NEW TREATMENT FOR DIASTOLIC DYSFUNCTION BY PREVENTING CARDIAC FIBROSIS -GENE THERAPY USING A MUTANT TGF-β, RECEPTOR-

(1)利用PCR技术，将人TGF-β受体胞外区与人IgG Fc段连接，构建了可溶性突变型TGF-β受体（T β RII：Fc）。(2)为了阻断TGF-β的体内活性，我们使用抗TGF-β单克隆TGF-β中和抗体（NAb）。慢性每日治疗NAb并没有改变血压升高和左室肥大引起的主动脉缩窄（AC）的大鼠，但几乎取消AC诱导的成纤维细胞增殖和心肌纤维化。此外，NAb预防AC大鼠的舒张功能障碍。(3)在AC大鼠的心肌内动脉，ICAM-1和MCP-1的表达迅速和短暂的观察，与血管周围的巨噬细胞的积累。抗ICAM-1单克隆抗体不仅能减少巨噬细胞聚集，而且能防止心肌纤维化。(4)慢性NAb治疗对OLETF大鼠的Dahl盐敏感大鼠的心脏纤维化进展没有显著影响，这可能是因为NAb的活性在太长的治疗期间（> 6周）可能不会保持。

(1) By using PCR, a soluble mutant TGF-β receptor (TβRII : Fc) is being constructed by conjugating an extracellular domain of human TGF-β receptor with human IgG Fc segment.(2) To block the in vivo activity of TGF-β, we used an anti-TGF-β monoclonal TGF-β neutralizing antibody (NAb). Chronic daily treatment with NAb did not change blood pressure elevation and LV hypertrophy induced by aortic constriction (AC) in rats, but almost abolished the AC-induced fibroblast proliferation and myocardial fibrosis. Furthermore, NAb prevented of diastolic dysfunction in AC rats.(3) In the intramyocardial arteries of AC rats, ICAM-1 expression and MCP-1 expression were rapidly and transiently observed, associated with the perivascular macrophage accumulation. Anti-ICAM-1 monoclonal antibody not only reduced macrophage accumulation but also prevented myocardial fibrosis.(4) Chronic NAb treatment did not significantly affected the progression of cardiac fibrosis in Dahl salt-sensitive rats of OLETF rats, probably because the activity of NAb might not remain during the too long treatment (>6 weeks).