Research ArticleNanomedicine

RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction

Science Translational Medicine  08 Jun 2016:
Vol. 8, Issue 342, pp. 342ra80
DOI: 10.1126/scitranslmed.aaf1435

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Knocking down adhesion, knocking out inflammation

Cells that are central to inflammation lodge in damaged or fatty regions of the vessels (called plaques) by “feeling out” the vessel surface. Neutrophils and monocytes first “roll” along the wall, then firmly plant themselves at an ideal site, and lastly pass through the cells lining the blood vessel: the endothelial cells. This recruitment and transmigration process is mediated by surface receptors called cell adhesion molecules (CAMs). Sager et al. developed a nanomedicine approach to preventing such inflammatory cell adhesion and exacerbation of plaques, by transiently knocking down five different CAMs simultaneously. The authors delivered small interfering RNA (siRNA) targeting the CAMs inside nanoparticles that had been optimized to reach endothelial cells. The five siRNAs reduced leukocyte recruitment to atherosclerotic plaques in mice that were engineered to develop certain features of human atherosclerosis. In the same mice, the siRNAs also attenuated inflammation after myocardial infarction—the equivalent of a heart attack. Current therapies for atherosclerosis and cardiovascular disease do not target inflammatory cells, and this multipronged siRNA-based nanomedicine approach could complement existing options to prevent heart disease from worsening.

Abstract

Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE−/− mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)–targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI.

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