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Prevention of Cardiac9 Remodeling and Diastolic Dysfunction by inhibiting Fibrotic Process.

通过抑制纤维化过程预防心脏重塑和舒张功能障碍。

基本信息

批准号：
12670711
负责人：
KAI Hisashi
金额：
$ 2.3万
依托单位：
Fukuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-B in myocardial remodeling and cardiac dysfunction were examined (in press)ure-overloaded rats.Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3-7. Thereafter, myocyte hypertrophy and myocWdial fibrosis developed by day 28. At day 28, echocardiography showed normal LV fractional shortening but the decreased early to late filling ratio of the transmitral Doppler velocity, and hemodynamic measurement revealed LV end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-B mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28.An anti-TGF-B neutralizing antibody (NAb), which was intraperitoneally administered daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. NAb reversed diastolic dysfunction without affecting blood pressure and systolic function.TGF-B plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in

过度的心肌纤维化会损害高血压心脏的心功能。在压力超负荷的大鼠中，研究了转化生长因子-B在心肌重构和心功能不全中的作用。成纤维细胞的活性(增殖和表型向肌成纤维细胞的转变)在第3天观察到，在第3-7天达到高峰。此后，心肌细胞肥大和心肌纤维化发展到第28天。第28天超声心动图显示左室短轴缩短率正常，但二尖瓣血流速度早、晚期充盈比降低，血流动力学检查显示左室舒张末压升高，提示收缩功能正常，但舒张期功能异常。术后3d开始诱导心肌组织中转化生长因子-β的表达，7d达高峰，术后28d持续轻度升高。抗转化生长因子-β中和抗体(NAB)可抑制成纤维细胞的活化，从而抑制成纤维细胞的活化，从而抑制胶原蛋白的诱导和心肌纤维化，但对心肌细胞肥大无明显影响。在不影响血压和收缩功能的情况下，NAB逆转了舒张期功能障碍。转化生长因子-B通过激活成纤维细胞在心肌纤维化和舒张期功能障碍中起因果作用。