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

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.

• Authors: Ken Kusaba, Hisashi Kai, Mitsuhisa Koga, Narimasa Takayama, Ayami Ikeda, Hideo Yasukawa, Yukihiko Seki, Kensuke Egashira, Tsutomu Imaizumi
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 49 Issue 4 Pg. 909-15 (Apr 2007) ISSN: 1524-4563 [Electronic] United States
• PMID: 17309951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• Receptors, Interferon
• Interferon-gamma

Topics

• Animals
• Blood Vessels (injuries, metabolism)
• Catheterization (adverse effects)
• Cell Proliferation (drug effects)
• Gene Expression (drug effects)
• Gene Transfer Techniques
• Injections, Intramuscular
• Interferon-gamma (antagonists & inhibitors)
• Male
• Muscle, Smooth, Vascular (drug effects, pathology, physiopathology)
• Myocytes, Smooth Muscle (drug effects, pathology)
• RNA, Small Interfering (genetics, pharmacology)
• Rats
• Rats, Wistar
• Receptors, Interferon (genetics)
• Thigh
• Time Factors
• Tunica Intima (pathology, physiopathology)
• Interferon gamma Receptor