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

Sci Transl Med. 2016 Jun 8;8(342):342ra80. doi: 10.1126/scitranslmed.aaf1435.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • E-Selectin / genetics
  • E-Selectin / metabolism
  • Female
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / cytology
  • Myocardial Infarction / immunology
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / therapy*
  • Nanoparticles
  • Neutrophil Infiltration / genetics
  • Neutrophil Infiltration / physiology*
  • P-Selectin / genetics
  • P-Selectin / metabolism
  • Parabiosis
  • RNA Interference
  • RNA, Small Interfering / genetics*
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Antigens, CD
  • Cell Adhesion Molecules
  • E-Selectin
  • ICAM-2 protein, mouse
  • Icam1 protein, mouse
  • P-Selectin
  • RNA, Small Interfering
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1