Published Online
on February 19, 2007

A more recent version of this article appeared on April 1, 2007

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Submitted on December 22, 2006
Revised on January 12, 2007

Inhibition of Intrinsic Interferon- Function Prevents Neointima Formation After Balloon Injury

Ken Kusaba; Hisashi Kai^*; Mitsuhisa Koga; Narimasa Takayama; Ayami Ikeda; Hideo Yasukawa; Yukihiko Seki; Kensuke Egashira; and Tsutomu Imaizumi

From the Department of Internal Medicine (K.K., H.K., M.K., N.T., A.I., Y.S., T.I.), Division of Cardio-vascular Medicine, Kurume University School of Medicine, Kurume, Japan; the Department of Pharmaceutical Care and Health Sciences (M.K.), Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; the Cardiovascular Research Institute (H.Y.), Kurume University, Kurume, Japan; and the Department of Cardiovascular Medicine (K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

^* To whom correspondence should be addressed. E-mail: naikai{at}med.kurume-u.ac.jp.

Abstract--It is still controversial whether intrinsic interferon (IFN)- promotes or attenuates vascular remodeling in hyperproliferative vascular disorders, such as neointima formation after balloon injury. Thus, we investigated whether inhibition of intrinsic IFN- function prevents neointima formation. For this purpose, naked DNA plasmid encoding a soluble mutant of IFN- receptor -subunit (sIFNR; an IFN- inhibitory protein) or mock plasmid was injected into the thigh muscle of male Wistar rats 2 days before balloon injury (day -2). sIFNR gene transfer significantly elevated serum levels of sIFNR protein for 2 weeks. In mock-treated rats, balloon injury induced smooth muscle cell proliferation in the neointima with a peak at day 7 and produced thick neointima at day 14. sIFNR treatment reduced the number of proliferating intimal smooth muscle cells by 50% at day 7 and attenuated neointima formation with a 45% reduction of the intima/media area ratio at day 14. In mock-treated rats, at day 7, balloon injury induced phosphorylation of signal transducer and activator of transcription-1 and upregulations of IFN regulatory factor-1 (a transcription factor mediating IFN- signal). Balloon injury also upregulated the key molecules of neointima formation, such as intercellular adhesion molecule-1 and platelet-derived growth factor -receptor. These changes were suppressed by sIFNR treatment. In conclusion, it is suggested that intrinsic IFN- promotes neointima formation probably through IFN regulatory factor-1/intercellular adhesion molecule-1-mediated and platelet-derived growth factor-mediated mechanisms. Thus, inhibition of IFN- signaling may be a new therapeutic target for prevention of neointima formation of hyperproliferative vascular disorders.

Key words: IFN- • neointima • gene therapy • inflammation • signaling

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