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Hypertension. 2007 Apr;49(4):909-15. Epub 2007 Feb 19.

Inhibition of intrinsic interferon-gamma function prevents neointima formation after balloon injury.

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1
Department of Internal Medicine, Division of Cardiovascular Medicine, Kurume University School of Medicine, Kurume, Japan.

Abstract

It is still controversial whether intrinsic interferon (IFN)-gamma promotes or attenuates vascular remodeling in hyperproliferative vascular disorders, such as neointima formation after balloon injury. Thus, we investigated whether inhibition of intrinsic IFN-gamma function prevents neointima formation. For this purpose, naked DNA plasmid encoding a soluble mutant of IFN-gamma receptor alpha-subunit (sIFNgammaR; an IFN-gamma inhibitory protein) or mock plasmid was injected into the thigh muscle of male Wistar rats 2 days before balloon injury (day -2). sIFNgammaR gene transfer significantly elevated serum levels of sIFNgammaR 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. sIFNgammaR 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-gamma signal). Balloon injury also upregulated the key molecules of neointima formation, such as intercellular adhesion molecule-1 and platelet-derived growth factor beta-receptor. These changes were suppressed by sIFNgammaR treatment. In conclusion, it is suggested that intrinsic IFN-gamma 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-gamma signaling may be a new therapeutic target for prevention of neointima formation of hyperproliferative vascular disorders.

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