Research in the inhibitory effect of sarcoplasmic reticulum Ca release channel stabilizer on the development of heart failure
肌浆网钙释放通道稳定剂抑制心力衰竭发展的研究
基本信息
- 批准号:13670717
- 负责人:
- 金额:$ 2.56万
- 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:2001
- 资助国家:日本
- 起止时间:2001 至 2002
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In heart failure, abnormal function of sarcoplasmic reticulum (SR) is one of the major pathogenic mechanisms in heart failure. Here, we assessed the effects of 1,4-benzothiazepine derivative JTV519 (intracellular Ca2+ modulator) and propranolol on cardiac and SR functions. SR vesicles were isolated from dog LV muscles {normal (N), n=11; 4-weeks rapid RV pacing with or without JTV519 (JT:14.4 mg/Kg/day) or propranolol (PL:0.05mg/kg/day) [untreated: n=10, JT(+): n=10, PL(+): n=10, respectively]}. 1) In either JT(+) or PL(+), cardiac function was improved compared with untreated group. 2) Abnormal SR Ca2+ leak was found in untreated failing SR. A benzothiazepine Ca^<2+> antagonist diltiazem as well as JTV519 acutely inhibited this Ca^<2+> leak in failing SR (IC50= 0.3μM, 0.03μM, respectively), and neither nifedipine nor verapamil affected the Ca^<2+> leak. There was no abnormal SR Ca^<2+> leak either in JT(+) and PL(+). 3) Both JTV519 and propranolol prevented the decrease in the stoichiometry of RyR vs FKBP12.6 assessed by [^3H]ryanodine and [^3H]FK 506-bindng assays [1:3.6 in normal, 1:1.3 in untreated, 1:3.6 in JT(+), 1:2.4 in PL(+)]. 4) In untreated group, RyR was PKA- hyperphosphorylated, whereas it was reversed both in JT(+) and in PL(+). 5) The amount of RyR-bound FKBP12.6 was tremendously less in untreated group than normal RyR, whereas it was reversed both in JT(+) and PL(+). 6) RyR was labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetate (MCA). In both J(+) and P(+), the level of MCA fluorescence, which was higher in untreated group, was decreased back towards normal, suggesting the improvement of RyR conformational state by both treatments. Both JTV519 and proplanolol improved cardiac function and attenuated LV remodeling by ameliorating the defective interaction of FKBP12.6 with RyR through restoration of PKA-hyperphosphorylation of RyR and the following conformational change of RyR.
在心力衰竭中,肌浆网功能异常是心力衰竭的主要发病机制之一。在这里,我们评估了1,4-苯并硫氮类化合物JTV519(细胞内钙调节剂)和心得安对心脏和SR功能的影响。从犬左室肌分离出SR囊泡[正常(N),n=11;快速右室起搏加或不加JTV519(JT:14.4 mg/kg/d)或普奈洛尔(PL:0.05 mg/kg/d)][未处理:n=10,JT(+):n=10,PL(+):n=10]。1)无论是JT(+)组还是PL(+)组,心功能均较未治疗组明显改善。2)未治疗失败的SR存在异常的肌浆网钙离子泄漏。苯并硫氮类钙离子拮抗剂地尔硫卓和JTV519可显著抑制SR失败时的钙泄漏(IC_(50)分别为0.3μM和0.03μM),硝苯地平和维拉帕米均不影响钙泄漏。JT(+)和PL(+)均未发现异常的SR钙渗漏。3)JTV519和普奈洛尔均能阻止RyR与FKBP12.6结合的RyR与FKBP12.6的化学计量比下降[正常1:3.6,未治疗1:1.3,JT(+)1:3.6,PL(+)]。4)在未治疗组,RyR蛋白过度磷酸化,而在JT(+)和PL(+)中均发生逆转。5)未治疗组RyR结合FKBP12.6的数量明显少于正常RyR,而JT(+)和PL(+)的RyR结合FKBP12.6的数量则相反。6)用荧光构象探针甲基香豆素醋酸酯(MCA)定点标记RyR。在J(+)和P(+)中,未治疗组的MCA荧光水平均下降至正常水平,提示两种治疗方法均能改善RyR的构象状态。JTV519和心得安均通过恢复RyR的PKA过度磷酸化及随后的RyR构象变化,改善FKBP12.6与RyR的异常相互作用,从而改善心功能,减轻LV重构。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Takayuki Hisaoka: "Enhancement of Rho/Rho-kinase system in regulation of vascular smooth muscle contraction in tachycardia-induced heart failure"Cardiovascular Research. 49. 319-329 (2001)
Takayuki Hisaoka:“增强 Rho/Rho 激酶系统对心动过速引起的心力衰竭中血管平滑肌收缩的调节”心血管研究。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Masahiro Doi: "Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor"Circulation. 105. 1374-1379 (2002)
Masahiro Doi:“普萘洛尔通过恢复 FKBP12.6 介导的兰尼定受体的稳定性来预防心力衰竭的发展”。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Doi M., Yano M., Kobayashi S., et al.: "Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor"Circulation. 105. 1374-1379 (2002)
Doi M.、Yano M.、Kobayashi S. 等人:“普萘洛尔通过恢复 FKBP12.6 介导的兰尼碱受体稳定性来预防心力衰竭的发生”循环。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Masateru Kohno: "A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure"American Journal of Physiology. 284. H1035-H1042 (2003)
Masateru Kohno:“一种新的心脏保护剂 JTV519 可改善心力衰竭中兰尼碱受体的通道门控缺陷”《美国生理学杂志》。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Masateru Kohno: "A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure"American Journal of Physiology. 284. 1035-1042 (2003)
Masateru Kohno:“一种新型心脏保护剂 JTV519 可改善心力衰竭中兰尼碱受体的通道门控缺陷”《美国生理学杂志》。
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YANO Masafumi其他文献
Real-time Control of Bipedal Movement based on Basal ganglia and Brainstem Systems
基于基底神经节和脑干系统的双足运动实时控制
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:0
- 作者:
TOMITA Nozomi;YANO Masafumi - 通讯作者:
YANO Masafumi
YANO Masafumi的其他文献
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{{ truncateString('YANO Masafumi', 18)}}的其他基金
Comprehensive treatment of heart failure, cardiac hypertrophy, and arrhythmia by controlling ryanodine receptor bound calmodulin
通过控制兰尼碱受体结合钙调蛋白综合治疗心力衰竭、心脏肥大和心律失常
- 批准号:
17H04178 - 财政年份:2017
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
An attempt to regress cardiac hypertrophy by cardiomyocyte intracellular calmodulin control
通过心肌细胞内钙调蛋白控制来逆转心脏肥大的尝试
- 批准号:
16K15443 - 财政年份:2016
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
New molecular targeting therapy for regression of cardiac hypertrophy by inhibiting abnormal Ca2+ leak through RyR2 in hypertrophic cardiomyopathy
通过 RyR2 抑制异常 Ca2 渗漏来消退肥厚型心肌病的新型分子靶向治疗
- 批准号:
26670404 - 财政年份:2014
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Comprehensive strategy of heart failure, cardiac hypertrophy and lethal arrhythmia via stabilizing the stricture of ryanodine receptor
通过稳定兰尼碱受体狭窄治疗心力衰竭、心肌肥厚和致死性心律失常的综合策略
- 批准号:
26293189 - 财政年份:2014
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of comprehensive treatment of heart failure, hypertrophy, and arrhythmia by regulating intracellular Ca
调节细胞内Ca综合治疗心力衰竭、肥厚、心律失常的进展
- 批准号:
23390215 - 财政年份:2011
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of therapeutic therapy for regression of cardiac hypertrophy in hypertrophic cardiomyopathy
肥厚型心肌病心肌肥厚消退治疗方法的开发
- 批准号:
22659154 - 财政年份:2010
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Development of new therapy for heart failure and arrhythmia by correction of signal transduction within cardiac ryanodine receptor
通过校正心脏兰尼碱受体内的信号转导开发心力衰竭和心律失常的新疗法
- 批准号:
20390226 - 财政年份:2008
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Establishment of molecular targeting therapy for duonic heart failure bystabilizmgryanodine receptor
稳定麦草碱受体治疗双元心力衰竭分子靶向治疗的建立
- 批准号:
18390234 - 财政年份:2006
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Computational study on acoustic-image perception of object-shape from single-emission echo in bats
蝙蝠单次发射回声物体形状声像感知的计算研究
- 批准号:
17500190 - 财政年份:2005
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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 - 财政年份:1999
- 资助金额:
$ 2.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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