛋白渗漏可能是评估旨在恢复内皮完整性的干预措施的体内评价的替代标志物。
