RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.
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.
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Hendrik B
HB
Sager
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Partha
P
Dutta
Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.|Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA.
James E
JE
Dahlman
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Maarten
M
Hulsmans
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Gabriel
G
Courties
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Yuan
Y
Sun
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Timo
T
Heidt
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Claudio
C
Vinegoni
Alnylam Pharmaceuticals, Cambridge, MA 02142, USA.
Anna
A
Borodovsky
Alnylam Pharmaceuticals, Cambridge, MA 02142, USA.
Kevin
K
Fitzgerald
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Gregory R
GR
Wojtkiewicz
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Yoshiko
Y
Iwamoto
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Benoit
B
Tricot
David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
Omar F
OF
Khan
David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.|Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.
Kevin J
KJ
Kauffman
Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
Yiping
Y
Xing
Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
Taylor E
TE
Shaw
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Peter
P
Libby
Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.|Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA.|Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.
Robert
R
Langer
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Ralph
R
Weissleder
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Filip K
FK
Swirski
Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.|Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA.|Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.
Daniel G
DG
Anderson
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Matthias
M
Nahrendorf
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D053758:Nanoparticles; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology*; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010227:Parabiosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D019040:E-Selectin; C480027:ICAM-2 protein, mouse; C090509:Icam1 protein, mouse; D019007:P-Selectin; D034741:RNA, Small Interfering; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1