Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001.
Heart institute, Hadassah, University Hospital, Jerusalem, Israel 91120.
Theranostics. 2019 Aug 12;9(20):5731-5738. doi: 10.7150/thno.34402. eCollection 2019.
Despite the common use of lipid-lowering medications, cardiovascular diseases continue to be a significant health concern. Atherosclerosis, one of the most frequent causes of cardiovascular morbidity, involves extensive inflammatory activity and remodeling of the vascular endothelium. This relentless inflammatory condition can ultimately give rise to clinical manifestations, such as ischemic heart disease or stroke. Accumulating evidence over the past decades implicates cysteine protease cathepsins in cardiovascular disorders. In particular, Cathepsins B, L, and S are over-expressed during vascular inflammation, and their activity is associated with impaired clinical outcomes. Here we took advantage of these molecular events to introduce a non-invasive detection and treatment approach to modulate vascular inflammation using a Photosensitizing quenched Activity-Based Probed (PS-qABP) that targets these proteases. We tested the application of this approach in LDL receptor-deficient mice and used non-invasive imaging and heart cross-section staining to assess the theranostic efficacy of this probe. Moreover, we used fresh human endarterectomy tissues to analyze cathepsin signals on gel, and verified cathepsin identity by mass spectrometry. We showed that our PS-qABP can rapidly accumulate in areas of inflammatory atheromas , and application of light therapy profoundly reduced lesional immune cell content without affecting smooth muscle cell and collagen contents. Lastly, using human tissue samples we provided proof-of-concept for future clinical applications of this technology. Photodynamic therapy guided by cysteine cathepsin activity is an effective approach to reduce vascular inflammation and attenuate atherosclerosis progression. This approach could potentially be applied in clinical settings.
尽管降脂药物的应用非常普遍，但心血管疾病仍然是一个严重的健康问题。动脉粥样硬化是心血管发病率最常见的原因之一，涉及广泛的炎症活动和血管内皮细胞的重塑。这种持续不断的炎症状态最终可能导致临床表现，如缺血性心脏病或中风。过去几十年来的大量证据表明半胱氨酸蛋白酶组织蛋白酶参与心血管疾病。特别是，在血管炎症期间，组织蛋白酶 B、L 和 S 过度表达，其活性与受损的临床结果相关。在这里，我们利用这些分子事件，引入了一种非侵入性的检测和治疗方法，使用针对这些蛋白酶的光敏猝灭活性基探针 (PS-qABP) 来调节血管炎症。我们在 LDL 受体缺陷型小鼠中测试了这种方法的应用，并使用非侵入性成像和心脏切片染色来评估这种探针的治疗效果。此外，我们使用新鲜的人类动脉内膜切除术组织来分析凝胶上的组织蛋白酶信号，并通过质谱法验证组织蛋白酶的身份。我们表明，我们的 PS-qABP 可以快速积聚在炎症性动脉粥样硬化斑块区域，并且光疗的应用可以显著减少病变中的免疫细胞含量，而不影响平滑肌细胞和胶原含量。最后，使用人类组织样本，我们为这项技术的未来临床应用提供了概念验证。基于半胱氨酸组织蛋白酶活性的光动力疗法是一种减少血管炎症和减轻动脉粥样硬化进展的有效方法。这种方法可能在临床环境中得到应用。
