Development of molecular therapy correcting abnormal intracellular Ca^<2+> regulation in chronic heart failure

纠正慢性心力衰竭细胞内Ca^<2>异常调节的分子疗法的发展

基本信息

批准号：
16209026
负责人：
MATSUZAKI Masunori
金额：
$ 27.79万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

An abnormal regulation of intracellular Ca^<2+> by sarcoplasmic reticulum has been shown to be involved in the mechanism underlying contractile and relaxation dysfunction in heart failure. We investigated molecular targeting strategies of correcting the abnormal calcium regulation either via the ryanodine receptor (RyR) or via the SR calcium ATPase (SERCA) /phospholamban (PLN) complex in chronic heart failure. In RyR, we have found that a single amino acid mutation seen in the patient with arrhythmogenic right ventricular dysplasia can trigger abnormal domain interaction between amino-terminal and central peptide domain, leading to abnormal SR calcium leak and subsequent fetal arrhythmia. The same conformational change was observed in the failing heart, suggesting the similar arrhythmogenic mechanism. In addition, this kind of calcium leak is also triggered by the increased production of reactive oxygen species (ROS) in the failing heart. Therfore, reduction of ROS could be a novel str … More ategy to prevent fetal arrhythmia in heart failure Furthermore we also found that a classical medicine for malignant hyperthermia, dantrolene, can interfere with these abnormal conformational changes in RyR, thereby potentially correcting impaired calcium cycling in the failing heart.On the other hand, calcium uptake function via SERCA pump and phospholamban in the network SR is also impaired in the failing heart. This has in part been attributed to the decreased levels of pholpholamban phosphorylation at Ser 16, possibly caused by the increased protein phosphatase 1 (PP1) activity in the failing heart. We have attempted to correct this abnormal increase in PP1 activity. Using in vivo high efficiency gene delivery technique, we have introduced an endogenous constitutive PP1 inhibitor, inhibitor-2, into the cardiomyopathic hamster heart. Inhibitor-2 gene delivery not only rescued the cardiac finction but also ameliorated BNP expression, cardiac fibrosis and extended the consequent survival time.In summary, molecular targeting strategy in RyR or SERCA/PLN complex and associated PP1 could be a good therapeutic target for heart failure. Less

肌质网对细胞内Ca^<2+>的异常调节已被证明参与了心力衰竭的收缩和松弛功能障碍的机制。我们研究了通过ryanodine受体（RYR）或通过慢性心力衰竭中的SR钙ATPase（SERCA） /Phospholamban（PLN）配合物来纠正绝对钙调节的分子靶向策略。在RYR中，我们发现心律失常右心室发育不良的患者中看到的单个氨基酸突变会触发氨基末端和中央肽结构域之间异常的结构域相互作用，从而导致异常的SR钙泄漏和随后的胎儿心律失常。在失败的心脏中观察到了相同的会议变化，这表明具有相似的心律失常机制。此外，这种钙泄漏还会是由于心脏失败的活性氧（ROS）的产生增加而触发的。因此，减少ROS可能是一种新颖的STR……更多的症状，以防止心力衰竭中胎儿心律不齐，此外，我们还发现，一种恶性高温（Dantrolene）的经典药物可以干扰RYR的这些异常构象变化，从而在失败的心脏中校正钙的钙循环受损。另一方面，在失败的心脏中，网络SR中通过SERCA泵和Phospholamban的钙吸收功能也受到了损害。这部分归因于Ser 16时腓腓力性磷酸化水平的降低，这可能是由于衰竭心脏中蛋白质磷酸酶1（PP1）活性的增加引起的。我们试图纠正PP1活性的异常增加。使用体内高效率基因递送技术，我们将内源性组成型PP1抑制剂抑制剂2引入了心肌病仓鼠心脏。抑制剂-2基因递送不仅反应了心脏小说，还可以改善BNP表达，心脏纤维化并延长了随之而来的生存时间。总而言之，RYR或SERCA/PLN复合物中的分子靶向策略以及相关的PP1可能是心力衰竭的良好治疗靶点。较少的

项目成果

期刊论文数量（54）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heart Failure Pathophysiology (Supportive Care for Cardiac Patient)

心力衰竭病理生理学（心脏病患者的支持治疗）

DOI：
发表时间：
2007
期刊：
影响因子：
0
作者：
Kawai;M.Yoshida;K.Arakawa;T.Kumamoto;N.Morikawa;N.Tanaka;K.Masamura;H.Tada;S.Ito;H.Hoshizaki;S.Oshima;K.Taniguchi;H.Terasawa;I.Miyamori;K.Kishi;T.Yasuda.;Ikeda Y et al.
通讯作者：
Ikeda Y et al.

Progression of heart failure was suppressed by inhibition of apoptosis-signal regulating kinase 1(ASK-1) via transcoronary gem transfer

通过冠状动脉宝石转移抑制凋亡信号调节激酶 1（ASK-1），从而抑制心力衰竭的进展