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

本研究旨在探讨神经调节蛋白对心肌细胞的影响。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。神经调节蛋白的抗凋亡作用是通过激活磷酸肌醇-3激酶（PI3-K）来实现的。接下来，我们比较了神经调节蛋白与表皮生长因子（Epidermal Growth Factor， EGF）在心肌细胞上的信号转导系统。我们发现神经调节蛋白通过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。我们认为ErbB-2受体在EGF家族信号转导中起着重要作用。为了进行更详细的研究，我们截断ErbB-2激酶结构域，构建了ErbB-2显性阴性腺病毒载体。我们把它感染进了心肌细胞由于内源性ErbB-2表达丰富，显性负性ErbB-2仅使ErbB-2磷酸化降低20- 30%，而ERK和PI3-K活化没有变化。我们尝试了ErbB-2反义寡核苷酸法。然而，ErbB-2反义寡核苷酸对心肌细胞具有致死性，这表明ErbB-2对心肌细胞是不可或缺的。我们现在正计划使用5'阿扎替嗪和曲妥珠单抗（赫赛汀）作为ErbB-2信号抑制剂的脐带血诱导心肌细胞进行更详细的研究。

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.