Study for the Abnormality of Intracellular Ca^<2+> Regulation in Failing Hearts

衰竭心脏细胞内Ca^<2>调节异常的研究

• 批准号: 13670701
• 负责人: SATOH Hiroshi
• 金额: $ 1.92万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670701/
• 关键词: Heart failure; Calcium ion; Sarcoplasmic reticulum; FK506-binding proteins; Excitation-contraction coupling

In cardiac myocytes the Ca-induced Ca release from the sarcoplasmicr reticulum (SR) plays pivotal roles in Ca transients. FK-506 binding protein (FKBP) binds to the SR Ca release channels (ryanodine receptors : RyRs) and stabilizes the SR Ca release channel gating. Recent bilayer studies showed that an immunosuppressant agent, FK506 can dissociate FKBP from RyRs, thereby increasing SR Ca leak. Although the displacement of FKBP is an important aspect in failing heart, its relevance to physiological Ca regulation is still undefined. We examined the effects of FK506 on steady-state (SS) twitch Ca transients (CaT), post rest (PR) caffeine-induced CaT (as an index of SR Ca content) and Ca sparks (as an index of SR Ca leak) using laser scanning confocal microscopy and fluo-3 in rat ventricular myocytes. (1) In intact myocytes, FK506 (50 μM) increased SS (0.5Hz) twitch CaT amplitude and Ca spark frequency during rest periods, but did not change the PR twitch- and caffeine- CaT. (2) In myocytes treated either with thapsigargin and low extracellular Ca concentration, FK506 did not change the SS twitch and PR caffeine CaTs, and (3) In myocytes treated with both thapsigargin and low extracellular Ca concentration, SS twitch CaT and PR caffeine CaT largely reduced, and FK506 significantly accelerated the reduction. In conclusion, the SR Ca leak by displacement of FKBP from RyRs may not be enough to disturb normal excitation-contraction coupling in intact myocytes. However, when the SR Ca uptake was reduced and the sarcolemmal Ca extrusion was, the displacement could induce a significant SR Ca loss.

在心肌细胞中，钙诱导的肌浆网（SR）钙释放在钙瞬变中起关键作用。FK-506结合蛋白（FKBP）与SR Ca释放通道（ryanodine受体：RyR）结合并稳定SR Ca释放通道门控。最近的双层研究表明，免疫抑制剂FK 506可以使FKBP与RyR解离，从而增加SR Ca泄漏。虽然FKBP的移位是心力衰竭的一个重要方面，但其与生理性Ca调节的相关性仍不明确。我们使用激光扫描共聚焦显微镜和Fluo-3在大鼠心室肌细胞中检测了FK 506对稳态（SS）颤搐钙瞬变（CaT）、静息后（PR）咖啡因诱导的CaT（作为SR钙含量的指标）和钙火花（作为SR钙泄漏的指标）的影响。(1)在完整肌细胞中，FK 506（50 μM）可增加SS（2）在低钙和毒胡萝卜素处理的心肌细胞中，FK 506均不改变PR收缩和PR咖啡因收缩的CaTs。（3）在毒胡萝卜素和低钙处理的心肌细胞中，SS收缩CaT和PR咖啡因CaT显著降低，FK 506显著促进这种降低。总之，FKBP从RyRs置换引起的SR Ca泄漏可能不足以干扰完整心肌细胞的正常兴奋-收缩偶联。但当肌浆网钙摄取减少，肌膜钙排出减少时，移位可引起肌浆网钙丢失。

项目成果

Kazuyuki Ohnishi: "Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia : need for careful electrocardiogram monitoring"Leukemia. 16. 617-622 (2002)

Kazuyuki Ohnishi：“三氧化二砷治疗复发或难治性日本急性早幼粒细胞白血病患者：需要仔细心电图监测”白血病。

Hiroshi Satoh: "Involvement of Na^+/Ca^<2+> exchange in normal cardiac excitation-contraction coupling and in Ca^<2+> overload during ischemia and reperfusion"Myocardial Ischemia and Preconditioning. In Press.

Hiroshi Satoh：“Na ^ /Ca ^ 2 交换参与正常心脏兴奋-收缩耦合以及缺血和再灌注期间的Ca ^ 2 超载”心肌缺血和预处理。

Noriyuki Nomura: "CaMKII-dependent reactivation of SR Ca^<2+> uptake and contractile recovery during intracellular acidosis"American Journal of Physiology Heart Circ Physiol. 283. 193-203 (2002)

Noriyuki Nomura：“细胞内酸中毒期间 SR Ca^<2> 摄取和收缩恢复的 CaMKII 依赖性再激活”美国生理学杂志 Heart Circ Physiol。

Hiroshi Watanabe: "Sildenafil for primary and secondary pulmonary hypertension"Clin.Pharmacol.Ther.. 71. 398-402 (2002)

Hiroshi Watanabe：“西地那非治疗原发性和继发性肺动脉高压”Clin.Pharmacol.Ther.. 71. 398-402 (2002)

Hiroshi Satoh: "III. Arrhythmogenesis and Contractile Dysfunction during Ischemia/Reperfusion"Involvement of Na^+/Ca^2 exchange in normal cardiac excitation-contraction coupling and in Ca^<2+>overload during ischemia and reperfusion(In press).

Hiroshi Satoh：“III. 缺血/再灌注期间的心律失常和收缩功能障碍”Na^/Ca^2 交换参与正常心脏兴奋-收缩耦合以及缺血和再灌注期间 Ca^2> 过载（正在出版）。