Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure
Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure
复制标题
DOI：
10.1161/01.res.0000141528.54850.bd
复制
发表时间：
2004-09-17
影响因子：
20.1
通讯作者：
Fujiwara, H
中科院分区：
文献类型：
--
作者：
Li, YW;Takemura, G;Fujiwara, H
在心肌梗死（MI）中，肉芽组织细胞通过凋亡消失，以完成最终的瘢痕形成，细胞稀少。据报道，这种细胞凋亡的阻断可改善MI后心室重塑和心力衰竭。然而，细胞凋亡的分子生物学机制尚不清楚。Fas和Fas配体在小鼠心肌梗死亚急性期（MI后1周）的肉芽组织中过度表达，细胞凋亡频繁发生。在缺乏功能性Fas的小鼠（lpr株）和缺乏Fas配体的小鼠（gld株）中，肉芽组织细胞凋亡率明显低于遗传控制小鼠，MI后心室重构和功能障碍大大减弱。在MI第三天，用编码可溶性Fas（sFas）的腺病毒转染小鼠，可溶性Fas是Fas配体的竞争性抑制剂。治疗导致肉芽组织细胞凋亡的抑制，并产生了厚的，细胞丰富的梗塞瘢痕，含有丰富的血管和平滑肌细胞束，在慢性阶段（MI后4周）具有收缩表型。这不仅缓解了心力衰竭，而且改善了生存率。然而，在瘢痕组织期sFas基因递送是无效的，这表明sFas基因治疗的有益效果归因于抑制肉芽组织细胞凋亡。Fas/Fas配体相互作用在心肌梗死后肉芽组织细胞凋亡中起重要作用。通过干扰Fas/Fas配体的相互作用阻断这种凋亡可能成为大面积心肌梗死后慢性心力衰竭的治疗策略之一。
In myocardial infarction (MI), granulation tissue cells disappear via apoptosis to complete a final scarring with scanty cells. Blockade of this apoptosis was reported to improve post-MI ventricular remodeling and heart failure. However, the molecular biological mechanisms for the apoptosis are unknown. Fas and Fas ligand were overexpressed in the granulation tissue at the subacute stage of MI ( 1 week after MI) in mice, where apoptosis frequently occurred. In mice lacking functioning Fas (lpr strain) and in those lacking Fas ligand (gld strain), apoptotic rate of granulation tissue cells was significantly fewer compared with that of genetically controlled mice, and post-MI ventricular remodeling and dysfunction were greatly attenuated. Mice were transfected with adenovirus encoding soluble Fas (sFas), a competitive inhibitor of Fas ligand, on the third day of MI. The treatment resulted in suppression of granulation tissue cell apoptosis and produced a thick, cell-rich infarct scar containing rich vessels and bundles of smooth muscle cells with a contractile phenotype at the chronic stage ( 4 weeks after MI). This accompanied not only alleviation of heart failure but also survival improvement. However, the sFas gene delivery during scar tissue phase was ineffective, suggesting that beneficial effects of the sFas gene therapy owes to inhibition of granulation tissue cell apoptosis. The Fas/Fas ligand interaction plays a critical role for granulation tissue cell apoptosis after MI. Blockade of this apoptosis by interfering with the Fas/Fas ligand interaction may become one of the therapeutic strategies against chronic heart failure after large MI.