MAb therapy against the IFN-α/β receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden.
OBJECTIVE
IFN-beta (IFNβ) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNβ hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNβ treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNβ signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis.


RESULTS
In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-α/β receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNβ were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice.


CONCLUSIONS
Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.
Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
Paul F A
PF
Teunissen
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Marieke C
MC
Boshuizen
Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
Maurits R
MR
Hollander
Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
Paul S
PS
Biesbroek
Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
Nina W
NW
van der Hoeven
Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
Jan-Quinten
JQ
Mol
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands Department of Pathology and Molecular Genetics, CARIM, Maastricht, The Netherlands.
Marion J
MJ
Gijbels
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Saskia
S
van der Velden
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Tineke C
TC
van der Pouw Kraan
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Anton J
AJ
Horrevoets
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands m.dewinther@amc.uva.nl n.vanroyen@vumc.nl.
Menno P
MP
de Winther
Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands m.dewinther@amc.uva.nl n.vanroyen@vumc.nl.
Niels
N
van Royen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D003097:Collateral Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000276:immunology* / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology*; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000276:immunology*
D000911:Antibodies, Monoclonal; D053633:Receptor, Interferon alpha-beta
Animal model cardiovascular disease; Atherosclerosis; Collateral circulation; Cytokine; MAbs