Miéville Arnaud, Wolint Petra, Cesarovic Nikola, Falk Volkmar, Vogel Viola
Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, Institute of Translational Medicine, ETH Zürich, Zürich, Switzerland.
Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland.
Front Cardiovasc Med. 2025 Aug 8;12:1627917. doi: 10.3389/fcvm.2025.1627917. eCollection 2025.
Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) accounts for up to 15% of acute Myocardial Infarction (MI) cases and presents significant diagnostic and therapeutic challenges. The specific targeting of microthrombi involved in microthrombi-induced MINOCA with molecule-specific precision has been challenging due to their omnipresence in the bloodstream, highlighting the need for novel biomarkers and imaging strategies. Fibronectin, one of these omnipresent extracellular matrix (ECM) proteins, exists in distinct physical states in healthy versus diseased tissues, presenting stretched versus untensed fibers, which may serve as potential diagnostic and therapeutic targets.
The peptide FnBPA5, a highly specific probe that binds selectively to untensed fibronectin fibers, as its multivalent binding motif is destroyed upon fiber stretching, was employed here to assess fibronectin's fiber tension in microthrombi before and after the onset of MINOCA in a pig model of autologous microthrombi-induced MINOCA.
Loss of fibronectin fiber tension was identified here as a novel key feature of microthrombi in a pig model of autologous microthrombi-induced MINOCA, whereas fibronectin fibers in the surrounding healthy myocardium remained highly stretched. FnBPA5 can thus effectively visualizes fibronectin's physical signature, thereby distinguishing microthrombi from the surrounding healthy tissue.
These findings underscore FnBPA5's unique capacity to discriminate not merely the presence of an abundant ECM molecule within a thrombus, but its distinct physical conformation. FnBPA5 enables the selective detection of microthrombi in coronary arteries by targeting untensed fibronectin fibers, a novel mechanical biomarker of microthrombi. Targeting a protein's physical state with high specificity makes FnBPA5 a promising tool for advanced microthrombi detection and for mechano-therapeutic strategies involving the targeted delivery of therapeutic agents.
非阻塞性冠状动脉心肌梗死（MINOCA）占急性心肌梗死（MI）病例的比例高达15%，并带来了重大的诊断和治疗挑战。由于微血栓在血液中普遍存在，以分子特异性精度特异性靶向参与微血栓诱导的MINOCA的微血栓一直具有挑战性，这凸显了对新型生物标志物和成像策略的需求。纤连蛋白是这些普遍存在的细胞外基质（ECM）蛋白之一，在健康组织与患病组织中以不同的物理状态存在，呈现伸展的纤维与未张紧的纤维，这可能成为潜在的诊断和治疗靶点。
肽FnBPA5是一种高度特异性的探针，因其多价结合基序在纤维伸展时被破坏，所以能选择性地结合未张紧的纤连蛋白纤维。在此，我们使用FnBPA5来评估在自体微血栓诱导的MINOCA猪模型中，MINOCA发作前后微血栓中纤连蛋白的纤维张力。
在自体微血栓诱导的MINOCA猪模型中，纤连蛋白纤维张力的丧失被确定为微血栓的一个新的关键特征，而周围健康心肌中的纤连蛋白纤维仍高度伸展。因此，FnBPA5能够有效地可视化纤连蛋白的物理特征，从而将微血栓与周围健康组织区分开来。
这些发现强调了FnBPA5不仅能够区分血栓中丰富的ECM分子的存在，还能区分其独特的物理构象。通过靶向未张紧的纤连蛋白纤维，FnBPA5能够选择性地检测冠状动脉中的微血栓，这是微血栓的一种新的机械生物标志物。以高特异性靶向蛋白质的物理状态使FnBPA5成为先进的微血栓检测以及涉及治疗剂靶向递送的机械治疗策略的一个有前景的工具。
