Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Business Development of Research, IRCCS San Raffaele Hospital, Milan, Italy.
Cardiovasc Res. 2021 Nov 22;117(13):2652-2663. doi: 10.1093/cvr/cvab074.
Recent evidence suggests that 'vulnerable plaques', which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbour neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage.
We developed Collagen IV-targeted nanoparticles (Col IV NP) to deliver PAD4 inhibitors selectively to regions of endothelial cell sloughing and collagen IV-rich basement membrane exposure. We assessed the binding capability of the targeting ligand in vitro and evaluated Col IV NP targeting to areas of denuded endothelium in vivo in a mouse preparation that recapitulates features of superficial erosion. Delivery of the PAD4 inhibitor GSK484 reduced NET accumulation at sites of intimal injury and preserved endothelial continuity.
NPs directed to Col IV show selective uptake and delivery of their payload to experimentally eroded regions, illustrating their translational potential. Our results further support the role of PAD4 and NETs in superficial erosion.
最近的证据表明，几十年来，作为急性冠脉综合征潜在机制的“易损斑块”实际上很少破裂并导致临床事件。在包括降脂、降压治疗和戒烟在内的预防措施日益增加的时代，浅层斑块侵蚀已成为动脉粥样硬化残余血栓并发症不断增加的一个原因。斑块侵蚀的机制仍知之甚少，我们目前缺乏针对浅层侵蚀的经过验证的有效诊断或治疗方法。侵蚀斑块具有丰富的细胞外基质、完整的纤维帽、稀疏的脂质和少量单核细胞，但确实存在中性粒细胞胞外陷阱 (NETs)。我们最近报道，NETs 放大并传播了动脉病变部位的内皮损伤，该病变部位在小鼠中再现了浅层侵蚀。我们发现，蛋白精氨酸脱亚氨酶 (PAD)-4 功能的遗传缺失抑制了 NETosis 并维持了内皮完整性。本研究使用系统给予靶向纳米颗粒来输送一种限制 NET 形成的药物，以探讨斑块侵蚀的机制并证明一种限制内皮损伤的新型治疗方法。
我们开发了针对Ⅳ型胶原的纳米颗粒 (Col IV NP)，以将 PAD4 抑制剂选择性递送至内皮细胞脱落和富含Ⅳ型胶原的基底膜暴露的区域。我们评估了靶向配体的体外结合能力，并在一种模拟浅层侵蚀特征的小鼠制备物中评估了 Col IV NP 对裸露内皮区域的靶向作用。PAD4 抑制剂 GSK484 的递送达可减少内膜损伤部位的 NET 积累并维持内皮连续性。
靶向 Col IV 的 NPs 显示出对其有效载荷的选择性摄取和递送至实验性侵蚀区域，这说明了它们的转化潜力。我们的结果进一步支持了 PAD4 和 NETs 在浅层侵蚀中的作用。
