PREVENTION OF VASCULAR REMODELING BY INHIBITING EARLY INFLAMMATORY PROCESS - GENE THERAPY USING A MUTANT INTERFERON-GAMMA RECEPTOR GENE -

(1)应用PCR技术，将人INF-γ受体的胞外区与人IgG Fc片段连接，构建了可溶性突变型INF-γ受体（INFGR：Fc）。（2）为研究INF-γ功能阻断对血管损伤后血管重塑的影响，在大鼠颈动脉损伤前2天，用裸DNA法将INFGR：Fc基因转移到大腿肌肉。在血管损伤后14天，INFGR：Fc基因治疗使新生内膜形成减少了40%。巨噬细胞和T细胞浸润不受基因治疗的影响。然而，INFGR：Fc处理的大鼠的BrdU阳性增殖平滑肌细胞的数量显著减少。（3）通过使用显性负性STAT 3（DNS 3）基因转移来研究JAK-STAT通路（介导INF-γ介导的信号传导的推定通路）在血管损伤后血管重构中的作用。在球囊损伤后立即通过使用腺病毒载体转移DNS 3基因。DNS 3通过特异性抑制新生内膜平滑肌细胞增殖和促进凋亡，显著改善新生内膜的形成。（4）重复转染INFRG：Fc基因可改善apoE基因敲除小鼠动脉粥样硬化病变的进展

(1) By using PCR, a soluble mutant INF-gamma receptor (INFGR : Fc) is being constructed by conjugating an extracellular domain of human INF-gamma receptor with human IgG Fc segment(2) To investage the effects of INF-gamma function blocking on vascular remodeling after vascular injury, INFGR : Fc gene transfer using the naked DNA method to the thigh muscle 2 days before vascular injury of rat carotid artery. INFGR : Fc gene therapy reduced the neointima formation by 40% 14 days after vascular injury. Macrophage and T-cell infiltration were not affected by gene therapy. However, the number of BrdU-positive proliferating smooth muscle cells was significantly decreased by INFGR : Fc-treated rats(3) Roles of JAK-STAT pathway, the putative pathway which mediates INF-gamma-mediated signaling, were investigated during vascular remodeling after vascular injury by using a dominant negative STAT3 (DNS3) gene transfer. DNS3 gene was transferred immediately after balloon injury by using an adenovirus vector. DNS3 significantly ameliorated neointima formation by reducing proliferation and enhancing apoptosis specifically of neointimal smooth muscle cells(4) Repeated INFRG : Fc gene transfer into thigh muscle ameliorated the progression of atherosclerotic lesion in the apoE knockout mice