Normalization of increased protein phosphatase 1 activity by using an high efficiency myocardial gene transfer technique in chronic heart failure

在慢性心力衰竭中使用高效心肌基因转移技术使增加的蛋白磷酸酶 1 活性正常化

• 批准号: 15590754
• 负责人: IKEDA Yasuhiro
• 金额: $ 2.11万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590754/
• 关键词: chronic heart failure; dilated cardiomyopathy; protein phosphatase 1; adenovirus vector; adeno-associated virus vector; cardiomyopathic hamster; high-efficiency in vivo myocardial gene transfer; アデノウイルスベクター; アデノ関連ウイルスベクター; 高効率心筋遺伝子導入

Background : The type 1 protein phosphatase (PP1) has been reported to be overactivated in experimental and human failing hearts, leading to a depression of Ca^<2+> cycling and contractility. We previously reported that increased PP1 activity was also observed in the models of genetic cardiomyopathy, UMX cardiomyopathic(CM) hamster, and in vivo inhibition of PPl by overexpressing inhibitor-2(I-2) improved short-term cardiac function. Method and Results : We here investigated the effect of chronic PP1 inhibition by using high efficiency adeno-associated virus (rAAV-) mediated cardiac I-2 gene delivery on heart failure progression and survival in CM hamster. Endogeonus inhibitor-2 (I-2) was only detected in the microsomal fraction of cardiomyocytes, and adenoviral overexpresion of I-2 preferentially localized in the sarcolemma, suggesting that I-2 is a membrane-bound (m-) endogenous PP1 inhibitor. In addition, PP1 activity following adenovirus I-2 transfection in cardiomyocytes dramatically decreased PP1 activity and augmented Ca^<2+> cycling and cell shortening in cardiomyocytes. rAAV-mediated in vivo cardiac I-2 gene delivery restored cardiac function and extended survival time for 3 months in CM hamsters. Conclusions: These findings suggest that increased m- PP1 in cardiomyocytes is an important contributor of depressed Ca2+ cycling, and inhibition of m- PP1 via inhibitor-2 may provide a new molecular target for the treatment of heart failure.

背景：据报道，1型蛋白磷酸酶(PP1)在实验心脏和人类衰竭心脏中过度激活，导致Ca 2+ 循环和收缩性抑制。我们之前报道过，在遗传性心肌病、UMX 心肌病（CM）仓鼠模型中也观察到 PP1 活性增加，并且通过过表达抑制剂 2（I-2）体内抑制 PP1 可改善短期心脏功能。方法和结果：我们在此研究了使用高效腺相关病毒 (rAAV-) 介导的心脏 I-2 基因递送慢性 PP1 抑制对 CM 仓鼠心力衰竭进展和存活的影响。内源性抑制剂 2 (I-2) 仅在心肌细胞的微粒体部分中检测到，并且 I-2 的腺病毒过度表达优先位于肌膜中，表明 I-2 是一种膜结合 (m-) 内源性 PP1 抑制剂。此外，心肌细胞中腺病毒I-2转染后的PP1活性显着降低了心肌细胞中的PP1活性并增强了Ca 2+ 循环和细胞缩短。 rAAV 介导的体内心脏 I-2 基因递送恢复了 CM 仓鼠的心脏功能并将生存时间延长了 3 个月。结论：这些发现表明心肌细胞中 m-PP1 的增加是 Ca2+ 循环抑制的重要因素，通过抑制剂 2 抑制 m-PP1 可能为心力衰竭的治疗提供新的分子靶点。

项目成果

myocardial gene therapy as a prototype prodrug delivery system for intractable heart failure (Molecular Mechanism of Heart Diseases (edited by Dr.Mizukami))

心肌基因疗法作为顽固性心力衰竭的原型前药递送系统（心脏病的分子机制（由水上博士编辑））

• 发表时间: 2005
• 作者: Ikeda Y;Yamada M;Matsuzaki M
• 通讯作者: Matsuzaki M

心不全に対する遺伝子治療の開発と展望

心力衰竭基因治疗的进展与展望

• 发表时间: 2004
• 期刊: ケミカルエンジニアリング 49
• 作者: 池田 安宏;山田 倫生;松崎 益徳
• 通讯作者: 松崎 益徳

心不全の遺伝子治療としてのCa2+制御蛋白

Ca2+ 调节蛋白作为心力衰竭的基因治疗

• 发表时间: 2005
• 期刊: Heart View 9
• 作者: Ikeda Y;Yamada M;Matsuzaki M;Oda T et al.;Matsumoto T et al.;池田 安宏
• 通讯作者: 池田 安宏

心不全に対する心筋遺伝子治療の開発

心力衰竭心肌基因治疗的进展

• 发表时间: 2005
• 期刊: 心臓 37
• 作者: Ikeda Y;Yamada M;Matsuzaki M;Oda T et al.;Matsumoto T et al.;池田 安宏;池田 安宏
• 通讯作者: 池田 安宏

Defective regulation of inter-domain interaction within the ryanodine receptor plays a key role in the pathogenesis of heart failure

兰尼碱受体内结构域间相互作用的缺陷调节在心力衰竭的发病机制中起着关键作用

• 发表时间: 2005
• 期刊: Circulation (in print)
• 作者: Oda T;Yano M;Yamamoto T;Tokuhisa T;Okuda;S;Doi M;Ohkusa T;Ikeda Y;Kobayashi;S;Ikemoto N;Matsuzaki M
• 通讯作者: Matsuzaki M