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

细胞Ca^<2+>处理的改变在心力衰竭的病理生理中起关键作用。心脏细胞衰竭的一个典型特征是肌浆网（SR）钙<2+>负荷能力下降，导致钙<2+>瞬态振幅下降，衰减速度减慢，舒张[钙<2+>]_i升高。这种无负荷的SR Ca <2+>可归因于SR Ca <2+> atp酶（SERCA）对Ca <2+>再摄取的减少，Na^+/Ca <2+>交换（NCX）的过度表达导致Ca <2+>挤压的增加，以及fk506结合蛋白与SR Ca <2+>释放通道解离导致SR Ca <2+>泄漏的增加。包括洋地黄和β受体激动剂在内的许多肌力药物在临床研究中未能改善心力衰竭的长期预后。对于SR Ca2+摄取，以camp不依赖的方式增强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，我们初步研究了直接SERCA激活剂MCC-135对分离大鼠心肌细胞Ca^<2+>瞬态和细胞收缩的影响。不幸的是，我们无法获得MCC-135显著的肌力作用。2006年，我们研究了I-1（一种特异性蛋白磷酸酶-1抑制剂）对渗透大鼠心室肌细胞Ca^<2+>处理的影响。结果表明，I-1增加了SR Ca^<2+>含量，但未改变SR Ca^<2+>的释放方式。对于NCX，我们利用膜片钳技术明确了新型特异性抑制剂NCX、SEA0400和SN-6在豚鼠心室肌细胞中的抑制方式。SN-6选择性地抑制NCX的Ca^<2+>内流模式，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。尽管临床使用有局限性，但这些药物联合使用可以恢复细胞Ca^<2+>循环并改善心功能，而且毒性较小。少

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

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

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

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