Sydney Medical School Nepean, Faculty of Medicine and Health, Department of Cardiology, The University of Sydney, Nepean Hospital, Sydney, NSW, Australia.
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
J Transl Med. 2024 May 1;22(1):412. doi: 10.1186/s12967-024-05231-6.
Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI).
Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21.
Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p < 0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by > 50% (p < 0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p < 0.05), approximately 20-fold greater platelet adhesion (p < 0.05), and increased staining for markers of platelet transforming growth factor-β1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology.
Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.
涉及血小板黏附到血管内皮表面相关 von Willebrand 因子（VWF）的血栓炎症，与 MI 后非罪犯斑块的加速进展有关。本研究的目的是使用动脉内皮分子成像技术，从机械上评估内皮相关 VWF 作为减少心肌梗死后（MI）远程斑块激活的治疗靶点。
载脂蛋白 B 编辑酶 1 缺失（ApoBec-1）的高脂血症小鼠进行闭胸 MI，并接受以下慢性治疗：（i）负责从内皮表面蛋白水解去除 VWF 的重组 ADAMTS13；（ii）N-乙酰半胱氨酸（NAC），通过二硫键还原去除 VWF；（iii）功能阻断抗因子 XI（FXI）抗体；或（iv）无治疗。还研究了非缺血对照。在第 3 天和第 21 天，使用针对血管内皮相关 VWF A1 结构域、血小板 GPIbα、P-选择素和血管细胞黏附分子-1（VCAM-1）的探针，在易损部位的主动脉进行超声分子成像。在第 21 天进行组织学检查。
与 sham 处理的动物相比，MI 后小鼠的主动脉 P-选择素、VCAM-1、VWF 和血小板 GPIbα信号均增加数倍（p<0.01），在第 3 天和第 21 天，NAC 和 ADAMTS13 治疗显著降低了所有 4 个分子靶标治疗后的 MI 增加量（p<0.05 与第 3 天和第 21 天的非治疗组相比）。在主动脉根部组织学上，与对照组相比，发生 MI 的小鼠斑块大小和巨噬细胞含量增加了 2-4 倍（p<0.05），血小板黏附增加了约 20 倍（p<0.05），血小板转化生长因子-β1 信号标记物的染色增加。ADAMTS13 和 NAC 几乎完全阻止了斑块的生长和炎症激活。FXI 抑制对分子成像信号或斑块形态无显著影响。
MI 后远程动脉中的斑块炎症激活受 VWF 介导的血小板黏附到内皮的强烈影响。这些发现支持对 MI 后减少非罪犯动脉事件的新二级预防治疗进行研究。
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