Assessment of cardiac excitation-contraction coupling and effect of positive inctropic agent on Ca^<2+> regulating function of sarcoplasmic reticulum in heart failan

心衰患者心脏兴奋-收缩耦合及正性收缩剂对肌浆网Ca^2调节功能的影响

• 批准号: 11670684
• 负责人: YANO Masafumi
• 金额: $ 2.3万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670684/
• 关键词: heart failure; sarcoplasmic reticulum; ryanodine receptor; FK506 binding protein; Ca^<2+> release; カルシウム

In tachycardia-induced heart failure (HF), LV function was assessed in parallel with the function of sarcoplasmic reticulum (SR) taken from LV muscle. First, in HF, positive inotropic effects of milrinone or dobutamine were decreased, whereas positive lusitropic effects were well preserved. The enhancement of the sensitivity of SR Ca^<2+>-ATPase on cyclic AMP was observed in HF, which might be involved in this preservation of positive lusitropy. Second, a prominent abnormal Ca^<2+> leak occurred through the Ca^<2+> release channel of the SR (ryanodine receptor ; RyR) in HF, in which the stoichiometry of FK binding protein per RyR was decreased. This partial loss of RyR-bound FKBP12.6 seems to induce an instability in the channel's properties through a protein conformational change. This leads to a prominent Ca^<2+> leak, which is a possible cause of Ca^<2+> overload and hence diastolic dysfunction, as well as of systolic dysfunction. Third, in HF the altered interaction between FKBP12.6 and RyR induced an instability of RyR-channel properties and a resulting impairment of the Ca^<2+>-release function of RyR.

在心动过速诱发的心力衰竭 (HF) 中，左室功能与取自左室肌肉的肌浆网 (SR) 功能同时进行评估。首先，在心力衰竭中，米力农或多巴酚丁胺的正性肌力作用减弱，而正性舒张作用则得到很好的保留。在HF中观察到SR Ca ^ 2+ -ATP酶对环AMP的敏感性增强，这可能与正向松弛性的保留有关。其次，HF中SR（兰尼碱受体；RyR）的Ca ^ 2+ 释放通道发生显着的异常Ca ^ 2+ 泄漏，其中每个RyR的FK结合蛋白的化学计量减少。 RyR 结合的 FKBP12.6 的部分丢失似乎通过蛋白质构象变化导致通道特性的不稳定。这导致显着的Ca ^ 2+ 泄漏，这是Ca ^ 2+ 过载并因此导致舒张功能障碍以及收缩功能障碍的可能原因。第三，在HF中，FKBP12.6和RyR之间相互作用的改变引起了RyR通道性质的不稳定，并导致RyR的Ca ^ 2+ -释放功能受损。

项目成果

Taketo Tanigawa: "The mechanism of preserved positive lusitropy by cyclic AMP-dependent drugs in heart failure"American Journal of Physiology. 278. H313-H320 (2000)

Taketo Tanikawa：“环AMP依赖性药物在心力衰竭中保留正向松弛性的机制”美国生理学杂志。

Masafumi Yano: "Abnormal sarcoplasmic reticulum Ca2+ release in heart failure"Cardiovasc Res. 45. 1070-1071 (2000)

Masafumi Yano：“心力衰竭中肌浆网 Ca2 释放异常”Cardiovasc Res。

Taketo Tanigawa: "The mechanism of preserved nositive lusitropy by cyclicAMP-dependent drugs in heart failure."Am J Physiol. 278. H313-H320 (2000)

Taketo Tanikawa：“环AMP依赖性药物在心力衰竭中保留鼻窦松弛的机制。”Am J Physiol。

Taketo Tanigawa et al: "Mechanism of preserved positive lusitropy by cAMP-dependent drugs in heart failure"American Journal of Physiology. 278. H313-H320 (2000)

Taketo Tanikawa 等人：“心力衰竭中 cAMP 依赖性药物保留正向松弛的机制”美国生理学杂志。

Kaoru Ono: "Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca^<2+> release in heart failure."Cardio vascular Research. 48. 323-331 (2000)

Kaoru Ono：“FKBP12.6 与兰尼碱受体相互作用的改变是心力衰竭中异常 Ca^2 释放的原因。”心血管研究。