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

通过预防心脏纤维化来治疗舒张功能障碍的新方法 - 使用突变型 TGF-β 受体的基因疗法 -

• 批准号: 13670767
• 负责人: KAI Hisashi
• 金额: $ 2.24万
• 依托单位: KURUME UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670767/
• 关键词: TGF-β; myocardial fibrosis; hypertension; diastolic dysfunction; gene therapy; neutralizing antibody; 高血圧; 拡張不全

(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).

(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（TβRII：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单克隆抗体不仅可以减少巨噬细胞聚集，还可以预防心肌纤维化。(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。

项目成果

Tokuda K, Kai H, (他2名2番目): "Sub-suppressor dose of angiotensin type-1 receptor blocker inhibits TGF-β-mediated perivascular fibrosis in hypertensive rat hearts"J Cardiovasc Pharmacol. (印刷中).

Tokuda K、Kai H（另外 2 人）：“亚抑制剂剂量的 1 型血管紧张素受体阻滞剂抑制高血压大鼠心脏中 TGF-β 介导的血管周围纤维化”J Cardiovasc Pharmacol（印刷中）。

Kuwahara F, Kai H, (他6名2番目): "Hypoxia-inducible factor/vascular endothelial growth factor-mediated pathway for adventitial vasa vasorum formation in hypertensive aorta"Hypertension. 39(2). 46-50 (2002)

Kuwahara F，Kai H，（其他 6 人，第 2）：“高血压主动脉外膜血管滋养层形成的缺氧诱导因子/血管内皮生长因子介导的途径”39(2)。

Nagata N, Kai H, (他4名2番目): "Oncostatin M induces matrix metalloproteinase-9 through extracellular signaling-regulated protein kinases in cultured smooth musclec ells"Arterioscl Thromb Vasc Biol. 23(4). 588-593 (2003)

Nagata N，Kai H，（其他 4 人，第 2）：“制瘤素 M 在培养的平滑肌细胞中通过细胞外信号调节蛋白激酶诱导基质金属蛋白酶 9”Arterioscl Thromb Vasc Biol 23(4)。

Shibata R, Kai H, (他7名1番目): "Inhibition of STAT3 prevents neointime formation by inhibiting proliferation and promoting apoptosis of neointimal smooth muscle cells"Human Gene Ther. 14(7). 901-910 (2003)

Shibata R，Kai H，（其他 7 人，第 1）：“抑制 STAT3 通过抑制新生内膜平滑肌细胞的增殖和促进细胞凋亡来防止新生内膜形成”Human Gene Ther 14(7) (2003)。

Kai H, (他8名1番目): "Coexistence of hypercholesterolemia and hypertension impairs adventitial vascularization"Hypertension. 39(2). 455-459 (2002)

Kai H，（8 其他第 1）：“高胆固醇血症和高血压的共存损害外膜血管化”高血压 39(2) 455-459 (2002)。