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The effect of Neuregulin on cardiac myoctes - The relationship with isolated left ventricular noncompaction, and left ventricular remodeling

神经调节蛋白对心肌细胞的影响——与孤立性左心室致密化不全和左心室重构的关系

基本信息

批准号：
12670787
负责人：
FUKAZAWA Ryuji
金额：
$ 1.73万
依托单位：
NIPPON MEDICAL SCHOOL
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

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670787/
关键词：
Neuregulin Erb Cardiac Myocytes Cardiotoxicity

项目摘要

The purpose of this study was to investigate how Neuregulin effected on cardiac myocytes. First, we confirmed Neuregulin anti-apoptotic effect, which was induced by Daunorubicin, on cardiomyocytes. The anti-apoptotic effect of Neuregulin was proved to be through the activation of Phospho Inositol-3 Kinase (PI3-K). Next, we compared Neuregulin signal transduction system on cardiomyocytes with Epidermal Growth Factor (EGF), which was the same peptide family with Neuregulin. We found Neuregulin activated both of MAP kinase (ERK) and PI3-K via ErbB-2 and ErbB-4 receptors. On the other hand, EGF only activated ERK via ErbB-1 and ErbB-2. We concluded ErbB-2 receptor greatly contribute to EGF family signal transduction. For more detail examination, we truncated ErbB-2 kinase domain and constructed dominant negative ErbB-2 adenovirus vector. We infected it into cardiomyocyte. Because of abundant expression of intrinsic ErbB-2, dominant negative ErbB-2 only reduced ErbB-2 phosphorylation by 20-30 %, and there were no changes about ERK and PI3-K activation. We tried next ErbB-2 anti-sense oligo method. However, ErbB-2 anti-sense oligo was lethal to cardiomyocytes, which probed ErbB-2 was indispensable for cardiomyocytes. We are now planning to use cardiomyocytes, which was induced by cord blood using 5' azathitizine, and tratuzamab (Herceptin) as ErbB-2 signal inhibitor for more detail study.

本研究的目的是研究神经调节蛋白如何影响心肌细胞。首先，我们证实了柔红霉素诱导的神经调节蛋白对心肌细胞的抗凋亡作用。 Neuregulin 的抗细胞凋亡作用被证明是通过激活磷酸肌醇-3 激酶 (PI3-K) 来实现的。接下来，我们将心肌细胞上的神经调节蛋白信号转导系统与表皮生长因子（EGF）进行比较，EGF与神经调节蛋白属于同一肽家族。我们发现 Neuregulin 通过 ErbB-2 和 ErbB-4 受体激活 MAP 激酶 (ERK) 和 PI3-K。另一方面，EGF仅通过ErbB-1和ErbB-2激活ERK。我们得出结论，ErbB-2 受体对 EGF 家族信号转导有很大贡献。为了进行更详细的检查，我们截短了 ErbB-2 激酶结构域并构建了显性失活的 ErbB-2 腺病毒载体。我们将其感染到心肌细胞中。由于内在ErbB-2的丰富表达，显性失活ErbB-2仅使ErbB-2磷酸化降低20-30%，并且ERK和PI3-K激活没有变化。我们尝试了接下来的ErbB-2反义寡核苷酸方法。然而ErbB-2反义寡核苷酸对心肌细胞具有致死作用，由此可见ErbB-2对于心肌细胞是不可缺少的。我们现在计划使用5'氮杂噻嗪通过脐带血诱导的心肌细胞和曲妥珠单抗（赫赛汀）作为ErbB-2信号抑制剂进行更详细的研究。