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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

在包括心肌梗死和心力衰竭在内的心血管疾病中，不同类型的细胞（如内皮细胞）释放各种内源性调节因子，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，心肌收缩功能障碍一直被认为是该疾病的关键过程，而逆转心肌收缩功能障碍的强心剂可能是该疾病药物治疗的主要目标。目前的治疗目标被认为是抑制调节机制，如肾上腺素能调节、肾素-血管紧张素和醛固酮系统，以及通过减少负荷前和负荷后的心脏卸载。在心力衰竭中，血浆中去甲肾上腺素（NE）和内皮素-1 （ET-1）的水平随着病情的加重而升高。NE和ET-1极有可能调节心衰患者的心肌收缩功能。因此，我们研究了NE与ET-1的串扰对犬心室心肌和单个肌细胞心肌收缩力和Ca^<2+>的调节。单独的ET-1对犬心室心肌没有任何肌力作用，但根据NE的共存浓度诱导复杂的调节。当NE在阈值浓度（10^<-10> ~ 10^<-9>mol/L）附近存在时，ET-1引起浓度依赖的正性肌力效应（PIE），与肌丝Ca^<2+>敏感性的增加有关。ET-1的PIE是独特的，它需要同时激活PKA和PKC。有趣的是，PKA的激活将收缩力和[Ca^<2+>]_i的关系向右转移，这意味着肌丝Ca^<2+>敏感性的降低，这是由于肌钙蛋白I和磷蛋白的磷酸化（导致SERCA2a激活）。相反，很明显，通过串扰激活PKA与PKC激活引发PIE，并增加肌丝Ca^<2+>敏感性。PKA抑制剂、PKC抑制剂、PLC抑制剂或β-阻滞剂均可使ET-1的PIE消失。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。少