Inhibition of intrinsic interferon-gamma function prevents neointima formation after balloon injury.
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.
Kusaba
Ken
K
Department of Internal Medicine, Division of Cardiovascular Medicine, Kurume University School of Medicine, Kurume, Japan.
Kai
Hisashi
H
Koga
Mitsuhisa
M
Takayama
Narimasa
N
Ikeda
Ayami
A
Yasukawa
Hideo
H
Seki
Yukihiko
Y
Egashira
Kensuke
K
Imaizumi
Tsutomu
T
D000818:Animals; D001808:Blood Vessels / Q000293:injuries* / Q000378:metabolism; D002404:Catheterization / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017471:Receptors, Interferon / Q000235:genetics; D013848:Thigh; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor