Lee Regent, Fischer Roman, Charles Philip D, Adlam David, Valli Alessandro, Di Gleria Katalin, Kharbanda Rajesh K, Choudhury Robin P, Antoniades Charalambos, Kessler Benedikt M, Channon Keith M
Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Clin Proteomics. 2017 Jun 19;14:22. doi: 10.1186/s12014-017-9157-x. eCollection 2017.
Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation.
We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption.
We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption.
This novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption.
动脉粥样硬化斑块破裂是引发大多数急性血管综合征（如急性心肌梗死）的关键事件。斑块破裂的新型生物标志物有助于加深对可能出现急性血管综合征患者的生物学理解并改善其临床管理，但此类生物标志物仍未找到。在人类新生斑块破裂的背景下研究生物标志物，由于无法将斑块破裂归因于生物标志物释放的来源而受到困扰，因为斑块破裂通常与心肌坏死和全身炎症的即时下游事件相关。
我们开发了一种新方法，通过在血管成形术诱导的斑块破裂人体模型中，将使用光学相干断层扫描的斑块成像与斑块和血浆蛋白质组分析相结合，来识别斑块破裂的潜在生物标志物。
我们比较了通过FilterWire装置捕获的两对冠状动脉斑块碎片及其相应的对照样本，发现基质金属蛋白酶9（MMP9）在斑块中显著富集。光学相干断层扫描所定义的斑块内容物会影响MMP9的全身变化。富含脂质斑块的破裂导致血浆MMP9迅速升高，而非富含脂质斑块的破裂则导致血浆MMP9延迟升高。全身MMP9升高与相关的心肌坏死和全身炎症（分别通过肌钙蛋白I和C反应蛋白测量）无关。这些信息指导我们选择了一部分受试者，通过液相色谱串联质谱（LC-MS/MS）进行进一步的无标记蛋白质组学分析。我们发现五种新的、在斑块中富集的蛋白质（脂多糖结合蛋白、膜联蛋白A5、真核生物易位起始因子、 syntaxin 11、细胞色素B5还原酶3）在斑块破裂后5分钟时在全身循环中显著升高。
这种在人类冠状动脉斑块破裂中发现生物标志物的新方法可以识别与人类冠状动脉斑块组成和破裂相关的新生物标志物。
