Basic research for regulation and disorder of cardiac Ca signal

心脏Ca信号调控与紊乱的基础研究

基本信息

批准号：
14370778
负责人：
ENDOH Masao
金额：
$ 9.09万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370778/
关键词：
crosstalk norepinephrine endothelin-1 cardiac contractility Ca signal Ca transient protein kinase A protein kinase C エンドセリンマウス心筋細胞イヌ心室筋 Na-Ca交換機構 Caセンシタイザー心筋細胞アシドーシスエクオリン

项目摘要

In cardiovascular disorders, including myocardial infarction and heart failure, various endogenous regulators are released from divergent types of cell, such as endothelial cells, and play crucial role in progress and recovery of diseases. In chronic congestive heart failure, it has been considered that the myocardial contractile dysfunction is the key process of the disorder and the cardiotonic agents that reverse the dysfunction may be the primary target of drug therapy of the disease. The current therapeutic target has been recognized to be addressed to the suppression of modulatory mechanisms, such as adrenergic regulation, rennin-angiotensin and aldosterone system, in addition to cardiac unloading by reduction of pre-load and after-load. In heart failure it has been elucidated that the plasma levels of norepinephrine (NE) and endothelin-1 (ET-1) are elevated in the course of progress of severity of the disease. It is highly likely that NE and ET-1 regulate the myocardial contracti … More lity in patients with heart failure. We investigated, therefore, the regulation of myocardial contractility and Ca^<2+> by crosstalk of NE with ET-1 in canine ventricular myocardium and single myocytes. ET-1 alone did not cause any inotropic effect on canine ventricular myocardium, but induced complex regulation depending on the co-existing concentrations of NE. In the presence of NE around threshold concentrations (10^<-10>〜10^<-9>mol/L) ET-1 elicited a concentration-dependent positive inotropic effect (PIE) in association with an increase in myofilament Ca^<2+> sensitivity. The PIE of ET-1 is unique in that it requires simultaneous activation of both PKA and PKC. It is of interest that the activation of PKA has been established to shift the relationship of contractile force and [Ca^<2+>]_i to the right to direction implying a decrease in myofilament Ca^<2+> sensitivity due to phosphorylation of troponin I and phosphlamban (leading to SERCA2a activation). In contrast, it became evident that the activation of PKA by crosstalk with PKC activation elicits a PIE in association with an increase in myofilament Ca^<2+> sensitivity. The PIE of ET-1 was abolished by the PKA inhibitor, PKC inhibitor, PLC inhibitor or β-blocker. The present results imply that the crosstalk of NE and ET-1 plays a crucial role in contractile regulation in patients with heart failure. Less

在包括心肌梗塞和心力衰竭在内的心血管疾病中，各种内源性调节剂从不同类型的细胞（例如内皮细胞）中释放出来，并在疾病的进展和恢复中起着至关重要的作用。在慢性充血性心力衰竭中，人们认为心肌收缩功能障碍是该疾病的关键过程，而逆转功能障碍的心差可能是该疾病药物治疗的主要靶点。当前的治疗靶标已被认为是针对调节机制的抑制，例如肾上腺素调节，肾上腺素 - 血管紧张素和醛固酮系统，除了通过减少预载和后负载和后负载和卸载。在心力衰竭中，已经阐明了在疾病严重程度进展的过程中，去甲肾上腺素（NE）和内皮素-1（ET-1）的血浆水平升高。 NE和ET-1很有可能调节心肌肌的心肌……对心力衰竭患者更有责任。因此，我们研究了心肌收缩性的调节，并通过NE与犬室心肌和单个心肌细胞中的ET-1串扰对CA^<2+>调节。仅ET-1就不会对犬心室心肌产生任何肌力作用，而是根据NE的共存浓度诱导复杂调节。在存在周围阈值浓度（10^<-10> 10^<-9> mol/l）的情况下，ET-1与肌丝Ca^<2+敏感性的增加相关的浓度依赖性阳性肌效应（PIE）。 ET-1的馅饼是独一无二的，因为它需要简单地激活PKA和PKC。人们很感兴趣的是，已经建立了PKA的激活，以将收缩力的关系和[Ca^<2+>] _ I转移到方向的权利，这意味着肌丝Ca^<2+>>敏感性降低，肌肉I和phosponin I和phosphlamban（导致Serca2A激活）。相比之下，证据表明，通过与PKC激活串扰PKA的激活引起了一种与肌丝Ca^<2+>敏感性增加相关的PIE。 PKA抑制剂，PKC抑制剂，PLC抑制剂或β受体阻滞剂消除了ET-1的馅饼。目前的结果表明，NE和ET-1的串扰在心力衰竭患者的收缩调节中起着至关重要的作用。较少的