Blocking Interferon beta Stimulates Vascular Smooth Muscle Cell Proliferation and Arteriogenesis

Stephan H. Schirmer, Pieter T. Bot, Joost O. Fledderus, Anja M. van der Laan, Oscar L. Volger, Ulrich Laufs, Michael Boehm, Carlie J. M. de Vries, Anton J. G. Horrevoets, Jan J. Piek, Imo E. Hoefer, Niels van Royen, M. Bohm

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Increased interferon (IFN)-beta signaling in patients with insufficient coronary collateralization and an inhibitory effect of IFNbeta on collateral artery growth in mice have been reported. The mechanisms of IFNbeta-induced inhibition of arteriogenesis are unknown. In stimulated monocytes from patients with chronic total coronary artery occlusion and decreased arteriogenic response, whole genome expression analysis showed increased expression of IFNbeta-regulated genes. Immunohistochemically, the IFNbeta receptor was localized in the vascular media of murine collateral arteries. Treatment of vascular smooth muscle cells (VSMC) with IFNbeta resulted in an attenuated proliferation, cell-cycle arrest and increased expression of cyclin-dependent kinase inhibitor-1A (p21). Growth-inhibitory effect of IFNbeta was attenuated by inhibition of p21 by RNA-interference. IFNbeta-treated THP1 monocytes showed enhanced apoptosis. Subsequently, we tested if collateral artery growth can be stimulated by inhibition of IFNbeta-signaling. RNA-interference of the IFNbeta receptor-1 (IFNAR1) increased VSMC proliferation, cell cycle progression, and reduced p21 gene expression. IFNbeta-signaling and FAS and TRAIL expression were attenuated in monocytes from IFNAR1-/- mice, indicating reduced monocyte apoptosis. Hindlimb perfusion restoration one week after femoral artery ligation was improved in IFNAR1-/- mice compared to wildtype mice as assessed by infusion of fluorescent microspheres. These results demonstrate that IFNbeta inhibits collateral artery growth and VSMC proliferation through p21-dependent cell cycle arrest and induction of monocyte apoptosis. Inhibition of IFNbeta stimulates VSMC proliferation and collateral artery growth
Original languageEnglish
Pages (from-to)34677-34685
JournalJournal of biological chemistry
Issue number45
Publication statusPublished - 2010

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