Resumption of intracellular Ca2+ cycling as a novel therapeutic strategy for heart failure

恢复细胞内 Ca2 循环作为心力衰竭的新治疗策略

• 批准号: 17590717
• 负责人: SATOH Hiroshi
• 金额: $ 1.66万
• 依托单位: Hamamatsu University School of Medicine
• 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: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590717/
• 关键词: heart failure; calcium; cardiac myocytes; sarcoplasmic reticulum; Na^+; Ca^<2+> exchange; protein phosphatases; 心筋; 興奮収縮連関

Altered cellular Ca^<2+> handling plays a key role in the pathophysiology of heart failure. A typical aspect of failing heart cells is a decrease in the ability to load Ca^<2+> in the sarcoplasmic reticulum (SR), which results in a decreased amplitude and a slowed decay rate of Ca^<2+> transients, and an increased diastolic [Ca^<2+>]_i. This unloaded SR Ca^<2+> could be ascribed to a decrease in Ca^<2+> re-uptake by SR Ca^<2+> ATPase (SERCA), an increase in Ca^<2+> extrusion by the over-expression of Na^+/Ca^<2+> exchange (NCX), and an increase in the SR Ca^<2+> leak by the dissociation of FK506-binding proteins from the SR Ca^<2+> release channel. Many inotropic agents including digitalis and β-receptor agonists have failed to improve long-term prognosis of heart failure in clinical studies. For the SR Ca2+ uptake, drugs that enhance SR Ca^<2+> uptake in a cAMP-independent manner, including protein phosphatase inhibitors and MCC-135, are candidates. In 2005, we initially investigated … More the effect of a direct SERCA activator, MCC-135, on the profiles of Ca^<2+> transients and cell contraction in isolated rat cardiomyocytes. Unfortunately, we could not obtain significant inotropic effects of MCC-135. In 2006, we studied the effect of I-1, a specific protein phosphatase-1 inhibitor on cellular Ca^<2+> handling in permeabilized rat ventricular myocytes. As a result, I-1 increased SR Ca^<2+> content without altering SR Ca^<2+> release manner. For NCX, we clarified the inhibition modality of novel specific inhibitors of NCX, SEA0400 and SN-6 using patch clamp technique in guinea pig ventricular myocytes. SN-6 inhibited Ca^<2+> influx mode of NCX selectively, and SEA0400 equally blocked both Ca^<2+> efflux and influx mode. SEA0400 also protected rat perfused hearts against ischemia/reperfusion injury by preserving high energy metabolism. Despite limitations for clinical use, the combination of these agents may restore cellular Ca^<2+> cycling and improve cardiac function with less toxicity. Less

改变的细胞Ca 2+ 处理在心力衰竭的病理生理学中起关键作用。衰竭心脏细胞的一个典型方面是肌浆网(SR)中装载Ca ^ 2+ 的能力下降，这导致Ca ^ 2+ 瞬变幅度降低和衰减速率减慢，以及舒张期[Ca ^ 2+ ]_i增加。这种卸载的 SR Ca^<2+> 可归因于 SR Ca^<2+> ATPase (SERCA) 对 Ca^<2+> 再摄取的减少、Na^+/Ca^<2+> 交换 (NCX) 过表达导致的 Ca^<2+> 挤出增加以及 FK506 结合蛋白从 SR 解离导致的 SR Ca^<2+> 泄漏增加。 Ca^<2+>释放通道。在临床研究中，包括洋地黄和β受体激动剂在内的许多正性肌力药物未能改善心力衰竭的长期预后。对于SR Ca 2+ 摄取，以不依赖于cAMP的方式增强SR Ca 2+ 摄取的药物，包括蛋白磷酸酶抑制剂和MCC-135，是候选药物。 2005 年，我们最初研究了直接 SERCA 激活剂 MCC-135 对离体大鼠心肌细胞中 Ca^2+ 瞬变和细胞收缩的影响。不幸的是，我们无法获得 MCC-135 显着的正性肌力作用。 2006年，我们研究了I-1（一种特异性蛋白磷酸酶1抑制剂）对透化大鼠心室肌细胞中细胞Ca^2+处理的影响。结果，I-1增加了SR Ca ^ 2+ 含量而不改变SR Ca ^ 2+ 释放方式。对于NCX，我们利用膜片钳技术在豚鼠心室肌​​细胞中阐明了NCX、SEA0400和SN-6的新型特异性抑制剂的抑制方式。 SN-6选择性地抑制NCX的Ca^2+内流模式，而SEA0400同样阻断Ca^2+外流和内流模式。 SEA0400 还通过保持高能量代谢来保护大鼠灌注心脏免受缺血/再灌注损伤。尽管临床使用有限制，这些药物的组合可以恢复细胞Ca 2+ 循环并以较小的毒性改善心脏功能。较少的

项目成果

Evaluation of right and left ventricular function by quantitative blood-pool SPECT (QBS) : Comparison with conventional methods and quantitative gated SPECT (QGS).

通过定量血池 SPECT (QBS) 评估右心室和左心室功能：与常规方法和定量门控 SPECT (QGS) 的比较。

• 发表时间: 2006
• 期刊: Annals of Nuclear Medicine 20
• 作者: Chimushi M;Izumi D;Komura S;Ahara S;Satoh A;Furushima H;Washizuka T;Aizawa Y;Keiichi Odagiri
• 通讯作者: Keiichi Odagiri

Different actions of cardioprotective agents on mitochondrial Ca2+ regulation in a Ca2+ paradox-induced Ca2+ overload.

在 Ca2 悖论诱导的 Ca2 超载中，心脏保护剂对线粒体 Ca2 调节的不同作用。

• 发表时间: 2005
• 期刊: Circulation Journal
• 影响因子: 3.3
• 作者: Masaki Matsunaga;M. Saotome;H. Satoh;H. Katoh;H. Terada;H. Hayashi
• 通讯作者: H. Hayashi

Endoplasmic reticulum Ca2+ depletion induces endothelial cell apoptosis independently of caspase-12

• DOI: 10.1016/j.cardiores.2005.11.023
• 发表时间: 2006-03-01
• 期刊: CARDIOVASCULAR RESEARCH
• 影响因子: 10.8
• 作者: Nakano, T;Watanabe, H;Hayashi, H
• 通讯作者: Hayashi, H

A selective inhibitor of Na+/Ca2+ exchanger, SEA400, preserves cardiac function and high-energy phosphates against ischemia/reperfusion injury.

SEA400 是 Na /Ca2 交换器的选择性抑制剂，可保护心脏功能和高能磷酸盐免受缺血/再灌注损伤。

• 发表时间: 2006
• 期刊: Journal of Cardiovascular Pharmacology. 47
• 作者: Buensuceso CS;Obergfell A;Soriani A;Eto K;Miosses WB;Arias-Salgado EG;Kawakami T;Shattil SJ;Niu Chenfung et al.
• 通讯作者: Niu Chenfung et al.

Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles.

• DOI: 10.1253/circj.70.1407
• 发表时间: 2006-11
• 期刊: Circulation journal : official journal of the Japanese Circulation Society
• 作者: K. Yamazaki;H. Terada;H. Satoh;K. Naito;A. Takeshita;A. Uehara;H. Katoh;K. Ohnishi;H. Hayashi