Abstract 535: Interferon-Gamma Is New Target for Prevention of Vascular Remodeling after Vascular Injury
Interferon-gamma is a multi-functional cytokine with both pro- and anti-atherogenic properties. Thus, it is still controversial whether the net effect of interferon-gamma promotes or attenuates vascular remodeling after vascular injury. In vascular smooth muscle cells (SMCs), interferon-regulating factor-1 (IRF-1) is induced by interferon-gamma, and in turn upregulates expression of inducible nitric oxide synthase (iNOS), which results in SMC proliferation. Recently, we have shown that blocking of interferon-gamma by overexpressing a soluble mutant of the interferon-gamma receptor (sIFNgR), an interferon-gamma inhibiting protein, regresses and stabilizes advanced atherosclerotic plaque in apoE-deficient mice. Thus, we investigated the role of interferon-gamma on neointima formation after vascular injury by inhibiting the interferon-gamma-mediated pathway in vivo. For this purpose, naked DNA plasmid encoding the sIFNgR or the empty plasmid (mock) was injected into the thigh muscle of male Wistar rats 2 days before balloon injury (day -2)(n=6/group). sIFNgR gene transfer significantly elevated serum levels of sIFNgR protein at days 2 to 14. In the mock-treated rats, balloon injury induced a transient proliferation of neointimal SMCs with a peak at day 7, assessed by PCNA labeling, and the maximum neointimal thickening was observed at day 14. At day 7, balloon injury markedly upregulated IRF-1 and iNOS mRNAs in the mock-treated rats. sIFNgR gene transfer almost inhibited the balloon injury-induced inductions of IRF-1 and iNOS at day 7. And, the number of proliferating neointimal SMCs was reduced by 50% in the sIFNgR-treated rats relative to the mock-treated rats. Moreover, at day 14, sIFNgR gene transfer prevented neointima formation, resulting in 45% reduction of the intima/media area ratio compared with mock-treated rats. In conclusion, the role of interferon-gamma was suggested in the neointima formation through IRF-1 regulation of iNOS expression and subsequently SMC proliferation in balloon-injured artery. The present study provided an insight into a new strategy for prevention of vascular remodeling after vascular injury by targeting interferon-gamma.