Myocardial protection during heart surgery by IGF-1 and bcl-2 gene introduction.

通过引入 IGF-1 和 bcl-2 基因来保护心脏手术期间的心肌。

基本信息

批准号：
10671275
负责人：
OTANI Hajime
金额：
$ 1.6万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671275/
关键词：
myocardial ischemia IGF-1 Bcl-xL Bax Bcl-2 IGF-I

项目摘要

Insulin like growth factor-1 (IGF-1) has become a promising tool for treatment with end-stage heart failure. Although the underlying mechanism for myocardial protection remains elusive, recent studies suggest that altered regulation of Bcl-2 family proteins may be involved in the cytoprotective action of IGF-1. It has also been clear that intracellular localization of Bcl-2 family proteins is crucial in regulating the release of death-promoting cytochrome c from mitochondria. Therefore, we have investigated the effect of IGF-1 on Bcl-2 family protein expression and cytochrome c release in isolated rat heart mitochondria. Rats were treated with intra-peritoneal injection with IGF-1(3mg/kg). Mitochondria were isolated from the heart 12, 24, and 36 hours after the treatment. Western blot analysis showed that Bcl-xL expression was maximally increased in the rat heart mitochondria 24 hours after IGF-1 treatment, while Bax expression was maximally down-regulated in the same mitochondrial fra … More ction. Neither Bcl-xL nor Bax protein was detected in the cytosol fraction at any time point after IGF-1treatment. Bcl-2 protein was undetectable in mitochondria, cytosol, microsome or nuclearmyofibrillar fraction. Immunohistochemical staining revealed that IGF-1-induced overexpression of Bcl-xL in the heart was confined to cardiomyocytes. Isolated rat heart mitochondria did not release cytochrome c without a respiratory substrate succinate even in the presence of 10μM CaィイD12+ィエD1. However, respiring mitochondria released cytochrome c in a CaィイD12+ィエD1 dependent manner. Cytochrome c release was attenuated in mitochondria obtained from the heart treated with IGF-1. These results suggest that IGF-1 differentially regulates expression of Bcl-xL and Bax proteins in the rat heart mitochondria. IGF-1-Induced inhibition of cytochrome c release from the mitochondria may represent a mechanism for inhibition of apoptotic cardimyocyte cell death in patients with end-stage heart failure, or with reperfusion injury. Less

胰岛素样生长因子-1 (IGF-1) 已成为治疗终末期心力衰竭的有前景的工具，尽管心肌保护的潜在机制仍不清楚，但最近的研究表明 Bcl-2 家族蛋白的调节改变可能参与其中。 Bcl-2 家族蛋白的细胞内定位对于调节线粒体促进死亡的细胞色素 c 的释放至关重要。 IGF-1对离体大鼠心脏线粒体中Bcl-2家族蛋白表达和细胞色素c释放的影响腹腔注射IGF-1(3mg/kg)，从心脏12、24和36中分离线粒体。 Western blot 分析显示，IGF-1 处理后 24 小时，大鼠心脏线粒体中 Bcl-xL 表达最大程度增加，而 Bax 表达最大程度下调。在 IGF-1 处理后的任何时间点，在线粒体、细胞质、微粒体或核肌原纤维部分中均未检测到 Bcl-xL 和 Bax 蛋白。免疫组织化学染色显示 IGF。 - 1诱导的Bcl-xL在心脏中的过度表达仅限于心肌细胞，甚至在没有呼吸底物琥珀酸的情况下也不会释放细胞色素c。然而，在 10μM CaiD12+D1 存在下，呼吸线粒体以 CaiD12+D1 依赖性方式释放细胞色素 c，这些结果表明 IGF-1 具有差异调节作用。 Bcl-xL 和 Bax 蛋白在大鼠心脏线粒体中的表达 - IGF-1 诱导的线粒体细胞色素 c 释放抑制可能代表了一种机制。抑制终末期心力衰竭或再灌注损伤患者心肌细胞凋亡的机制较少。