Exploration of abnormal dephosphorylation mechanism via Protein phosphatase 1β in heart failure
心力衰竭中蛋白磷酸酶1β异常去磷酸化机制的探讨
基本信息
- 批准号:17590739
- 负责人:
- 金额:$ 2.24万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2005
- 资助国家:日本
- 起止时间:2005 至 2006
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
We previously reported that overactivation of protein phosphatase 1 (PP 1) is responsible for the decrease in phospholamban (PLN) phosphorylation and concomitant decrease in cardiac contractility in the failing heart. In this regard, increased expression level in PP 1β was evident in failing cardiomyopathic hamster hearts. However, specific role of each PP 1 isoform in cardiomyocytes is unclear. We therefore investigated the isoform specific role of PP 1 in contractility and phosphorylation regulation using adenoviral RNA interference (RNAi) technique.Methods : We created recombinant adenoviruses encoding short hairpin RNA, that induce isoform-specific RNAi for PP 1 a (Ad.PP1ai), 1β (Ad.PP1βi), and γ (Ad.PP1γi) in normal adult rat cardiomyocytes at 8-10 weeks of age. Isolated cardiomyocytes were transfected with each adenoviral vector at MOI of 20, 100, and 500, followed by the analysis for phosphorylation, cell shortening and intracellular calcium transient 72 hours after transfection. Results : All adenoviral RNAi transfection induced approximately 90% decrease in mRNA expression and significant decrease in protein level ranging from 60 to 80% without affecting other isoform expressions. Expression levels of major regulatory protein including phospholamban (PLN), A kinase (PKA), sarcoendoplasmic reticulum ATPase (SERCA2a), ryanodine receptor type 2 (RyR2) were not affected. Increase in PLN phosphorylation at Ser16 was observed in Ad.PP1ai (1.5 folds) and Ad.PP1βi (2 folds), but not in PP1γ-transfected cardiomyocytes. PP 113i most effectively augmented cell shortening and Ca^<2+> transient among the group at normal culture state, and under the beta-adrenergic stimulated state. Conclusion: PP 1βi appears to be the major PLN phosphatase that regulates cardiomyocyte contractility. Because PP 113 expression is increased in various heart failure models and human heart failure, it may be a good therapeutic target for heart failure.
我们之前报道过,蛋白磷酸酶 1 (PP 1) 的过度激活是导致衰竭心脏中受磷蛋白 (PLN) 磷酸化降低以及随之而来的心肌收缩力降低的原因。在这方面,PP 1β 的表达水平在衰竭的心肌病仓鼠心脏中明显增加。然而,每种 PP 1 同工型在心肌细胞中的具体作用尚不清楚。因此,我们使用腺病毒 RNA 干扰 (RNAi) 技术研究了 PP 1 在收缩性和磷酸化调节中的异构体特异性作用。方法:我们创建了编码短发夹 RNA 的重组腺病毒,在正常情况下诱导 PP 1 a (Ad.PP1ai)、1β (Ad.PP1βi) 和 γ (Ad.PP1γi) 的异构体特异性 RNAi 8-10周龄成年大鼠心肌细胞。用每种腺病毒载体以 20、100 和 500 的 MOI 转染分离的心肌细胞,然后在转染后 72 小时分析磷酸化、细胞缩短和细胞内钙瞬变。结果:所有腺病毒 RNAi 转染均诱导 mRNA 表达降低约 90%,蛋白质水平显着降低 60% 至 80%,而不影响其他亚型表达。主要调节蛋白包括受磷蛋白 (PLN)、A 激酶 (PKA)、肌内质网 ATP 酶 (SERCA2a)、兰尼碱受体 2 型 (RyR2) 的表达水平不受影响。在 Ad.PP1ai(1.5 倍)和 Ad.PP1βi(2 倍)中观察到 PLN Ser16 磷酸化增加,但在 PP1γ 转染的心肌细胞中未观察到。在正常培养状态和β-肾上腺素能刺激状态下,PP 113i 最有效地增强了组中的细胞缩短和Ca 2+ 瞬变。结论:PP 1βi 似乎是调节心肌细胞收缩力的主要 PLN 磷酸酶。由于PP 113在各种心力衰竭模型和人类心力衰竭中表达增加,因此它可能是心力衰竭的良好治疗靶点。
项目成果
期刊论文数量(22)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase
- DOI:10.1038/nm1335
- 发表时间:2005-12-01
- 期刊:
- 影响因子:82.9
- 作者:Yoshimura, K;Aoki, H;Matsuzaki, M
- 通讯作者:Matsuzaki, M
Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes
- DOI:10.1152/ajpheart.00669.2005
- 发表时间:2006-04-01
- 期刊:
- 影响因子:4.8
- 作者:Maruyama, R;Takemura, G;Fujiwara, H
- 通讯作者:Fujiwara, H
Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure
- DOI:10.1016/j.jacc.2007.01.064
- 发表时间:2007-04-24
- 期刊:
- 影响因子:24
- 作者:Mochizuki, Mamoru;Yano, Masafumi;Matsuzaki, Masunori
- 通讯作者:Matsuzaki, Masunori
Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy
- DOI:10.1096/fj.05-5299fje
- 发表时间:2006-06-01
- 期刊:
- 影响因子:4.8
- 作者:Yamada, Michio;Ikeda, Yasuhiro;Matsuzaki, Masunori
- 通讯作者:Matsuzaki, Masunori
医学のあゆみ 特集「心不全UPDATE」、カルシウム制御蛋白をターゲットとした心不全の分子標的治療法
医学史专题“心力衰竭更新”,针对钙调节蛋白的心力衰竭分子靶向治疗
- DOI:
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:Fukunaga R;Hirano K;Hirano M;Niiro N;Nishimura J;Maehara Y;Kanaide H;池田 安宏
- 通讯作者:池田 安宏
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IKEDA Yasuhiro其他文献
IKEDA Yasuhiro的其他文献
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20791259 - 财政年份:2008
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Normalization of increased protein phosphatase 1 activity by using an high efficiency myocardial gene transfer technique in chronic heart failure
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15590754 - 财政年份:2003
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14370642 - 财政年份:2002
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Research in the mechanism of ischemic cell death of cardiomyocyte and the role of mitochondria
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13670716 - 财政年份:2001
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