MAb therapy against the IFN-α/β receptor subunit 1 stimulates arteriogenesis in amurine hindlimb ischaemiamodel without enhancing atherosclerotic burden.
In: Cardiovascular Research, Jg. 107 (2015-07-15), Heft 2, S. 255-266
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Zugriff:
Aims: 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. Methods and results: In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR-/-) micewere 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 responsewas quantified using laser Doppler perfusion imaging (LDPI) aswell 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. Thiswas accompanied by a decrease inCXCL10expression 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]
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MAb therapy against the IFN-α/β receptor subunit 1 stimulates arteriogenesis in amurine hindlimb ischaemiamodel without enhancing atherosclerotic burden.
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Autor/in / Beteiligte Person: | Teunissen, Paul F. A. ; Boshuizen, Marieke C. ; Hollander, Maurits R. ; Biesbroek, Paul S. ; van der Hoeven, Nina W. ; Mol, Jan-Quinten ; Gijbels, Marion J. ; van der Velden, Saskia ; van der Pouw Kraan, Tineke C. ; Horrevoets, Anton J. ; de Winther, Menno P. ; van Royen, Niels |
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Zeitschrift: | Cardiovascular Research, Jg. 107 (2015-07-15), Heft 2, S. 255-266 |
Veröffentlichung: | 2015 |
Medientyp: | academicJournal |
ISSN: | 0008-6363 (print) |
DOI: | 10.1093/cvr/cvv138 |
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